Cases Of Acute Cellular Rejection Research Articles

Acute Cellular Rejection Presenting With Sinusoidal Obstruction Syndrome and Refractory Ascites Postliver Transplantation

ABSTRACT Sinusoidal obstruction syndrome (SOS) is a rare cause of ascites postliver transplantation. We describe the case of a 21-year-old woman transplanted for glycogen storage disease type 1a who developed ascites posttransplantation and was determined to have SOS in the setting of acute cellular rejection (ACR). This case has implications for the management of patients who develop ascites in the setting of ACR postliver transplantation. To our knowledge, this is the only reported case of ACR complicated by SOS in a patient status postliver transplantation for glycogen storage disease type 1a.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis

Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

Late acute cellular rejection after switch to everolimus monotherapy at 11 months following liver transplantation

BackgroundAcute cellular rejection beyond the 6th month posttransplant is an uncommon complication after liver transplantation. The inadequate immunosuppression (IS) remains the main risk factor. We report a case of acute cellular rejection after a switch to everolimus monotherapy at 11 months following liver transplantation.Case presentationThis was a 69-year-old man who underwent liver transplantation after hepatocellular carcinoma. The initial immunosuppression was a combination of three immunosuppressive drugs (corticosteroids + tacrolimus + mycophenolate mofetil). The corticosteroid therapy was stopped at the 4th month posttransplant. Serious side effects of the immunosuppressive drugs (agranulocytosis and renal dysfunction), which occurred 4 months after transplantation, required a reduction and then a discontinuation of tacrolimus and mycophenolate mofetil. Everolimus was introduced as a replacement. The patient was consulted at 11 months after liver transplantation, 1 month after stopping the two immunosuppressive drugs, for liver function test abnormalities such as cytolysis and anicteric cholestasis. A moderate late acute cellular rejection was confirmed by a liver biopsy. A satisfactory biological evolution was observed following corticosteroid boluses and optimization of basic immunosuppressive drugs.ConclusionLate acute cellular rejection remains an uncommon complication, observed mostly in the first year after liver transplantation. The main risk factor is usually the decrease of immunosuppression.

Abstract 14843: Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Associated Myocarditis

Introduction: Immune checkpoint inhibitor (ICI)-myocarditis is a new syndrome with estimated 50% mortality. Similar to acute cellular rejection (ACR), it is pathologically characterized by lymphocytic infiltration. We aimed to characterize the electrocardiograph features of ICI-myocarditis, compare them to ACR, and evaluate their association with adverse outcome. Methods: Presenting ECG of 130 cases of ICI-myocarditis were collected from a multicenter network spanning 12 countries and compared to 50 cases of ACR. ECG were quantified and interpreted by two blinded cardiologists. 53 patients with ICI-myocarditis had baseline ECG available for comparison via paired univariate analysis. Cox models correcting for age and sex determined association with a composite outcome of life-threatening arrhythmia or myocarditis-related death. Results: ICI-myocarditis patients had average age of 68(58-76), were 61.2% male, and 64.8% had prior cardiovascular disease. QRS prolongation (26% vs 13%, p=0.008), conduction disorders (67% vs 44%, p=0.007) such as left bundle branch block (LBBB) (18% vs 4% p=0.008), ST/T wave changes (50% vs 24%, p=0.004), and PVCs (16% vs 6%, p=0.020) were more prevalent on presenting ECG compared to baseline. ICI-myocarditis showed more PVCs (16% vs 2%, p=0.011) and less ST/T wave changes (41% vs 66%, p=0.002) when compared to ACR. On multivariate analysis, the combined outcome of life-threatening arrhythmia or myocarditis-related death was associated with pathological Q waves (HR=3.60 (1.78-7.27) p&lt;0.001), QRS prolongation (HR=3.35 [1.00-11.21] p=0.05), LBBB (HR=2.24 [1.13-4.45] p=0.021), and supraventricular arrhythmia (HR=2.03 [1.05-3.91] p=0.035) on presenting EKG. Conclusions: ICI-myocarditis manifests as new conduction delays, ST/T-wave changes, and PVCs. QRS prolongation, LBBB, pathological Q waves, and supraventricular arrhythmias were associated with subsequent adverse outcomes.

