Recurrent Acute Rejection Episodes Research Articles

Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions.

Balancing the immune response after solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA) remains an ongoing clinical challenge. While immunosuppressants can effectively reduce acute rejection rates following transplant surgery, some patients still experience recurrent acute rejection episodes, which in turn may progress to chronic rejection. Furthermore, these immunosuppressive regimens are associated with an increased risk of malignancies and metabolic disorders. Despite significant advancements in the field, these IS related side effects persist as clinical hurdles, emphasizing the need for innovative therapeutic strategies to improve transplant survival and longevity. Cellular therapy, a novel therapeutic approach, has emerged as a potential pathway to promote immune tolerance while minimizing systemic side-effects of standard IS regiments. Various cell types, including chimeric antigen receptor T cells (CAR-T), mesenchymal stromal cells (MSCs), regulatory myeloid cells (RMCs) and regulatory T cells (Tregs), offer unique immunomodulatory properties that may help achieve improved outcomes in transplant patients. This review aims to elucidate the role of cellular therapies, particularly MSCs, T cells, Tregs, RMCs, macrophages, and dendritic cells in SOT and VCA. We explore the immunological features of each cell type, their capacity for immune regulation, and the prospective advantages and obstacles linked to their application in transplant patients. An in-depth outline of the current state of the technology may help SOT and VCA providers refine their perioperative treatment strategies while laying the foundation for further trials that investigate cellular therapeutics in transplantation surgery.

P8.054: Out of the Box. Immunosuppressive Therapy With Four Drugs As Rescue Therapy in Kidney Transplant Recipients With Chronic Allograft Rejection

Introduction: Persistent or repeated episodes of acute rejection (AR) may lead to chronic allograft damage. Antibody-mediated rejection (AMR); T-cell mediated rejection (TCMR) and mixed variants (MR) of chronic kidney allograft rejection (CR) are nowadays considered as the main causes of graft loss (GL). This encompasses from endothelial damage up to fibrosis challenging immunosuppressive therapy (IT) management. IT reinforcement with a four-drug scheme (4D) including m-TOR inhibitors, anticalcineurinics, mycophenolate and steroids, could be a good strategy in this scenario, nevertheless there is no consensus about it. We present our experience with 4D in kidney transplant recipients (KT) That presented with CR or recurrent episodes of AR. Objectives: To evaluate kidney graft function (KGF), incidence of rejection and safety of a 4D in KT with CR or recurrent episodes of AR. Methods: KT on treatment with 4D from 2008 to 2021 were included. KGF was evaluated by estimated glomerular filtration rate with CKD-EPI (eGFR) and urinary protein/creatinine ratio (PCR) at 3, 6 and 12 months. Kidney biopsies and panel reactive antibodies (PRA) by Luminex were performed before and after introduction of 4D. BK virus (BKV) incidence, infectious (IE) and neoplastic (NE) events were recorded during the follow up. Results: 16 KT (median age 45 ± 11 years) were treated with 4D during 52.8 (17-106) months. 43.8% of them were women, 50% were deceased KT. The median post transplant time was 108 (60-129) months. Reasons for 4D introduction were CR in 87.4% of the cases (MR 50%; TCMR 31.3%; AMR 6.3%) and in the remaining 12, 6%, recurrent or persistent acute TCMR. Median eGFR was 42 (27-66); 44 (31-62); 48 (33-60) and 48 (32-65) ml/min prior to IT change, at 3, 6 and 12 months respectively. At baseline, mean PCR was 179 (147-664) mg/g without significant changes during follow up. Biopsy proven AR was found in 37% of KT under 4D. No NE were registered. 43% of the patients presented a non major IE, and only one patient was BKV positive during follow up with 4D. There was one GL, one loss of follow up and one death due to sepsis with functioning graft. Conclusions: KT patients with CR or recurrent episodes of AR changed to 4D IT stabilized their renal function and proteinuria. The incidence of new biopsy proven AR was 37%, and no new DSA were found or serious adverse events reported during follow-up. 4D could be a good option to halt the progression of renal damage due to rejection in KT.

Long-term Outcomes After Facial Allotransplantation: Systematic Review of the Literature.

