Late Acute Cellular Rejection Research Articles

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

T-cell infiltrate intensity is associated with delayed response to treatment in late acute cellular rejection in pediatric liver transplant recipients.

Late acute cellular rejection (ACR) is associated with donor-specific antibodies (DSA) development, chronic rejection, and allograft loss. However, accurate predictors of late ACR treatment response are lacking. ACR is primarily T-cell mediated, yet B cells and plasma cells (PC) also infiltrate the portal areas during late ACR. To test the hypothesis that the inflammatory milieu is associated with delayed response (DR) to rejection therapy, we performed a single-center retrospective case-control study of pediatric late liver ACR using multiparameter immunofluorescence for CD4, CD8, CD68, CD20, and CD138 to identify immune cell subpopulations. Pediatric liver transplant recipients transplanted at <17 years of age and treated for biopsy-proven late ACR between January 2014 and 2019 were stratified into rapid response (RR) and DR based on alanine aminotransferase (ALT) normalization within 30 days of diagnosis. All patients received IV methylprednisolone as an initial rejection treatment. Immunofluorescence was performed on archived formalin-fixed paraffin embedded (FFPE) liver biopsy tissue. Liver biopsies from 60 episodes of late ACR in 54 patients were included in the analysis, of which 33 were DR (55%). Anti-thymocyte globulin was only required in the DR group. The frequency of liver-infiltrating CD20+ and CD8+ lymphocytes and the prevalence of autoantibodies were higher in the DR group. In univariate logistic regression analysis, serum gamma-glutamyl transpeptidase (GGT) level at diagnosis, but not ALT, Banff score or presence of DSA, predicted DR. Higher serum GGT level, presence of autoantibodies, and increased CD8+ T-cell infiltration portends DR in late ACR treatment in children.

Biliary Epithelial Senescence in Cellular Rejection Following Live Donor Liver Transplantation

As with the hepatocytes, cholangiocyte senescence can also easily be detected in damaged small bile ducts and bile ductules during liver disease affecting the biliary system and cholangiocytes. Despite cellular senescence being a feature of chronic progressive cholangiopathies in adults, only a few studies have investigated its role in liver transplant rejection. Transplant biopsies displaying features of rejection were reviewed and classified based on the type of rejection and the time since transplantation. An immunohistochemistry panel has been applied for 3 senescent cell markers (p53, p21, p16). Immunohistochemical expression analysis for the biliary senescence markers (53 biopsies) was done in the post-transplantation periods (Group 1-4) for the cases with the histologically proven diagnosis of rejection. In post-transplant group 1 (<3 months), group 2 (3-6 months), group 3 (6-12 months) and group 4 (>12 months), any 2 senescent markers' positivity was noted in 5/14 (35.7%), 8/13 (61.5%), 16/17 (94.1%) and 9/9 (100%) biopsies respectively and were comparable in all four groups (P= 0.001). A comparison of early biopsies (Group1; 3 months) and late biopsies (Group 2,3&4; >3 months) revealed significantly higher expression in late biopsies (>3 months) (P= 0.001 for any two markers). In ACR, LAR, ECR, and CR/DR any two senescent markers were positive in 14/28 (50%), 12/13 (92.3%) cases, 9/9 (100%), and 3/3cases (100%). Senescent markers (any two) were comparable in all four histological groups (P < 0.001).LAR group had increased expression (P= 0.009 for any two markers and 0.001 for all three markers) and has increased progression to CR (P= 0.019) as compared to ACR. This study on a large number of LDLT allograft biopsies demonstrates the role of biliary senescence in rejection and suggests a pathobiological role for senescence in the poor prognosis seen in late acute cellular rejection and chronic rejection.

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.

LIVER TRANSPLANTATION: TACROLIMUS BLOOD LEVELS VARIATION AND SURVIVAL, REJECTION AND DEATH OUTCOMES.