P1785KIDNEY TRANSPLANTATION ACROSS VERY HIGH DONOR SPECIFIC ANTIBODIES(DSA) - A SINGLE CENTER EXPERIENCE OF A TERTIARY LEVEL HOSPITAL FROM INDIA

Abstract Background and Aims Kidney Transplantation across very high donor specific antibodies (DSA) poses a significant challenge even today . With our current understanding and precise desensitization techniques, we are now able to do kidney transplantation across such high DSA . Here we are reporting ten such cases where baseline DSA were more than 10,000 mean fluroscent intensity (MFI) on Single Antigen Bead (SBA) Luminex. Method: It is a retrospective analiysis of ten kidney transplant patients from January 2017 to March 2019 . Patients with MFI more than 10,000 to class II HLA antigens at baseline with negative CDC and flow cytometry cross match were included in this study. All patients were treated with 1 dose of Rituximab (375mg/M? before plasma exchanges (PLEX) were started . Each session of PLEX was followed by 10 grams of intravenous human immunoglobulin (IVIg). Solid based SBA Luminex for both class I and II antigens was repeated after the third exchange and fifth exchange and seventh exchange depending on the level of MFI . Results Ten patients ( seven males three females ) of age 37± 7 years were included in this study . History of blood transfusion with 5±2 units was present in 7 patients . All females were multiparous ( 3±1children). Mean solid based SBA Luminex for class I HLA antigens was 12000 ± 1500 and for II HLA antigens with MFI 16500 ± 3500 (Chart 1). Mean number of PLEX needed was 5 ± 2 . All patients had solid based SBA MFI was 1500±300 and for class II antigens 2500 ± 1500 before transplantation(Chart 2).There was no incidence of acute antibody mediated rejection . Baseline serum creatinine at discharge was1.35±0.35mg%. There were 3 (30%) biopsy proven cases of acute cellular rejection . There was evidence of BK viremia in 3(30%) patients, CMV infection in 1 (10%) patient, Klebsiella pneumonia in 1(10%) patient and cryptosporium infection in 1 (10%) patient each . There was no mortality and mean serum creatinine at 6 months follow-up was 1.55±1.05mg%. All 3 patients of BK Viremia were treated with modification of immunosupression with substitution of leflunamide for mycophenolate and all are doing well with good graft function with a mean serum creatinine of 1.75±0.55mg% . Other infections were treated accordingly. Conclusion: Transplantation across very high donor specific antibodies is possible with excellent immediate and short term graft function with judicious de-sensitization techniques . There was increase in infection rate but none was life threatening and can be managed with proper care.

Acute cellular rejection in lung transplantation

Lung transplantation is an important therapy for end-stage respiratory failure in patients who have exhausted other therapeutic options. The lung is unique among solid-organ transplants in that it is exposed to the outside environment, and undergoes continuous stimulation from infectious and non-infectious agents, which may play a part in upregulating the immune response to the allograft. Despite induction immunosuppression and the use of aggressive maintenance regimens, acute allograft rejection is still a major problem, especially in the first year after transplant, with important diagnostic and therapeutic challenges. As well as being responsible for early graft failure and death, acute rejection also initiates alloimmune responses that predispose patients to chronic lung allograft dysfunction, in particular bronchiolitis obliterans syndrome. Cellular responses to human leukocyte antigens (HLAs) on the allograft have traditionally been considered the main mechanism of acute rejection, although the influence of humoral immunity is increasingly recognised. Here, we present two cases of acute cellular rejection (ACR) in the early post-transplant period and review the pathophysiology, diagnosis, clinical presentation and treatment of ACR.

Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients

BackgroundHearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection.MethodsWe conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir–velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation.ResultsA total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders.ConclusionsIn patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.)

