Prior Rejection Episodes Research Articles

#99 Clinical characteristics and outcomes of PTLD after kidney transplant: a single center experience

Abstract Background and Aims Post-Transplant Lymphoproliferative Disorder (PTLD) is a serious and potentially fatal complication of immunosuppression in kidney transplantation. Given the rarity of this entity, a high index of suspicion is necessary. We aimed to review the incidence, clinical presentation, histological subtypes, treatment, patient and graft survival of PTLD in kidney transplant patients in our unit. Methods Observational retrospective study, including adults diagnosed with PTLD between 1998 and 2023 in a Kidney Transplantation Center. Results Of 1390 kidney transplant recipients, 4 (0.3%) developed PTLD with a mean age of 52 ± 12.5 years. All cases were late-onset, occurring one year after transplantation with a median time from transplantation to diagnosis of 16.7 ± 7.3 years (range: 5-22 years). Of these, none had EBV donor/recipient mismatch. Two patients had prior rejection episodes (one patient, acute T cell-mediated rejection and the other patient, acute T cell-mediated rejection and active antibody mediated rejection). Clinical presentation was variable. Non-specific constitutional symptoms such as fever, fatigue and night sweats were present in all patients. Organ-specific symptoms were also present: lumbar pain in one patient with bone involvement, and delirium and lethargy in two patients with central nervous system involvement. Laboratory analyses revealed an increase in serum LDH in all patients. The primary sites of involvement were central nervous system (50%), lymph nodes (25%) and bone (25%). At PTLD diagnosis, immunosuppression included: tacrolimus (100%), mycophenolate mofetil (75%), low-dose of steroids (50%) and everolimus (25%). Regarding histologic classification, 75% were monomorphic and 25% polymorphic. In the monomorphic group, all patients had Diffuse Large B Cell Lymphoma (CD20 positive). In the polymorphic group, the patient had a Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative). Immunosuppression therapy was reduced in all patients with discontinuation of mycophenolate mofetil and tacrolimus. In the patient who was taking everolimus, the dose was increased due to the potential clinical antitumor effects of mTOR inhibition. Additional therapies included, rituximab in monotherapy or in combination with chemotherapy (R-CHOP) in the monomorphic group. Palliative measures were selected for one patient of this group due to advanced disease. The patient with Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative) did chemotherapy with ABVD. None of the patients underwent surgery or radiation therapy. Two patients needed dialysis. Three patients died in the first four weeks after PTLD diagnosis, all due to infectious complications. Patient survival was 25% one year after diagnosis. Conclusions Although the incidence of PTLD was low following kidney transplantation, its impact was significant in kidney graft and overall patient survival. Given the poor prognosis, new therapies combining high efficacy and low toxicity are an urgent unmet medical need in this field.

BK Virus Infection and Its Management in Renal Transplantation: An Update

BK virus (BKV) is a common opportunistic pathogen in kidney transplant recipients and one of the most challenging causes of allograft dysfunction and loss. Although over-immunosuppression remains the primary risk factor for BKV infection after transplantation, male gender, older recipient age, prior rejection episodes, degree of human leukocyte antigen mismatching, prolonged cold ischemia time, BK virus serostatus and ureteral stent placement have all been implicated as risk factors. Routine screening post-renal transplant is important to prevent allograft loss in patients with BK viruria or viremia. Reduction of immunosuppression remains the mainstay of BKV nephropathy treatment and is the most studied intervention. In this review, we are going to discuss the epidemiology of BK virus infection, screening strategies, treatment options and new studies or evidence in the future.

FACTORS CAUSING RECURRENCE OF INFECTION IN THE CORNEAL GRAFT AFTER THERAPEUTIC PENETRATING KERATOPLASTY

Aim:-The aim of this study is to analyse the factors causing recurrence of infection in the corneal graft after therapeutic penetrating keratoplasty.Material and Methods:- This study was conducted at Upgraded Department of Ophthalmology, SVBPH,Meerut. This institution performs 120 keratoplasty procedures per year on an average. The study was conducted for a period of one year & 25 patients had reinfection and those who presented with reinfection constituted the sample size complete enumeration.The data thus obtained was compiled and analysed using Statistical Package for Social services (SPSS vs 20). The qualitative variables were analyzed by using frequencies and The qualitative variables were analyzed by using frequencies & percentages & chi square test was used as test of significance.The quantitative variables were presented as measures of central tendency and dispersion. A p value of less than 0.05 was considered as statistically significant Results Initial fungal etiology was the main risk factor for the recurrence of microbial keratitis after TPK in (24%) of the cases followed by persistent epithelial defects (16%),Initial bacterial etiology (12%), Lid abnormalities (8%) ,contact lens use (8%), Secondary ocular hypertension (8%), prior rejection episodes(8%), initial viral etiology (4%) ,peripheral ulcerative keratitis (8%) & suture related problems(4%). Conclusion:- .This study has shown that Fungal keratitis was the main reason for the initial TPK & initial Fungal aetiology was the main risk factor for the reinfection after TPK

Post-transplant lymphoproliferative disorder in kidney transplant patients: A multicenter report.