Immunosuppressive drugs have important role in transplant of solid grafts, it aim avoid episodes of acute and chronic rejection and improving graft survival and patient survival. In Brazil, in 2016, liver transplantation was the third most frequent, with 1,880 transplants performed, of which 150 in Rio Grande do Sul. Several studies evaluated the association between variability in blood levels of immunosuppressive tacrolimus and late acute cellular graft rejection. To investigate the association of tacrolimus blood levels with clinical outcomes late acute cellular rejection, death, patient survival and graft survival in patients undergoing liver transplantation. This is a retrospective longitudinal study including patients submitted to adult liver transplantation by the Liver Transplantation Group in the Santa Casa de Misericórdia Hospital of Porto Alegre, from January 2006 to January 2013, and who used tacrolimus as immunosuppressive therapy. Of the 127 patients included in the study, the majority were male (70.1%), 52-60 years old (33.9%) at the transplant. The most frequent causes of liver transplantation in this series were hepatitis C virus and hepatocellular carcinoma (24.4%) and alcohol (15.7%). Thirteen patients had late acute cellular rejection (10.2%); of these, three had two episodes. Regarding severity classification, seven patients had mild late acute cellular rejection. The mean time of rejection after liver transplantation was 14 months (ranging from 8 to 33 months). Overall survival was 8.98 years. Regarding tacrolimus blood levels, 52 patients with a variation ≥2 standard deviations were identified. Of these patients, eight had rejection; however, the association was not significant (P=0.146). A significant association was found between variation ≥2 standard deviations in tacrolimus blood levels and death (P=0.023) and survival (P=0.019). Regarding 5-year follow-up of graft survival, being two standard deviations above increases by 2.26 times the risk of transplanted graft loss, and for each unit of increase of standard deviation of tacrolimus blood levels there is a two-fold increase in the risk of graft loss in 5 years. Increased risk of graft loss associated with increased standard deviations of tacrolimus blood levels may indicate the need for more rigorous and prospective monitoring of tacrolimus blood levels.

Approaches to Research Determination of Late Acute Cellular Rejection in Pediatric Liver Transplant Recipients.

A central pathology or site reading of biopsy slides is used in liver transplant clinical trials to determine rejection. We evaluated interrater reliability of readings of "rejection or not" using digitized slides from the Medication Adherence in Children who had a Liver Transplant (MALT) study. Four masked experienced pathologists read the digitized slides and then reread them after a study-specific histologic endpoint development program. Agreement was expressed throughout as a Kappa or Fleiss Kappa statistic (ҡ). A ҡ>0.6 was predefined as desirable. Readings were correlated with immunosuppressant adherence (the Medication Level Variability Index, [MLVI]), and maximal liver enzyme levels during the study period. Interrater agreement between site and central review in MALT, and between 4 pathologists later on, was low (ҡ=0.44, Fleiss ҡ=0.41, respectively). Following the endpoint development program, agreement improved and became acceptable (ҡ=0.71). The final reading was better-aligned with maximal gamma-glutamyl transferase levels and MLVI as compared with the original central reading. We found substantial disagreement between experienced pathologists reading the same slides. A unique study-specific procedure improved interrater reliability to the point it was acceptable. Such a procedure may be indicated to increase reliability of histopathologic determinations in future research, and perhaps also clinically.