243 A Case of Acute Cellular Rejection Following Rapid Resolution of BK Viremia

243 A Case of Acute Cellular Rejection Following Rapid Resolution of BK Viremia

Ultrastructural Changes in Lung Allografts

Introduction Antibody mediated rejection (AMR) is a well-recognised cause of allograft injury; however only recently there is a growing recognition in lung transplantation (LTx). Allograft dysfunction can be multifactorial and challenges with C4d stain interpretation and the lack of specificity of histological criteria account for some of the difficulties in diagnosing pulmonary AMR. Donor Specific Antibodies (DSA) target the endothelium. In fact, in renal transplantation, endothelial activation markers and early ultrastructural changes of the endothelium correlate with AMR. The aim of this study was to identify ultrastructural changes in the endothelium of lung allografts in the presence of DSA, with the intent of determining if prospective use of electron microscopy might be helpful in establishing a diagnosis of AMR in LTx recipients. Materials & Methods The LTx database was queried for cases of pulmonary AMR between 07/2009 & 09/2015. The ISHLT guidelines were used to categorise these cases into definite, probable & possible AMR. Retrospective ultrastructural studies were performed on all these biopsies- either fresh or paraffin embedded. Cases of acute cellular rejection (4) and normal lung (3) were evaluated as controls. The findings on ultrastructural examination were correlated with the presence of DSA & diagnosis of AMR using the Pearson’s chi-square test of statistical significance. Results & Discussion Eleven patients (male, 54.5%) were included in this study.Mean age was 53yrs. Three cases were combined lung & heart Tx. We identified 7 cases of AMR (1 definite, 1 probable & 5 possible). The median time from LTx to biopsy (bx) was 210 days, with median follow up of 1063 days. Bronchiolitis Obliterans Syndrome was diagnosed in 5 patients. Ultrastructural studies were performed on 10 AMR bxs (pt 6:2 bxs; pt 7:3 bxs; all other pts: 1bx each), 4 ACR bxs & 4 controls. The results are shown.The presence of DSA as well as the ISHLT diagnosis of AMR significantly correlated with endothelial swelling, cytoplasmic vacuolisation & septal edema (p<0.01; each). Septal infiltration by neutrophils was only identified in AMR cases, although it did not achieve statistical significance. Importantly, these differences were still significant when using resin or paraffin based samples for EM, allowing larger retrospective studies to be performed; although endothelial swelling & vacuolisation occurred in non-DSA paraffin samples with EM.Conclusion Donor specific anti-HLA antibodies are associated with endothelial injury of the allograft. Ultrastructural findings such as endothelial swelling & vacuolization help in diagnosing antibody mediated allograft injury. Although paraffin embedded biopsy material can be used for this purpose, it is not without limitations and larger prospective studies are needed to validate these findings. The effect of DSA on the endothelial pathways will be important in all solid organ transplantation.

The Role of Monocyte/Macrophage and CXCR3 in Differentiation between Recurrent Hepatitis C and Acute Cellular Rejection Postliver Transplantation.

Objective Liver transplantation (LT) is the recommended treatment for patients with advanced liver disease and cirrhosis in all guidelines, mostly as a complication of HCV. The distinction between reinfection of the graft with HCV and acute cellular rejection (ACR) is essential because they are managed differently. Hepatic macrophages, which can either arise from circulating blood-derived monocytes (BDM) or from resident tissue Kupffer cells, are central in the pathogenesis of chronic liver injury. The aim of this work was to evaluate whether the origin of macrophages and the immune mediator CXCR3 could help in differentiating between acute recurrent HCV and ACR after liver transplantation. Methods Twenty-nine cases of recurrent hepatitis C and 26 cases of ACR were included in this study. The expression of CD 68 (macrophage marker), CD11b (BDM marker), and CxCR3 in the postliver transplant biopsy using immunohistochemistry was determined. Results CD11b expression highlighting macrophages of BDM origin was in favor of recurrent hepatitis C (P < 0.001) than in ACR (P = 0.44), while CXCR3 expression by hepatocytes was in favor of ACR (P = 0.001). Conclusion Macrophage infiltrating liver tissue post LT can distinguish between ACR by upregulation of CXCR3 and recurrent hepatitis C by predominant CD11b.

Comparative Study of Small Bowel and Colonic Biopsies with Acute Cellular Rejection in Intestinal Transplantation