7564 Background: Post-Transplant Lymphoproliferative Disorder (PTLD) is a complication of transplantation that often arises due to reactivation of the Epstein-Bar Virus (EBV). Given the rarity of this disease, a full understanding of its presentation and optimal therapies has yet to be determined. Methods: A multicenter retrospective analysis was performed utilizing data from kidney transplant patients (pts) who developed PTLD at the Hospital of the University of Pennsylvania and the Cleveland Clinic. The association between categorical variables and clinical response were assessed via Fisher’s exact testing. Results: 117 pts had diagnoses of PTLD after kidney transplantation. The median age at PTLD diagnosis was 52 yrs (range 17-89 yrs), and the median time from transplantation to diagnosis was 3.6 yrs (range: 7 days-36 yrs). Pt characteristics included: 84% Caucasian, 57% male, and 11% combined kidney and pancreas transplant patients. 68% pts had received unrelated donor transplants; 41% had prior rejection episodes. PTLD histology was 72% monomorphic and 28% polymorphic. Polymorphic PTLD was more likely to be EBV+ than monomorphic PTLD (81% vs. 54%, p = 0.05). At diagnosis, immunosuppression included: steroids (95%), mycophenolate (44%), azathioprine (40%), sirolimus (30%), cyclosporine (46%), and/or tacrolimus (45%). Common PTLD symptoms included fever (34%), pain (38%), weight loss (30%), fatigue (30%), and/or mass (26%). The most common sites of involvement were lymph nodes (64%), kidney allograft (22%), and/or GI tract (17%). At diagnosis, 61% of patients’ tumors were EBV+ and 59% of patients had elevated serum LDH. Overall, the majority of pts responded to first-line PTLD therapy, with 61% CR and 14% PR. Reduction of immunosuppression (RI) alone (36% of pts) led to 48% CR and 12% PR; RI with rituximab (16%) led to 47% CR and 7% PR; and RI with chemotherapy (14%) resulted in 58% CR and 42% PR. Patients treated with RI as well as resection (n = 18) of their limited stage disease had better outcomes (p = 0.05). Overall survival for all patients was 10.7 years (95%CI: 5.2-13 years). PTLD patients < 40 yrs were more likely to achieve CR after first line therapy (p < 0.001), have allograft involvement (p = 0.003), and have a polymorphic histology (p = 0.002). Allograft involvement tended to occur sooner after transplant (p = 0.001) and was more likely to present with allograft failure (p = 0.007). PTLD with allograft involvement had better response to first therapy than regular PTLD (p = 0.007) and often responded well to complete resection and RI. Conclusions: Pts with PTLD may achieve a CR through different initial therapies. Younger patients and those able to undergo complete resection of disease and RI had better prognoses. Allograft involvement by PTLD carries a good prognosis and should be identified and treated differently from other presentations.

Update on the Management of BK Virus Infection.

The BK polyomavirus was isolated in 1971; it has been a significant risk factor for both graft dysfunction and failure in renal transplant recipients. So far, no specific treatment option has been available for effective treatment or prophylaxis for BK virus infections. Although the use of heavy immunosuppression has been the main risk factor for BK virus infection, other risk factors are equally important, including elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged cold ischemia time, pretransplant BK virus serostatus, and ureteral stenting. Regular follow-up for BK virus infections according to each institution's policy has been, so far, effective in detecting patients with BK virus viremia and consequently preventing allograft loss. The mainstay of management continues to be reduction of immunosuppression. However, newer options are providing new insights, such as cellular immunotherapy. In this review, we will address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.

Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score-matched cohort analysis.

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low-dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard-dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3-year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n=128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P=.007) and biopsy-proven acute rejections (15 [23.4%] vs 31 [48.4%], P=.002). These results were confirmed in the overall cohort (n=213), after multivariable and inverse probability score weighting analyses. Renal function and donor-specific HLA-antibodies remained similar in both groups. Low-dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy.