P1760EXTRACORPOREAL PHOTOPHERESIS AND KIDNEY ALLOGRAFT REJECTION

Abstract Background and Aims Extracorporeal photopheresis (ECP) is an apheresis modality that in the field of solid organ transplantation (SOT) has an indication in the treatment or prophylaxis of pulmonary, cardiac or hepatic graft rejection. The usefulness of ECP in renal transplantation (RTx) remains contradictory because of the few studies that evaluate the effectiveness and safety of this technique. Method Case series study of kidney transplant patients with histological diagnosis of rejection who have been treated with ECP during the 2013-2018 period (n = 8 patients). The technical characteristics of the ECP sessions (n = 89) were studied, including tolerance and complications in each of them. Results Demographic and clinical characteristics are shown in Table 1. The indication of FEC was the contraindication to conventional treatment (n = 4), mainly due to concomitant infection (50%), or refractoriness (n = 4) to the treatment prescribed in each case and it is specified in Table 1. The initial schedule was 2 consecutive weekly sessions for 5 weeks, with additional sessions depending on the evolution at the end of the first batch. The scheduled sessions could be completed in most patients (n = 5). The 3 reasons for discontinuation were the lack of response to treatment, hospital admission and thrombosis of the arteriovenous fistula (AVF). The improvement of graft function in terms of creatinine reduction at the end of therapy occurred among patients presenting with acute cellular rejection (ACR) (n = 4) and it remained 3 months after the end of the treatment. The only late ACR (&amp;gt; 3 months post-transplant) could not complete the initial programming. No graft with humoral component showed improvement in renal function. Graft loss and dialysis restart occurred in a patient with chronic active antibody-mediated rejection (cAMR). The other patient with cAMR is in a pre-dialysis situation. A total of 89 procedures were studied, all performed with the THERAKOS® CELLEX® Photopheresis System, with the administration of the methoxsalen solution (UVADEX®) and photoactivation with ultraviolet A light. Vascular access per session was the AVF (76% ) or the central vascular catheter (CVC) (24%), under no circumstances was peripheral access used. Each procedure lasted on average 112.72 +/- 13.85 minutes (range, 86-145). The volume of treatment (“buffy coat”) was 189.11 +/- 28.67 mL per session, and the total volume of fluids administered (NaCl and anticoagulation) was 559.40 +/- 41.17 mL. The complications observed during the sessions were fever (n = 2), thrombosis of the AVF (n = 1), coagulation of the extracorporeal system (n = 1) and anemization (n = 1). Interprocedure there was a case of urinary infection that conditioned hospital admission and discontinuation of therapy. One patient died of cardiovascular cause with a functioning graft 4 years after therapy. Conclusion The utility of the ECP seems to be in cases of cell rejection, probably related to the triggering of an immunomodulatory response of lymphocytes. It can be considered a well-tolerated and safe treatment. Special care should be taken with patients who require water restriction (infusion of 560 mL on average per session). We need more studies with a greater number of patients and a control group to be able to confirm the effectiveness and safety of PEC in RTx and to be considered a useful therapeutic tool as in other SOT.

Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients.

Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known. We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12months. We also assessed the percentage time for tacrolimus levels <4μg/L (Tac < 4) and the concentration/weight-adjusted dose (C/D) ratio as a proxy marker of tacrolimus metaboliser status. LACR patients had higher CV (median, IQR 44%, 36-61% v. 24%, 19-35%, p< 0.0001) and higher MAD (33%, 25-48% v. 19%, 15-26%, p< 0.0001). The MAD was less affected by outlying tacrolimus results. Receiver operating curve analysis of the MAD resulted in a sensitivity of 76% and specificity of 76% at a threshold of 26% (AUC 0.85, p< 0.05). LACR patients had more Tac < 4 (50% v. 26%, p< 0.05). There was no difference in C/D suggesting that good IPV can be maintained in fast metabolisers. Patients with LACR had significantly increased creatinine at 12-month follow-up despite treatment (108 v. 5umol/L increase from baseline) and four patients lost their allograft. Monitoring of tacrolimus IPV using the MAD may be a clinical marker for LACR. A threshold IPV of 26% can potentially be used as a therapeutic target pending further validation studies.

Impact of TBX21, GATA3, and FOXP3 gene polymorphisms on acute cellular rejection after liver transplantation.

The single nucleotide polymorphisms (SNPs) rs4794067, rs2275806, rs2232365, and rs3761548 map in the genes of TBX21, GATA3, and FOXP3 involved in mediating acute cellular rejection. We investigated whether these SNPs are associated with acute cellular liver transplant rejection. The SNPs were analyzed in recipients with early acute cellular rejection (n = 97), recipients with late acute cellular rejection (n = 49), and recipients without rejection (n = 149). There was no association between acute cellular rejection and SNPs rs4794067, rs2275806, and rs2232365. In contrast, the allele -3279A of FOXP3 SNP rs3761548 exhibited a higher frequency in recipients with late acute cellular rejection as compared with recipients without rejection. This result indicates that the allele -3279A of the SNP rs3761548 may predispose to the development of late acute cellular rejection.

Immunomodulation, Acute Renal Failure, and Complications of Basiliximab Use After Liver Transplantation: Analysis of 114 Patients and Literature Review