Facial vascularized composite allotransplantation (fVCA) represents a reconstructive approach that enables superior improvements in functional and esthetic restoration compared with conventional craniomaxillofacial reconstruction. Outcome reports of fVCA are usually limited to short-term follow-up or single-center experiences. We merge scientific literature on reported long-term outcome data to better define the risks and benefits of fVCA. We conducted a systematic review of PubMed/MEDLINE databases in accordance with PRISMA guidelines. English full-text articles providing data on at least 1 unique fVCA patient, with ≥3 years follow-up, were included. The search yielded 1812 articles, of which 28 were ultimately included. We retrieved data on 23 fVCA patients with mean follow-up of 5.3 years. More than half of the patients showed improved quality of life, eating, speech, and motor and sensory function following fVCA. On average, the patients had 1 acute cell-mediated rejection and infectious episode per year. The incidence rates of acute rejection and infectious complications were high within first-year posttransplant but declined thereafter. Sixty-five percent of the patients developed at least 1 neoplastic or metabolic complication after transplantation. Chronic vascular rejection was confirmed in 2 patients, leading to allograft loss after 8 and 9 years. Two patient deaths occurred 3.5 and 10.5 years after transplant due to suicide and lung cancer, respectively. Allograft functionality and improvements in quality of life suggest a positive risk-benefit ratio for fVCA. Recurrent acute rejection episodes, chronic rejection, immunosuppression-related complications, and heterogeneity in outcome reporting present ongoing challenges in this field.

Long-term Outcomes After Facial Allotransplantation: Systematic Review of the Literature

Background Facial vascularized composite allotransplantation (fVCA) represents a reconstructive approach that enables superior improvements in functional and esthetic restoration compared to conventional craniomaxillofacial reconstruction. Outcome reports of fVCA are usually limited to short-term follow-up or single-center experiences. We merge scientific literature on reported long-term outcome data to better define the risks and benefits of fVCA. Methods We conducted a systematic review of PubMed/MEDLINE databases in accordance with PRISMA guidelines. English full-text articles providing data on at least 1 unique fVCA patient, with ≥ 3 years follow-up, were included. Results The search yielded 1812 articles, of which 28 were ultimately included. We retrieved data on 23 fVCA patients with mean follow-up of 5.3 years. More than half of the patients showed improved quality of life, eating, speech, and motor and sensory function following fVCA. On average, the patients had 1 acute cell-mediated rejection and infectious episode per year. The incidence rates of acute rejection and infectious complications were high within first year posttransplant but declined thereafter. Sixty-five percent of the patients developed at least 1 neoplastic and/or metabolic complication after transplantation. Chronic vascular rejection was confirmed in 2 patients, leading to allograft loss after 8 and 9 years. Two patient deaths occurred 3.5 and 10.5 years after transplant due to suicide and lung cancer, respectively. Conclusions Allograft functionality and improvements in quality of life suggest a positive risk-benefit ratio for fVCA. Recurrent acute rejection episodes, chronic rejection, immunosuppression related complications, and heterogeneity in outcome reporting present ongoing challenges in this field.

(813) - Extracorporeal Photopheresis in the Treatment of Complicated Acute Rejection After Heart Transplantation

Although immunosuppressive therapy after heart transplantation (HTX) has improved over recent years, complicated rejection episodes still threaten the survival of patients. The aim of this analysis was to investigate ECP as treatment of recurrent acute rejection episodes. Methods: All patients who developed recurrent rejection episodes, defined as bioptic diagnosed rejection episodes (≥ 2R ISHLT) detected after a successful treated rejection, were defined as complicated rejection. Hemodynamical stable patients were included in a ECP therapy protocol. All patients underwent serial biopsies as indicator for response to our treatment. Results: Seven of 348 (2.1%) Patients were included between 1/2006 and 11/2014. The mean age at the time of onset of ECP therapy was 43.29 (range 24 69), 3 were male and 4 female. Median time post transplant was 6 months (range 3 72). All patients received more than 6 ECP cycles and the median number of ECP cycles was 37 (range 6 74). Two patients are still treated with ECP as permanent therapy. All patients have survived the whole follow-up period. Median follow-up is 24 months (range: 12-96) One patient needed re-transplantation due to graftvasculopathy 12 months post start of ECP. In all patients, biopsies showed a remission from Grade 2R to Grade 1R and 0 during treatment. Conclusion: In our experience, ECP treatment appeared to be an effective and safe treatment option for recurrent rejection episodes. There is a strong need for bigger controlled studies.