Aim: Many centres now include a segment of transplanted colon with an intestinal graft as International Registry data show this is associated with less dependence on parenteral support and improved graft survival.[1] We here compare the diagnosis of acute cellular rejection (ACR) based on biopsies (Bx) performed simultaneously in the small bowel (SB) and colonic grafts (paired Bx) after intestinal transplantation (ITx). Method: We undertook a retrospective review of patients with Intestinal containing grafts at Addenbrooke’s hospital from 2007 to 2016 who developed ACR. Paired bx were reviewed before and after the ACR by an experienced GI pathologist and were graded based on the VIII International Small Bowel Transplant Symposium Consensus criteria with minor modifications for evaluation of colon biopsies. Each Bx was graded either negative or positive for ACR. If the histology suggested borderline paired with normal, this was counted as normal as it was likely not to be clinically relevant. However, if borderline was paired with mild this was included as a discordance as it was considered clinically relevant. Results: During the study a total of 71 ITx were performed in 65 patients. Of these, there were 32 cases of ACR in 30 patients, 18 of which had colon containing grafts. There were a total of 221 paired Bx included in the analysis. Of the 221 paired Bx, the number of concordant normal Bx was 153 (69%) & concordant abnormal Bx was 34 (16%). The total number of discordant Bx was 33 (15%). Among these discordant Bx, the number demonstrating ACR in the small bowel but not the large bowel was 19 and the converse was true in 14 cases. The overall concordance rate was 82.25%. The rate of discordance in ACR was 17%. If the large bowel demonstrated rejection there was a 71% positive predictive value of the small bowel also demonstrating rejection. If the large bowel was normal then the negative predictive value for the small bowel also being normal was 89%. If the small bowel demonstrated rejection then the positive predictive value of the large bowel demonstrating rejection was 64%. If the small bowel was normal then there is a 92% negative predictor value for the large bowel also being normal. Conclusion: Paired Bx in the SB and the colon are usually in agreement regarding the presence or the absence of ACR. However, colonic Bx alone may not suffice to exclude ACR following ITx. Reference: 1. Grant et al. Intestinal Transplant Registry Report: Global Activity and Trends American Journal of Transplantation 2015;15:210–219

Ten-Year Experience With Bowel Transplantation at Seoul St. Mary's Hospital

A retrospective review of intestinal transplantation (ITx) at Seoul St. Mary's Hospital was made by collecting clinical data over the past 10 years. Fifteen consecutive cases from 2004 were analyzed. Five children and 10 adults (6 months to 69 years of age) were included. Primary diseases in adults included 4 mesenteric vessel thromboses, 2 strangulations, and 1 each of visceral myopathy, malignant gastrointestinal stromal tumor (GIST), mesenteric lymphangiectasis, and injury. Pediatric cases involved 2 Hirschsprung disease, 2 visceral myopathy, and 1 necrotizing enterocolitis. Three of 7 stomas were closed using a serial transverse enteroplasty procedure before transplantation. The ITx were performed using 3 living-donor Itx, 12 deceased-donor ITx, 14 isolated Itx, and 1 modified multivisceral transplantation. Daclizumab, basiliximab, alemtusumab, or basiliximab with rabbit antithymocyte globulin (rATG) was used for the induction; tacrolimus monotherapy was used as the basic maintenance immunosuppressant; and m-TOR inhibitor was used for renal dysfunction patients. Seven cases of acute cellular rejection were treated with rATG. Three cases of antibody-mediated rejection were treated with rituximab alone or with rituximab and bortezomib combination. There were 4 cases of early mortality within 6 months after Itx. Causes of death were declamping shock, cardiac tamponade with acute cellular rejection, dysmotility, and sepsis. Surgical complications consisted of 1 feeding jejunostomy displacement, and a minor leakage at a colo-colostomy site. One-year survival of the patient and graft was 73.33% (Kaplan–Meier survival curve). Although the total number of ITx is small, its social impact has been remarkable in changing the related laws and reimbursement policy in Korea.

Application of Flow Cytometry to Measure Anti-A/B antibody in ABO-Incompatible Kidney Transplantation

BackgroundThe aim of this study was to compare anti-ABO antibody levels as measured by means of flow cytometry (FCM) with the levels measured with the use of the column agglutination test (CAT), and to evaluate the clinical outcome as it relates to the baseline mean fluorescence intensity (MFI) ratio obtained by FCM. MethodsWe reviewed 21 cases of ABO-incompatible kidney transplantation (ABO-i KT). In these patients, baseline IgG titers were measured with the use of both FCM and CAT methods. We investigated the correlation between levels measured by FCM and those by CAT with the use of correlation coefficients. Patients were classified into a high MFI ratio group (≥200; n = 7) or low MFI ratio group (<200; n = 14). ResultsThe MFI ratio for the FCM-based method was highly correlated with the titer measured by CAT (r = 0.890; P = .01). The relationship between MFI ratio and CAT titer can be expressed as follows: log (MFI ratio) = 0.879 × log (CAT titer) + 0.298. The number of pre-transplantation rounds of plasmapheresis significantly increased as the baseline MFI ratio increased. The allograft function was immediately recovered and stable. A single case of acute cellular rejection was observed in the low MFI ratio group. ConclusionsAnti-ABO antibody levels measured by means of the FCM-based method were highly correlated with the levels measured with the use of CAT in cases of ABO-i KT. The decreased level of anti-ABO antibody measured by means of FCM after plasmapheresis suggests its potential as an effective and objective method for assessment of anti-ABO antibody levels.