Assessing the Complex Causes of Kidney Allograft Loss.

Although graft loss is a primary endpoint in many studies in kidney transplantation and a broad spectrum of risk factors has been identified, the eventual causes of graft failure in individual cases remain ill studied. We performed a single-center cohort study in 1000 renal allograft recipients, transplanted between March 2004 and February 2013. In total, 365 graft losses (36.5%) were identified, of which 211 (57.8%) were due to recipient death with a functioning graft and 154 (42.2%) to graft failure defined as return to dialysis or retransplantation. The main causes of recipient death were malignancy, infections, and cardiovascular disease. The main causes of graft failure were distinct for early failures, where structural issues and primary nonfunction prevailed, compared to later failures with a shift towards chronic injury. In contrast to the main focus of current research efforts, pure alloimmune causes accounted for only 17.5% of graft failures and only 7.4% of overall graft losses, although 72.7% of cases with chronic injury as presumed reason for graft failure had prior rejection episodes, potentially suggesting that alloimmune phenomena contributed to the chronic injury. In conclusion, this study provides better insight in the eventual causes of graft failure, and their relative contribution, highlighting the weight of nonimmune causes. Future efforts aimed to improve outcome after kidney transplantation should align with the relative weight and expected impact of targeting these causes.

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

Shifting trends in microbial keratitis following penetrating keratoplasty in Taiwan.

To investigate the clinical and microbiological profiles from microbial keratitis following penetrating keratoplasty (PKP) in a tertiary referral center in Taiwan, the medical records of 648 consecutive patients (648 eyes) undergoing PKP between January 2003 and December 2007 were retrospectively reviewed. Patients who subsequently sustained microbial keratitis were enrolled and analyzed for potential risk factors, clinical manifestations, microbiological profiles, complications, graft survival, and final visual outcome. A total number of 42 corneal graft infections (6.5%) were recruited. Mean interval between corneal transplantation and graft infection was 12 ± 9.5 months. Potential risk factors included suture-related problems (31.0%), lid abnormalities (23.8%), persistent epithelial defect (23.8%), contact lens use (14.3%), dry eye (11.9%), and prior rejection episodes (4.8%). Lesions were discovered mostly at the donor-recipient junction ([DRJ] 45.2%). Positive cultures were identified in all of the morbid eyes, of which Pseudomonas aeruginosa was the most common pathogen (38.1%). Despite mandatory hospitalization and topical fortified antibiotics management, complications ensued such as graft failure (71.4%), hypopyon (21.4%), corneal perforation (14.3%), wound dehiscence (11.9%), and endophthalmitis (4.8%). The visual outcome was dismal that graft clarity was achieved in only 12 eyes (28.6%), and that final visual acuity deteriorated to less than 20/200 in 28 eyes (66.7%). In conclusion, microbial keratitis following PKP is a devastating event that severely impairs graft survival rate and postoperative visual outcome which usually occur within the first postoperative year. The incidence of post-PKP microbial keratitis has generally decreased in recent years whilst P. aeroginosa prevails as the leading cause of graft infection in our hospital. Close follow-up by ophthalmologists and elevated self-awareness of patients for at least one year are always encouraged to prevent late-onset infection.

(491) - Community Acquired Respiratory Viral Infection after Lung Transplantation: BOS Risk and Risks of Specific Viruses

Community acquired respiratory viral (CARV) infections are a reported risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) but the risk of specific viral infections is unknown. We assessed the risk of specific CARV for BOS and death after LTx. Retrospective, single-centre analysis of 380 LTx recipients 01/2003- 01/2013, (BLTx 318, SLTx 18, HLTx 11),(CF 81, IPF 61, COPD 107, A1AT 29, PAH 12, CHD 9, ILD 21, B 21, OB 6). 33 were excluded for insufficient data, survival < 90 days, or retransplantation. Data were collected through 07/2013 with a mean +/- SD (range) follow up of 1473±1029 (107-3776) days. 225/347 had 487 symptomatic CARV infections confirmed by direct fluorescence antigen, PCR or viral culture of nasopharyngeal swabs and/or bronchoalveolar lavage. Standard therapeutic protocols were followed for specific viruses. Univariate and multivariate time-dependent Cox models were used. CARV included 76 Parainfluenza virus (PIV), 82 Respiratory Syncytial virus (RSV), 5 Adenovirus (AV), 25 Human metapneumovirus (HMPV), 46 Influenza A (FluA), 12 Influenza B (FluB), and 241 Picornavirus (PRNA). Analysed as a time dependent variable initial CARV (PIV =37, RSV=47, AV=3, HMPV=6, FluA=24, FluB=7,PRNA=101) were a significant risk factor for BOS (HR 1.46 95%CI 1.06-2.01, p=0.02) but not death (HR 1.39 95%CI 0.94-2.03, p=0.10). Risk was not dependent on type of CARV (p=0.56, log rank) or stratification by antecedent rejection history (p=0.16, log rank). Biopsy proven rejection remained a significant independent risk factor for BOS (HR 1.23 95%CI 1.03-1.48, p=0.02) and BOS was the major risk for death (HR 7.73 95%CI 5.05-11.84, p<0.001). Symptomatic CARV infection is a significant risk factor for BOS but not death and the risk is independent of viral species or prior rejection episodes. Modification of natural history by antiviral therapy may explain in part the similarity of outcomes shown for specific viruses.