De Novo Everolimus (EVR) Versus Mycophenolate (MPA) in Kidney Transplant Recipients Receiving Tacrolimus (TAC).

Introduction: Head-to-head comparison of the efficacy of de novo use of EVR or MPA has not been investigated in kidney transplant recipients receiving TAC. Methods:This is a single center prospective randomized study including 288 low immunological risk kidney transplant recipients receiving: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure TAC (<5 ng/ml), EVR (4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), MPA(1440 mg/day) and prednisone. None of the patients received any CMV prophylaxis. All patients were followed for 6 months after transplant and 28%, 29% and 27% reached one year of follow up, respectively. This report includes detailed analysis of the incidence and characteristics of acute rejection (AR) up to one year after transplantation (mean follow up of 297±98 days). Results: There were no differences in demography including recipient age, gender, race, PRA, CMV recipient status, donor age and donor source. The incidence of delayed graft function was high but comparable among the groups (48 vs. 53 vs. 45%, p=0.391), respectively. The incidence of biopsy proven acute rejection (BPAR) was not different among the groups (8.2 vs. 19.6 vs 13.9%, p=0.085). There was no significant difference in mean time to first treated AR (64±55 vs 34±53 vs 60±113 days, p=0.419) or in the total number of BPAR episodes (10 vs. 24 vs. 17 p=0.112). Vascular involvement (grade IIA or IIB, Banff 97) was less frequent in G1 (0 vs. 29 vs. 52%, p=0.01) while the incidence of AR episodes requiring antithymocyte globulin treatment was not different (10 vs. 29 vs. 47%, p=0.07). There was no difference in the number of patients with recurrent AR episodes (3 vs. 4 vs. 3). Also, there were no differences in the number of graft losses (1 vs. 3 vs. 6) and patient death (3 vs. 3 vs. 4). The incidence of CMV infection was lower in EVR groups (4.7 vs. 7.8 vs. 35.6%, p<0.0001) with no differences in mean estimated GFR (64±24 vs. 58±23 vs. 66±29 ml/min, p=0.08 ml/min). Conclusions: In this cohort of patients receiving TAC, a single dose 3mg/kg antithymocyte globulin induction combined with reduced exposure TAC and EVR is associated with less severe AR and lower incidence of CMV infection compared to MPA.

Therapeutic Drug Monitoring of Mycophenolic Acid After Lung Transplantation—Is It Clinically Relevant?