Basiliximab is considered to be effective in preventing cellular rejection (CR) in solid organ transplantation and is commonly used for renal transplants. The aim of this study was describe the population of patients undergoing orthotopic liver transplantation (LT) receiving basiliximab in the period 2012–2016 in the liver transplant service at the State University of Campinas, São Paulo, Brazil. We analyzed 114 patients who underwent LT and received basiliximab; 83 (72.8%) were male and 31 (27.2%) female, with an overall mean age of 54.3 years. Immunosuppression was performed with corticosteroids during anesthetic induction, and postoperatively with tacrolimus in 85.5%, sodium mycophenolate in 81.7%, cyclosporine in 12.7%, and everolimus in 15.5% of patients. CR was observed in 25.43% of patients, confirmed by biopsy in 15 patients: 50% acute CR, 21.42% late acute CR, and 28.57% chronic CR. Thus, the data are consistent with the literature regarding the benefit of using basiliximab as induction therapy while reducing the incidence of CR after LT, but on univariate analysis to evaluate factors associated with the occurrence of CR, the analyzed variables did not present statistical significance. There was acute renal failure (ARF) in 46.84% of patients and hemodialysis was performed in 20% of cases. In a previous series in our service, there was an ARF rate of 50%, so the incidence reduction of ARF after basiliximab use was 3.16%. Moreover, there was 6.95% hepatic artery thrombosis, 2.6% portal vein thrombosis, 2.6% biliary fistulas, 17.4% pneumonia, and 3.4% sepsis, which did not differ from the literature or from our earlier study without the use of basiliximab, suggesting the safety of this medication. In conclusion, in this series, basiliximab influenced the decrease of the CR incidence with no proven benefit on improvement in the ARF.

Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival.

Classification of acute rejection (AR) based on etiology and timing may provide a means for enhancing therapeutic results and allograft survival. This study evaluated graft and patient survival after the first AR episodes among kidney transplant recipients with an early or late antibody-mediated rejection (AMR), acute cellular rejection (ACR) or mixed AR (MAR). A prospective institutional review board-approved database was queried to identify biopsy-proven first AR episodes occurring from January 2005 to October 2012. The ACR was defined by Banff criteria; borderline AR was excluded. The AMR was defined as 3 of 4 criteria: renal dysfunction, donor specific antibody, C4d positivity on biopsy, and histological changes. The MAR met criteria for both ACR and AMR. Early AR occurred within six months post-transplant. AR episodes were then assigned to 1 of the 6 categories--early AMR, early ACR, early MAR, late AMR, late ACR, and late MAR. One hundred eighty-two kidney transplant recipients identified with a first AR episode. Mean follow-up was 773 days (± 715 days). No difference was observed in patient survival. Death-censored graft survival was 84%. Death-censored graft loss was higher with late versus early AMR (P = 0.01) and late versus early ACR (P = 0.03), but not late versus early MAR (P = 0.3). The AR type demonstrated a hierarchy for graft survival with ACR better than MAR better than AMR, which persisted for both early and late AR. Improvement in long-term results of AR may require development of specific treatment for individual AR types.

Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation.

The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively. Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.

Management of Steroid-resistant Late Acute Cellular Rejection Following Face Transplantation: A Case Report

Face transplants have been clinically established, and early acute rejections have been reported. Late acute rejections have been less common. Immediate and accurate diagnosis along with successful treatment is critical to prevent graft damage. This case report describes the successful treatment of a severe, steroid-resistant rejection 2 years after a full face transplant.

The severity of acute cellular rejection defined by Banff classification is associated with kidney allograft outcomes.

It is unclear if the severity or the timing of acute cellular rejection (ACR) defined by Banff classification 2009 is associated with graft survival. Borderline changes, TCMR I (interstitial rejection), and TCMR II/III (vascular rejection) were defined as low, moderate, and high ACR severity, respectively. Approximately 270 patients who had at least one episode of ACR were enrolled, 270 biopsies were chosen which showed the highest ACR severity of each patient and were negative for donor-specific antibodies (DSA), C4d, and microcirculation changes (MC). Six months were used as the cutoff to define early and late ACR; 370 patients without biopsy posttransplantation were recruited in the control group. Up to 8-year posttransplantation, death-censored graft survival (DCGS) rates of control, borderline, TCMR I, and TCMR II/III groups were 97.6%, 93.3%, 79.6%, and 73.6% (log rank test, P<0.001); the control group had significantly higher DCGS rate than the three ACR groups (each pairwise comparison yields P<0.05). The DCGS rate of late ACR was significantly lower compared with early ACR (63.6% vs. 87.4%, P<0.001). Intimal arteritis (Banff v-lesion) was an independent histologic risk factor correlated with long-term graft loss regardless of the timing of ACR. The v-lesions with minimal or high-grade tubulitis displayed similar graft survival (72.7% vs. 72.9%, P=0.96). All types of ACR affect long-term graft survival. Vascular or late ACR predict poorer graft survival; the extent of tubulointerstitial inflammation (TI) is of no prognostic significance for vascular rejection.