BK virus infection: an update on diagnosis and treatment

BK virus, first isolated in 1971, is a significant risk factor for renal transplant dysfunction and allograft loss. Unfortunately, treatment options for BK virus infection are limited, and there is no effective prophylaxis. Although overimmunosuppression remains the primary risk factor for BK infection after transplantation, male gender, older recipient age, prior rejection episodes, degree of human leukocyte antigen mismatching, prolonged cold ischemia time, BK serostatus and ureteral stent placement have all been implicated as risk factors. Routine screening for BK has been shown to be effective in preventing allograft loss in patients with BK viruria or viremia. Reduction of immunosuppression remains the mainstay of BK nephropathy treatment and is the best studied intervention. Laboratory-based methods such as ELISPOT assays have provided new insights into the immune response to BK and may help guide therapy in the future. In this review, we will discuss the epidemiology of BK virus infection, screening strategies, treatment options and future research directions.

Patients Returning to Dialysis after Failed Kidney Transplant: How Do They Fare? A Gulf Perspective

An increasing number of failed transplant patients returning to dialysis (FTRD) have been observed with reported worse survival compared to transplant-naive dialysis (TxN) patients. This study aimed to assess outcomes of FTRD vs. matched TxN controls in a Gulf region multi-center trial of 800 HD patients. Similar mortality was seen, likely due to earlier start and better HD adequacy in FTRD. Younger age, less diabetes and living donor transplantation in majority with 27% graft nephrectomy (Nx) might also confer benefits. Subgroup analysis of Nx patients showed more hospitalizations and prior rejection episodes with lower graft survival. The deaths, however, oc-curred only in nonNx group and are likely explained by older age, longer duration on HD, more prevalence of diabetes and CAD. FTRD showed similar survival to TxN. Early intensive HD might account for the benefit. Whether Nx confers advantage is unclear because of the small sample size.

Granulocyte Colony-Stimulating Factor Therapy Is Associated With a Reduced Incidence of Acute Rejection Episodes or Allograft Vasculopathy in Heart Transplant Recipients

BackgroundWe evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients. MethodsOf 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 109cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence. ResultsAt baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67–37.2] and OR = 0.09 [0.02–0.52], respectively). ConclusionsG-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.

Growth hormone treatment after renal transplantation: a promising but underused chance to improve growth

Growth retardation remains a clinical problem in children with chronic kidney disease (CKD) prior to and during end-stage renal disease. The growth of approximately 40 % of children on dialysis is stunted. Even so, growth hormone treatment (GH) is not used in the majority of small children prior to transplantation. Also, GH is effective in improving growth after transplantation, but again, it is only rarely used in this situation mainly for fear of triggering rejection episodes. In controlled studies, the number of patients who developed rejection episodes with GH was no greater than the number in untreated controls. However, patients with prior frequent rejection episodes developed further repeated subsequent rejection episodes. Many patients with repeated rejection episodes before GH treatment have reduced renal function and are expected to proceed to dialysis or retransplantation. We believe that in these patients, early individual decisions for or against GH treatment should be made as soon as other treatment strategies, such as steroid withdrawal, have failed or are not indicated. Decisions for GH treatment at a later pubertal age come too late for significant growth response and/or improvement of final height.

Conversion to Sirolimus for Chronic Allograft Nephropathy and Calcineurin Inhibitor Toxicity and the Adverse Effects of Sirolimus After Conversion

Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drug's use. We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration. At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia. Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.