Mycophenolate mofetil (MMF) is a purine synthesis antagonist frequently used after solid organ transplantation including lung transplantation (LTx) (1). MMF is an inactive prodrug that is converted to its active metabolite mycophenolic acid (MPA) by intestinal, liver, and plasma esterases (2). MMF is normally administered at a fixed dose, and the role of therapeutic drug monitoring (TDM) for MPA in solid organ transplantation remains controversial (3). The aim of this study was to evaluate the role of MPA-TDM in lung transplant recipients. A retrospective analysis in a single center was performed in outpatient stable lung transplant patients receiving triple calcineurin inhibitor (CNI)-based immunosuppression during routine follow-up visits from January 2007 to May 2009. Inclusion criteria for MPA-TDM were clinical suspicion of over- or underdosing or fluctuating drug levels of CNIs. To evaluate clinical outcome, events occurring within 6 months before and after TDM were compared. Blood samples were collected before (C0), and 30 and 120 min (C30 and C120) after the morning dose. A target range of 30 to 60 mg/hr L according to recommended values in renal transplant patients was used (4). Serum concentrations of MPA were measured using reserve-phase high performance liquid chromatography (5, 6). MPA exposure (area under the curve [AUC]) was estimated by 3-point equation according to validated algorithms using the MPA concentration data from predose and at 30- and 120-min levels (7, 8). One hundred twenty-six patients were included. Indications for inclusion centered on recurrent acute rejection episodes (6%) or infections (10%), unexplained leucopenia or anemia (36%), gastrointestinal complaints (12%), and fluctuating CNI (13%). Patient demographics and results are listed in Table 1.TABLE 1: Baseline characteristics of patientsFifty-three patients (42%) had a MPA-AUC outside of 30 to 60 mg/hr L: subtherapeutic AUCs were found in 27% and supratherapeutic AUCs in 15%. Patients taking tacrolimus (44.6 [interquartile range: 35.5–59.4] mg/hr L) demonstrated significantly higher MPA AUCs in comparison with those receiving cyclosporine (vs. 35.4 [26.6–45.8] mg/hr L, P=0.001). C0 levels moderately correlated with AUC (see Figure, Supplemental Digital Content 1,https://links.lww.com/TP/A347). C0 levels were more predictive for MPA AUC in long-term LTx. In the first 6 postoperative months, significantly lower MPA exposure was observed. No significant differences between abnormal MPA-AUCs and incidence of acute rejections, infections, gastrointestinal side effects, or anemia were observed. Leukocytes and hemoglobin increased significantly by median 1.8 Tsd/μL (47 vs. 6.5 Tsd/μL) and 0.1 g/dL (12.3 vs. 12.4 g/dL) 6 months after dose reduction (P=0.035 and P=0.012) in 21 patients. No significant relationships between subtherapeutic MPA AUC and incidence of rejection episodes, cytomegalovirus, respiratory viral, or bacterial infections during the preceding 6 months were observed. In patients with cystic fibrosis (CF), subtherapeutic MPA-AUCs occurred more frequently (38% vs. 24% in non-CF patients, respectively) despite receiving significantly higher doses (29.9 [21.2–39.6] mg/kg/day vs. 21.7 [15.5– 29.0] mg/kg/day, P=0.002). No significant decrease in MPA exposure in patients with proton pump inhibitor (PPI) comedication (40 [29–52] mg/hr L) was observed, when compared with those without PPIs (42 [29–60] mg/hr L). Our results of MMF pharmacokinetics in a large lung transplant population indicate that subtherapeutic MPA levels are frequent in CF patients and early after transplantation. The cause for observed lowered MPA AUCs in the early posttransplant period seems multifactorial. Low serum albumin or increased urea may result in increased plasma clearance along with malabsorption or gastroparesis may explain the pharmacokinetic variation (9). Analysis of genetic polymorphisms in enzymes may also account for supratherapeutic MPA levels. The pharmacokinetics of drugs are altered in CF patients, and the plasma concentrations of many drugs are found to be lower than in individuals without CF (10). Our results regarding drug deposition of MMF in recipients with CF are consistent with those reported by Gerbase et al. (11). The majority of studies in other forms of transplantation similarly demonstrated no significant relationship between clinical outcomes and TDM of MPA (12, 13). In general, MPA monitoring correlated poorly with clinical suspicion of abnormal MMF dosing in our study. Rupprecht et al. (14) have recently shown that concomitant treatment with the PPI pantoprazole significantly decreased MPA in healthy volunteers. In our analysis, there was no significant decrease in MPA exposure in patients with long-term PPI comedication. In conclusion, a substantial clinical benefit of MMF TDM needs to be established. We suggest MPA monitoring in LTx only when dose reduction does not ameliorate side effects. Prospective trials to assess the potential risk of long-term MPA overexposure in LTx are needed. Claudia de Wall Thomas Fuehner Patricia Wehmeier Tobias Welte Jens Gottlieb Department of Respiratory Medicine Medical School Hanover Hanover, Germany