53-OR

The role of donor-specific HLA antibodies (DSA) following liver transplantation (LTx) is not clearly established. Our aim was to assess the presence of DSA in pediatric LTx recipients. We hypothesized that DSA would be detected (+DSA) in patients with late allograft dysfunction due to de-novo autoimmune hepatitis (d-AIH). Serum was collected at routine clinic visits from 50 pediatric LTx recipients a mean of 11.8 ± 5.3 years post LTx, and classified into four clinical phenotypes: non-tolerant with biopsy-proven late acute cellular rejection (n = 6) and/or d-AIH (n = 12); stable with normal liver function on maintenance tacrolimus (n = 25); tolerant with normal liver function off immunosuppression ⩾2 years (n = 7). Samples were blinded and antibody detection was performed using LABScreen HLA Class I and II Single Antigen beads (One Lambda) and Luminex multiplex technology. Descriptive statistics and multivariate logistic regression were performed with results reported as means and odds ratios (OR). HLA antibodies were detected in 28/50 (56%) of patients, with the majority of DSA directed against HLA Class II DR or DQ loci (40% and 52%, respectively). Patients with +DSA had a mean of 1.8 (range 1-4) DSA with a mean MFI of 11681 ± 8227. Patients with +DSA were younger at LTx (2.4 ± 2.9 vs 5.4 ± 5.4 years, p = 0.01). There were no differences in other clinical variables including sex, primary diagnosis, history of re-LTx, and early acute rejection. Age in years at LTx (OR 0.5, p = 0.01), history of post transplant lymphoproliferative disorder (OR 0.1, p = 0.01) and late rejection (OR 27, p = 0.02) are the strongest predictors of +DSA. Patients with d-AIH tended to be +DSA (10/12 patients, p = 0.05), a trend that was not observed in the other phenotypes. +DSA is the strongest multivariate predictor of d-AIH (OR 19, p = 0.03). DSA are common after pediatric LTx and detected more frequently in patients with d-AIH, suggesting d-AIH may be a form of antibody-mediated rejection.

Elevated Blood Eosinophil Count Is a Valuable Biomarker for Predicting Late Acute Cellular Rejection After Liver Transplantation

BackgroundRecent studies have indicated the value of increased blood eosinophil counts for the diagnosis of acute cellular rejection (ACR) after orthotopic liver transplantation (OLT). However, the relationship between eosinophil count and late ACR at more than 6 months after OLT is still unclear. MethodsWe sought to retrospectively analyzed the ACR predictive value of eosinophil counts. In the day before or the day of biopsy among 40 biopsies performed on 37 patients beyond 6 months after OLT. ResultsRelative eosinophil count was significantly higher in the ACR (n = 24) than the non-ACR cohort, albeit with no significant difference in absolute eosinophil count. Receiver operating characteristic (ROC) analysis showed an absolute eosinophil count of 0.145 × 109/L and a relative eosinophil count of 2.3% to show the highest Youden index with area under the ROC curves of 0.746 and 0.813, respectively. When absolute eosinophil count ≥0.145 × 109/L or relative eosinophil count ≥2.3% was defined to be elevated, the sensitivity and specificity to predict ACR were 45.8% and 87.5%, and 75% and 87.5%, respectively. When the absolute eosinophil count ≥ 0.285 × 109/L or relative eosinophil count ≥3% was defined as elevated, the sensitivity and specificity were 25% and 100%, and 50% and 100%, respectively. All patients with an absolute eosinophil count ≥0.285 × 109/L showed a relative eosinophil count ≥3%. ConclusionsElevated blood eosinophil count was a valuable biomarker to predict late ACR after OLT.