Prognostic Value of Tumor-Infiltrating TIA-1+ Cytotoxic T Cells (TIA1-CTCs) and FOXP3+ Regulatory T Cells (Tregs) in Post-Transplant Lymphoproliferative Disorder (PTLD) Following Solid Organ Transplant (SOT).

Background: PTLD is a rare, often fatal, complication of SOT. Several studies have identified clinical prognostic factors in PTLD. However, no published studies to our knowledge have yet correlated outcome with the number (#) or type of tumor infiltrating T-cells, which in other types of lymphoma may have prognostic value. We hypothesized that tumor infiltrating T-cells, including TIA1-CTCs and Tregs, would predict survival in SOT PTLD.Methods: We searched the Cleveland Clinic pathology archives for SOT patients (pts), who were diagnosed with PTLD between 1987 and 2007; reviewed the medical records and extracted clinical information and outcomes; performed immunohistochemical (IHC) studies for CD3, TIA-1, and FOXP3; and analyzed the data by Cox proportional univariate and multivariate analyses.Results: We identified 62 SOT pts (heart, 22; lung, 17; kidney 15; liver, 7; pancreas, 1), who were diagnosed with PTLD at median age of 51 years (range 7–73). The median time from SOT to PTLD was 1.8 years (range 0.2–20.9). 1st therapeutic intervention (1st TI) (usually >1) included “complete” resection (4), decreased immunosuppression (51), acyclovir or gancyclovir (32), rituximab (R) (18), “CHOP” chemotherapy (11), radiation therapy (7), and interferon (4). Response to 1st TI was CR (34) or PR (10). The median follow-up among surviving pts is 3.6 years (range 0.1–11.7). 35 (including 4 CHOP and 9 R) pts have died; only 2 CHOP but all 9 R pts died from PTLD. IHC studies in 42 evaluable cases showed the following median # (and range) of cells /10 hpf: CD3 525 (8–2451), TIA1-CTCs 304 (6–1238) and FOXP3 13 (1–338). On univariate analysis, younger age, prior rejection episodes <2, PS <2, LDH normal, extranodal sites (ENS) <2, IPI <4, 1st TI >1, 1st TI with CHOP, # of CD3 cells >550/10 hpf, and # of TIA1-CTCs >300/10 hpf were associated with an improved overall survival (OS), PTLD-specific survival (PSS), and/or progression-free survival (PFS). On multivariate analyses, only PS <2, ENS <2, and 1st TI with CHOP remained independent predictors of outcome. Among the subset of 47 pts with monomorphic B-cell (MMBC) PTLD, these same clinical factors were also independently statistically significant.Conclusions: High #s of infiltrating T cells and TIA1-CTCs are associated with a favorable outcome and may reflect a relatively intact local anti-tumor response. Tregs, which may potentially antagonize such a response, are uniformly low and do not correlate with outcome in PTLD. In this analysis, a significant minority of SOT pts treated initially with single agent R still died from PTLD while pts treated initially with CHOP (with or without R) appeared to have a better outcome, arguing for its early use - at least in a subset of pts. Future studies should attempt to identify biological factors that predict which MMBC PTLD pts might benefit from the addition of CHOP to standard R as part of 1st TI.

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+ HLADR+ T cells, combined with a sustained enhancement of CD4+ CD25(+high) lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+ CD25(+high) T cells, which showed donor-Ag specificity. FOXP3+ CD4+ CD25(+high) Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.

Is rituximab (R) the optimal therapeutic intervention (TI) for post-transplant lymphoproliferative disorder (PTLD) following solid organ transplant (SOT)?