Conversion to Sirolimus in Kidney–Pancreas and Pancreas Transplantation

Reports on the use of sirolimus (SRL) in pancreas transplantation are still limited. The aim of this study was to evaluate the outcome of SRL conversion in pancreas transplant patients. Among 247 patients undergoing simultaneous kidney-pancreas or solitary pancreas transplantation, 33 (13%) were converted to SRL. The reasons for conversion were calcineurin inhibitors (CNI) nephrotoxicity ( n = 24; 73%), severe neurotoxicity owing to CNI ( n = 1; 3%), severe and/or recurrent acute rejection episodes ( n = 7; 21%), gastrointestinal (GI) side effects of mycophenolate mofetil (MMF; n = 5; 15%), and hyperglycemia ( n = 4; 12%). Before conversion, all patients were maintained on a CNI, MMF, and low-dose steroids. They were gradually converted to SRL associated with either CNI or MMF withdrawal. Sixty-three percent ( n = 15) of patients who were converted owing to CNI nephrotoxicity, showed stable or improved renal function. At 12 months after conversion, serum creatinine levels were significantly decreased in this group (2.2 ± 0.5 vs 1.6 ± 0.3 mg/dL; P = .001) and C-peptide values increased (2.9 ± 1.1.1 vs 3.1 ± 1.3 nmol/L; P = .018). The only patient with leucoencephalopathy showed improved neurologic status after SRL conversion. All patients converted to SRL because of GI side effects of MMF showed improvements, and none of those converted because of hyperglycemia experienced improvement. There were no episodes of acute rejection after conversion. We concluded that conversion to SRL in pancreas transplantation should be considered an important alternative strategy, particularly for CNI nephrotoxicity and neurotoxicity, and in cases of severe diarrhea due to MMF.

RANTES/CCL5 polymorphisms as a risk factor for recurrent acute rejection

The chemokine system plays an important role in the pathogenesis of acute rejection or atherosclerosis. Three polymorphisms in the promoter region of the chemokine RANTES (-403G/A, -28G/C, In1.1T/C) are associated with a different expression of this chemokine as well as the occurrence of cardiovascular disease. Therefore, we investigated the impact of these three polymorphisms on the outcome after renal transplantation. In 261 patients receiving their first kidney transplant, we genotyped the RANTES promoter polymorphisms (-403G/A, -28G/C, In1.1T/C) by real-time PCR. For the RANTES -403G/A and for the intronic polymorphism In1.1T/C, we found a significantly higher rate of recurrent acute rejection episodes (-403G/A: 11.1 vs. 31.0%, In1.1T/C: 11.8 vs. 33.0%). For the overall rate of acute rejection, we observed no significant differences according to the RANTES promoter polymorphisms. The other tested variables (DGF, graft survival, renal function) were not associated with one of the three polymorphisms. Our data indicate a relevant role of RANTES in kidney transplantation, particularly for the occurrence of recurrent acute rejection. To clarify the role of the analysed polymorphisms for long-term survival, especially for the occurrence of cardiovascular events, larger studies in the future are needed.

382: The role of primary graft dysfunction or recurrent acute rejection episodes in the development of pseudomonas colonisation after lung transplantation

382: The role of primary graft dysfunction or recurrent acute rejection episodes in the development of pseudomonas colonisation after lung transplantation

Anti‐IL‐2 receptor antibody vs. polyclonal anti‐lymphocyte antibody as induction therapy in pediatric transplantation

Current concerns in pediatric transplantation focus on chronic rejection which commonly leads to graft loss, and on long-term maintenance immunosuppression toxicity. Acute rejection has been associated with the subsequent development of chronic rejection. Therefore, induction therapy may provide potential benefits by preventing early acute rejection episodes and allowing delayed administration of calcineurin inhibitors or steroid avoidance. This review of the literature showed that induction therapy can reduce early and recurrent acute rejection episodes after pediatric solid organ transplantation. Whether this might result in better long-term graft survival has still to be confirmed. However, induction therapy has beneficial effects in high-risk recipients and allows steroid avoidance or calcineurin inhibitor minimization. Because they are very well tolerated, anti-IL-2 receptor antibodies are increasingly preferred to rabbit-antithymocyte globulin, but the former have not yet been proven to be more effective or to have less late toxicity than polyclonal agents. Benefits in early outcome and no increase in adverse events lead to recommend the use of IL-2 receptor antagonists as induction therapy after pediatric organ transplantation.