An analysis of tacrolimus-related complications in the first 30 days after liver transplantation

OBJECTIVES:Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study.RESULTS:The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%), with a higher prevalence observed in male patients (68.18%). The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1±9.32 days and the mean Model for End-stage Liver Disease score was 26.18±4.28. There were five cases of acute cellular rejection (11.37%) and 16 cases of infection (36.37%). The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (p<0.05). Patients with infections had a higher serum level of Tacrolimus (p = 0.012). The dose and presence of rejection were significantly different (p = 0.048) and the mean glomerular filtration rate was impaired in patients who underwent rejection compared with patients who did not undergo rejection (p = 0.0084).CONCLUSION:Blood Tacrolimus levels greater than 10 ng/ml were correlated with impaired renal function. Doses greater than 0.15 mg/kg/day were associated with the prevention of acute cellular rejection but predisposed patients to infectious disease.

Endoscopic Evaluation of Small Intestine Transplant Grafts

The management of small bowel transplantation is unique because signs of rejection can be obtained visually by endoscopy. The aim of this study was to evaluate the accuracy of endoscopic appearance in assessing histologic evidence of acute cellular rejection (ACR). Endoscopies were performed in 66 asymptomatic "surveillance" small bowel transplant recipients and 71 symptomatic recipients from a single center. For surveillance patients, 125 ileoscopies were performed to collect 590 biopsies, and for the symptomatic group, 229 ileoscopies and jejunoscopies were conducted to obtain 434 biopsies. The sensitivity and specificity of endoscopic visualization in detecting ACR was 50% and 91.5% for the surveillance group and 43% and 67% for the symptomatic patients. In surveillance, visual impression alone would have missed three cases of moderate and no cases of severe ACR, whereas in the symptomatic group, visual inspection alone would have missed 20 cases of moderate ACR, and findings from visual inspection of the chimney were normal in 55% of cases with proximal ACR. However, chimney biopsy was generally representative of biopsy findings in the proximal graft but would have missed moderate to severe rejection in three patients (1%). In a subset of 23 endoscopies, zoom endoscopy did not improve visual discrimination. The only complication was a biopsy-related non-life-threatening bleed. In symptomatic patients, visual inspection detected all cases of severe rejection but would have missed patients with early readily treatable rejection and thus making biopsy mandatory in clinical practice. Our results support the current practice of ileoscopic biopsy alone for graft surveillance in asymptomatic patients.

The Histopathology of Lung Allograft Dysfunction Associated With the Development of Donor-specific HLA Alloantibodies

The histopathology of antibody-mediated rejection in lung allografts, outside of classical hyperacute rejection, has been poorly defined, in part because of the difficulty in identifying potential alloantibodies and in separating alloreactive and nonspecific complement-mediated reactions. In this study, we looked at lung biopsies coinciding with the development of anti-human leukocyte antigen (anti-HLA) antibodies and lung dysfunction in a diverse group of lung transplant recipients over a 3-year period. We identified 23 patients and found that 17 had coexistent high-grade acute cellular rejection, 5 had patchy acute lung injury, and 1 had bronchiolitis at the time that anti-HLA alloantibodies appeared. Capillaritis was seen in 4/22 (18%) cases, usually in the context of cellular rejection. When the 17 cases of acute cellular rejection with coexistent anti-HLA antibodies were compared with a matched group of 26 patients with equivalent cellular rejection grade without anti-HLA antibodies, the only morphologic feature that separated the 2 groups was capillaritis seen in a minority of cases. C4d deposits were seen in both groups, although more frequently in those cases with anti-HLA antibodies (76% vs. 24%). The development of anti-HLA alloantibodies often occurs in the setting of acute cellular rejection, which in only a minority of cases can be identified as likely having an antibody-mediated component. C4d staining does not consistently separate the 2 groups. Identifying and ascribing allograft dysfunction to antibody-mediated rejection related to the development of anti-HLA antibodies is a difficult task that cannot be solved exclusively by morphology and requires significant clinicopathologic correlation.