8074 Background: PTLD is a rare, often fatal, complication of SOT. Most are derived from CD20+ B-cells. Historically, patients (pts) received a variety of TIs ranging from decreased immunosuppression to chemotherapy (CT). Based on promising initial study results, most pts now receive rituximab (R) without CT as part of 1st TI. Methods: We searched the Cleveland Clinic pathology archives for SOT pts, who were diagnosed with PTLD between 1987 and 2006; reviewed the medical records; extracted clinical information and outcomes; and analyzed the data by Cox proportional univariate and multivariate analyses. Results: We identified 55 SOT pts (heart, 18; lung, 16; kidney 14; liver, 6; pancreas, 1), who were diagnosed with PTLD at median age 47 years (range 7–66). The median time from SOT to PTLD was 1.7 years (range .2–20.9). 1st TI (usually &gt;1) included “complete” resection (4), decreased immunosuppresion (53), acyclovir or ganciclovir (28), interferon (4), radiation therapy (6), CT (12), and/or R (17). Response to 1st TI was CR (30) or PR (10). The median follow-up among surviving pts is 5.0 years (range .1–11.4). 29 (including 5 CT and 5 R) pts have died; only 2 CT but all 5 R pts died from PTLD. On univariate analysis, younger age+, &lt;2 prior rejection episodes+*, PS &lt;2+*, normal LDH+*, &lt;2 extranodal sites+, lower IPI+*, &gt;1 1st TI+, and 1st TI with CT* were associated with an improved overall survival (OS)+ and/or PTLD-specific survival (PSS)*. On multivariate analysis, only PS &lt;2 (HR 0.04 [CI 0.01–0.14], p&lt;0.001) and &gt;1 1st TI (HR 0.43 [CI 0.19–0.97], p=0.041) were associated with improved OS while PS &lt;2 (HR 0.04 [0.01- 0.16], p&lt;0.001) and 1st TI with CT (HR 0.19 [CI 0.04–0.84], p&lt;0.028) were associated with improved PSS. Conclusions: A significant minority of SOT pts that receive R without CT as part of 1st TI still die from PTLD. PS is the most important predictor of outcome. In conjunction with the improved survival observed in de novo B-cell NHL pts treated with R+CT (compared to CT alone), this retrospective analysis suggests that some SOT PTLD pts should receive R+CT as part of 1st TI. No significant financial relationships to disclose.

A comparison of myocardial perfusion and rejection in cardiac transplant patients

Although histological evaluation of the cardiac tissue is the current gold standard for evaluation of rejection, we hypothesized that cardiac perfusion MRI is a safe non-invasive method that correlates tissue blood flow changes with biopsy proven rejection in the cardiac transplant patient. In a retrospective study from 1984-2001, 83 patients underwent 135 MR Gd-DTPA imaging studies. In 8 patients (9%), biopsies graded 2 or higher (by ISHLT criteria) provided evidence of rejection. Patients were age and sex matched to 11 non-rejected controls for imaging analysis. Time-signal intensity curves generated for a mid-ventricle LV short axis slice during rest and adenosine stress allowed determination of myocardial blood flow (MBF, ml/min/gm). ROC curve analysis by SPSS allowed estimation of sensitivity and specificity. At rest, there was no difference in MBF between patients with prior rejection vs. those without (1.18 +/- 0.26 vs. 1.16 +/- 0.29). At stress there was a decrease in MBF for patients with prior rejection episodes (3.27 +/- 0.74) compared to no rejection (3.60 +/- 0.72), P = 0.067). The area under the ROC curve was 0.82, with specificity and sensitivity of 75% and 81%, respectively. This study suggests that perfusion MR imaging can be used in assessing the cardiac transplant patient for rejection related microvascular changes. The high specificity and sensitivity recorded from the ROC curve illustrates the potential utility of this diagnostic test for future studies.

Abnormal Intrahepatic Portal Vasculature in Native and Allograft Liver Biopsies

Abnormal portal vessels in small portal tracts can be seen in association with various causes of portal hypertension, such as noncirrhotic portal hypertension (NCPH) and cirrhosis. Very little has been reported about the presence of abnormal portal vessels in livers with normal portal pressure. Little attention has also been given to the presence of abnormal vessels in liver allografts outside the setting of transplant vasculopathy/chronic rejection. This study reports on the portal vasculature abnormalities, many similar to those described in NCPH, encountered in routine native liver biopsies (n = 46) and allograft liver biopsies (n = 48). A classification scheme for the abnormal portal vasculature was adapted from the literature, and the portal vessels were divided into five groups (types 0-IV). Abnormal vessels were present in greater than 25% of the portal tracts in 88% of all the biopsies studied; there was no significant difference between the native and allograft biopsies. In the allograft biopsy group, there were correlations between vascular abnormalities and severity of a concurrent acute cellular rejection episode, the presence of prior rejection episodes, and length of time after transplant. Biopsies from patients with viral hepatitis C infection (HCV) showed more type IV lesions (absent or sclerosed portal vessels) with fragmentation when compared with biopsies obtained for other reasons. The number of portal tracts with abnormal portal veins and fragmented vessels correlated positively with increasing fibrosis. This is the first study to demonstrate the presence of abnormal portal vessels, some of the type seen in NCPH, in a significant number of both native and allograft liver biopsies in patients without evidence of portal hypertension. Abnormal portal vasculature tends to be associated with HCV and increased fibrosis, and, within the transplant group, with the severity of rejection, presence of prior rejection episodes, and increased time posttransplantation.