TNF‐α and TGF‐β1 gene polymorphisms and renal allograft rejection in Koreans

This study was performed in order to evaluate the association of tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) gene polymorphisms with renal allograft rejection in Koreans. Five TNF-alpha (-1031T/C, -863C/A, -857C/T, -308G/A and -238G/A) and two TGF-beta1 (codon 10 T/C and codon 25 G/C) single-nucleotide polymorphism (SNP) sites were studied by using polymerase chain reaction (PCR) single-strand conformation polymorphism and PCR restriction fragment length polymorphism methods in 100 controls and 164 patients. The patients underwent renal transplantation, having one or more Human leukocyte antigen (HLA)-A, HLA-B and HLA-DR antigens mismatched with their donors. For the TGF-beta1 gene, we also studied the polymorphism of donors. The allele frequencies of each SNP site in controls were not different from those of patients. The frequency of TNF-alpha high-producer genotype, -308GA, and TGF-beta1 lower (intermediate)-producer genotype, codon 10 CC and codon 25 GG, were significantly higher in patients with recurrent acute rejection episodes (REs), compared to those in patients with no or one RE. The highest risk group for developing recurrent REs showed the combination of TNF-alpha high- and TGF-beta1 lower-producer genotypes. Analysis of chronic renal allograft dysfunction (CRAD) revealed that TGF-beta1 high-producer genotype of donors, codon 10 TT/TC and codon 25 GG, is associated with CRAD especially in patients with recurrent REs. The highest risk group for developing CRAD showed the combination of recipient's TNF-alpha high- and donor's TGF-beta1 high-producer genotypes. These results would be useful for predicting high-risk group for acute rejection or CRAD in renal transplantation.

Risk factors for BK polyomavirus nephritis in renal allograft recipients.

Recurrent episodes of acute rejection (AR) and/or the intense immunosuppression used for their treatment have been proposed as risk factors for BK nephritis (BKN; BK refers to the initials of the first patient from whom this polyomavirus was isolated). To further examine the relationship between AR and BKN, we analyzed all kidney transplants performed at our center between January 1999 and August 2001 (n = 286). After a mean follow-up of 737 +/- 22 d, we identified nine cases of BKN (3.1%). The mean time to diagnosis of BKN was 326 +/- 56 d. No patient with BKN had a prior history of AR. During the same period, 62 patients were diagnosed with AR (22%). The mean time to diagnosis of AR was 197 +/- 40 d (p = 0.01 vs. time to diagnosis of BKN). Despite aggressive therapy with methylprednisolone and, in some cases, anti-lymphocyte antibody, none of these patients with AR developed BKN. We compared the baseline characteristics of patients in both groups and found that BKN patients were more likely to be white people (78 vs. 44%, p = 0.05) and male (89 vs. 53%, p = 0.04). Moreover, the mean tacrolimus (TAC) levels before diagnosis were higher in BKN than in AR patients (11.7 +/- 0.5 vs. 6.5 +/- 0.6 ng/mL, p < 0.001). In summary, our study shows that BKN often occurs in the absence of prior episodes of AR. In addition, our findings suggest that white males exposed to higher TAC levels are at greater risk of developing BKN.

Transforming growth factor beta (TGF-β) and obliterative bronchiolitis following pulmonary transplantation

Background: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-β has been implicated in the pathogenesis of fibrosis. Methods We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-β polyclonal antibodies. OB and interstitial fibrosis were diagnosed and graded in all biopsies. Other potential histologic and clinical risk factors for OB were analysed. Results Procedures were heart and lung ( n = 32), bilateral sequential lung ( n = 18), and single lung transplantation ( n = 41). The incidence of OB in this group was 28.5%. In all patients with OB, TGF-β was immunolocalized in the airways and lung parenchyma. TGF-β expression was greater in OB patients (median score 8, range 5–12) in comparison to patients without OB (median score 4, range 1–13), p < .0001. Positive TGF-β staining preceded the histologic confirmation of OB by 6 to 18 months. The development of OB was associated with two HLA mismatches at the A locus ( p = .02); recurrent acute rejection episodes ( p < .0005); lymphocytic bronchiolitis ( p = .0001); and tissue eosinophilia, regardless of the rejection grade ( p < .0001). Conclusions Increased expression of TGF-β is a risk factor for the development of OB. Other risk factors are recurrent acute rejection, lymphocytic bronchiolitis, tissue eosinophilia, and two mismatches at the HLA-A locus. This suggests that the pathogenesis of progressive small airway fibrosis characteristic of OB may be inflammatory damage, followed by an aberrant repair process due to excessive TGF-β production following allograft injury. Hence, modulation of TGF-β levels or function by antagonists may represent an important approach to control OB.