The Significance of Donor-Specific HLA Antibodies in Rejection and Ductopenia Development in ABO Compatible Liver Transplantation

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

Comparison of Clinical Outcome between High and Low Baseline Anti-ABO Antibody Titers in ABO-Incompatible Kidney Transplantation

High baseline anti-ABO antibody titer is still an important obstacle for successful ABO-incompatible kidney transplantation (ABO IKT). This study aims to investigate the clinical outcome of ABO IKT in patients with a high baseline titer in comparison with patients with a low baseline titer. Fourteen patients who received ABO IKT at our center were classified as the high-titer group (≥1:256, n = 8) or the low-titer group (≤1:128, n = 6). We used a protocol composed of rituximab, plasmapheresis, and intravenous immunoglobulin (RTX/PP/IVIG). We compared the intensity of preparation, complications, and clinical outcome between the two groups. The high-titer group required more sessions of pretransplant (10.5 ± 3.5 vs. 6.0 ± 1.3 times, p = 0.01) and posttransplant (1.6 ± 1.8 vs. 0 ± 0 times) PP/IVIG than the low-titer group did. All patients from both groups showed immediate recovery of graft function. The antibody titer and allograft function in the high-titer group were stable and did not differ significantly from those of the low-titer group up to 1 year after kidney transplantation. There was no antibody-mediated rejection in either group during follow-up, but three cases of acute cellular rejection developed in the high-titer group. The high-titer group showed two cases of opportunistic viral infection (herpes gingivitis and cytomegalovirus viremia) and one case of graft loss due to postoperative bleeding. ABO IKT can be safely performed even in patients with a high baseline anti-ABO antibody titer, but the risk for infection and bleeding should be considered before transplantation.

Clinical correlation of nitric oxide levels with acute rejection in renal transplantation

The objective of this study was to examine whether there was an association between acute rejection (AR) and nitric oxide (NO) levels and also to evaluate the clinical impact of NO measurement as a noninvasive marker for early detection of AR. Fifty consecutive patients aged 17-62 years old received a living-related kidney graft. Serum levels of total nitrite and nitrate (NOx) were measured 30 min after graft reperfusion (NOx 1) and on days 1 (NOx 2), 5 (NOx 3), and 10 (NOx 4) post-transplantation (Tx). If clinically indicated, graft biopsy was performed. Acute humoral rejection was diagnosed by biopsy on 3rd post-Tx day in one patient. His serum NOx 2 levels were remarkably higher (380%) compared with his NOx 1 measurement. At the same time, NOx 1-2 measurements in uncomplicated group showed lower levels (-12%). Additionally, during the first month post-Tx, 5 cases of acute cellular rejection (ACR) were diagnosed. The mean percent change of NOx 3-4 levels in ACR group was 180.7 versus 16.1 in uncomplicated patients (P < 0.01). In addition, >70 μmol/L change in NOx levels in consecutive samples had a sensitivity of 100% and a specificity of 97.7% in predicting AR episodes. Our study reports significant increase in serum NOx levels in episodes of AR. NOx might be an useful noninvasive marker for early diagnosis of AR.

Validity and Feasibility of Transient Elastography for the Transplanted Liver in the Peritransplantation Period

Transient elastography has recently been suggested to be capable of detecting dynamic changes in stiffness that accompanies acute liver damage. Its feasibility and usefulness in the perioperative period in living donor liver transplantation (LDLT) have not been studied. We evaluated 678 liver stiffness measurements (LSMs) obtained in the peritransplantation period from 24 LDLT recipients, 24 corresponding donors (preoperatively only), another five donors with a remnant right liver, and three deceased donor liver transplantation recipients. The LSM was performed once preoperatively, every morning postoperatively until postoperative day 14, and three times a week after that until the patient was discharged from the hospital. Overall LSM success rate (valid shots/total shots) was 0.929+/-0.119. There was a significant negative relationship between the LSM success rate and thoracic belt thickness (P<0.0021). The interquartile range to median value rate of LSMs remained high (21.1%+/-11.2%) compared with the preoperative values (15.6%+/-8.5%), even 1 month after the transplantation. Among LDLT recipients (n=24), the LSM value was highest in the first postoperative week and declined thereafter. Recipients with complications had significantly higher LSM values than those without complications in the fourth postoperative week (POW4; P=0.0066) and POW5 or later (P=0.0028). All cases of acute cellular rejection had a concomitant sharp rise in liver stiffness and a rapidly depleted portal flow. Despite the high variability of the results, transient elastography may be an efficient method for monitoring changes in dynamic liver stiffness in the early posttransplant period.