Hypersensitivity myocarditis and outcome after heart transplantation

Hypersensitivity myocarditis (HSM) is associated with the use of multiple drugs and has been occasionally observed in patients awaiting heart transplantation (HTx). However, whether HSM at the time of HTx affects long-term prognosis, including acute cellular rejection (ACR) and antibody-mediated rejection (AMR), after HTx remains unclear. Between 2000 and 2010, 759 consecutive patients underwent de novo HTx at Columbia University Medical Center and were retrospectively reviewed. Clinical characteristics and pathologic findings of patients with a pre-HTx HSM diagnosed by histologic evaluation of the explanted heart were analyzed. Prognosis after HTx was compared between patients with and without pre-HTx HSM. HSM was observed in 21 patients (2.7%), but in no case was HSM clinically diagnosed. Twelve patients (57%) had received dobutamine infusions. HSM patients had varying degrees of perivascular or interstitial eosinophilic infiltrates with rare necrosis in the explanted heart. The number of biopsy specimens diagnosed with ACR (International Society for Heart and Lung Transplantation Grade ≥2R) was 11 (3.9%) in HSM patients and 197 (2.2%) in patients without HSM (p = 0.06) during the first year post-HTx, and 11 (3.8%) in HSM patients and 78 (1.5%) in patients without HSM (p = 0.006) after the second year post-HTx. Post-HTx survival did not differ in patients with or without pre-HTx HSM. HSM at the time of HTx is associated with an increased frequency of late ACR after HTx. Post-HTx survival is not influenced by pre-HTx HSM.

How the latest evidence from clinical research informs patient care

How the latest evidence from clinical research informs patient care

Comparative Outcome Analysis of ABO-Incompatible and Positive Crossmatch Renal Transplantation: A Single-Center Experience

ABO-incompatible (ABOi) and positive crossmatch (XM) renal transplants pose special immunologic challenges. It is important to compare outcomes, study resource utilization, and attempt to risk stratify patients in these higher risk transplant settings. We compared apheresis utilization and transplant outcomes in ABOi, XM, and combined ABOi-XM renal transplants. We also analyzed multiple parameters, including patient and laboratory variables, to identify predictors of transplant outcome. Incidences of early (< or =30 days posttransplant) antibody-mediated rejection (AMR) and acute cellular rejection (ACR) were similar among the three incompatible groups whereas they differed in allograft rejection for late (>30 days posttransplant) AMR and ACR. Notably, there were no episodes of late AMR among ABOi patients. Patients treated with more than four pretransplant plasmapheresis/intravenous immunoglobulin (PP/IVIg) had a greater likelihood of experiencing early AMR. The median number of posttransplant PP/IVIg treatments was greater than twofold higher in ABOi-XM and XM patients compared to ABOi patients. Patients who required more than five posttransplant PP/IVIg procedures and those with one or more prior renal transplants had higher incidences of late ACR. Our analysis aids in defining apheresis resource utilization and helps in risk stratification of incompatible renal transplantation. It also aids in predicting allograft rejection and provides an opportunity for preemptive monitoring and treatment.

Characterization of C4d Immunostaining Utilizing Paraffin-Embedded Tissue of Nonpresensitized Pediatric Heart Transplant Patients

Immunoperoxidase techniques for demonstration of complement split product C4d on paraffin-embedded endomyocardial biopsy samples have been used for the evaluation of humoral rejection mainly in adult heart transplantation. Interpretation of suspected humoral rejection in children requires knowledge of the pattern and frequency of C4d deposition in nonpresensitized pediatric heart transplantation patients. Paraffin-embedded endomyocardial biopsy samples of 65 patients with no rejection, acute cellular rejection (ACR), or early ischemic/reperfusion injury were studied. Six biopsies within each grade of ACR both early (<6 months) and late (>6 months) after heart transplantation were reviewed, as were 5 biopsies of ischemic/reperfusion injury. None of the subjects was sensitized prior to transplant. All slides were blindly evaluated for histologic features traditionally associated with humoral rejection. C4d staining was quantified by counting the number of positive capillaries in 10 random high-power fields (hpf). C4d positivity (C4d+) was defined as >10 capillaries/10 hpf. C4d+ was observed in 6 (9%) endomyocardial biopsy samples; 2 in the early and 4 in the late ACR groups. Four had ACR grades 1A/B, and 2 had grade 3B/4. Thirteen (20%) endomyocardial biopsy samples had histologic features suggestive of humoral rejection. Of these, only 2 were C4d+ and both had ACR grade 3B/4. No C4d+ staining was found in the ischemic/reperfusion injury group. C4d immunostaining was negative in endomyocardial biopsy samples of the majority of our patients (91%). Endomyocardial biopsy samples with C4d+ did not show consistent ACR grade or time specificity. Contrary to previously reported data, none of the ischemic/reperfusion injury endomyocardial biopsy samples was C4d+, and histologic features alone were poor predictors of C4d+.