Donor cardiac troponin T: a marker to predict heart transplant rejection

Background. Noninvasive methodologies have shown poor sensitivity in predicting rejection when compared to serial endomyocardial biopsies. We studied the potential role of donor blood troponin T (Tn-T) as a marker for predicting heart transplant rejection.Methods. Blood cardiac Tn-T was measured from 16 heart donors. Transplant rejection and cardiac function in the recipients were monitored for 1 year.Results. When data were analyzed based on donor blood Tn-T levels, 6 patients who received hearts from donors with low Tn-T (<0.45 ± 0.1 ng/mL) showed no rejection, and patients whose hearts came from donors with higher Tn-T (6.01 ± 0.81 ng/mL) developed episodes of high-grade rejection (3A) within 38.5 ± 2.1 days after transplantation. Eight patients who received hearts from donors with intermediate levels of Tn-T (3.57 ± 0.55 ng/mL) showed mild rejection (grade 1). All recipients had qualitatively normal left ventricular systolic function by serial echocardiography. The mean donor ischemic time was 169 ± 47 minutes.Conclusions. The quality of the donor heart is an important prognostic factor in heart transplantation. It may be possible to identify severely damaged donor organs before transplantation and avoid their use or to develop more aggressive strategies for reducing recurrent acute rejection episodes in high-risk patients.

Clinical and immunological characteristics of transplant recipients with recurrent acute rejection episodes

D ESPITE intense and repeated antirejective therapy with triple combinations of cyclosporine A (CyA), cortisone (CORT), antithymocyte globuline (ATG), and consecutive monoclonal CD3 antibodies (OKT3) in acute rejection episodes, still confront transplant recipients who have relapses of acute rejection (AR). In a patient subset after allogenic TX we asked (1). Can this recipient group be characterized by risk factors? and (2) Is there an efficacious regimen for safe therapy of recurrent rejection episodes?

CsA LEVELS IN THE EARLY POSTTRANSPLANT PERIOD—PREDICTIVE OF CHRONIC REJECTION IN LIVER TRANSPLANTATION?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.

CsA LEVELS IN THE EARLY POSTTRANSPLANT PERIOD—PREDICTIVE OF CHRONIC REJECTION IN LIVER TRANSPLANTATION?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of >175 μg/L in the first 28 days post-transplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P=0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P<0.00001) and multiple episodes (two or more; P=0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 μg/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.

Radionuclide surveillance of the allografted pancreas.

To determine the value of scintigraphy to detect posttransplantation complications of the allografted pancreas, we retrospectively reviewed 209 scintigrams obtained with 99mTc-sulfur colloid (99mTc-SC) and 99mTc-glucoheptonate (99mTc-GH). The scintigraphic studies were performed in 37 recipients of simultaneous renal and pancreatic allografts harvested from the same donor. 99mTc-SC was used as an indicator of thrombotic vasculitis; pancreatic perfusion and blood-pool parameters were monitored with 99mTc-GH. In 11 of the 37 recipients, scintigraphic abnormalities suggested posttransplantation infarction. Recurrent episodes of acute rejection of the pancreatic allograft, which always coincided with acute rejection of the renal allograft, were monitored in 24 recipients. Rejection-induced ischemic pancreatitis was suggested in 12 of the 24 recipients and persisted in 10 recipients for several weeks after improvement of renal allograft rejection. Pancreatic atrophy was suggested scintigraphically in 16 of the 24 recipients with recurrent episodes of rejection. Spontaneous pancreatic-duct obstruction and obstructive pancreatitis were associated with a scintigraphic pattern similar to that of rejection-induced ischemic pancreatitis. We concluded that the specific radionuclides used in this series are useful for the surveillance and assessment of posttransplantation pancreatic infarction, acute rejection, pancreatitis, and atrophy.