Previous Rejection Research Articles

Circulating NK-Cell Subsets in Renal Allograft Recipients With Anti-HLA Donor-Specific Antibodies

Detection of posttransplant donor-specific anti-HLA antibodies (DSA) constitutes a risk factor for kidney allograft loss. Together with complement activation, NK-cell antibody-dependent cell mediated cytotoxicity (ADCC) has been proposed to contribute to the microvascular damage associated to humoral rejection. In the present observational exploratory study, we have tried to find a relationship of circulating donor-specific and non donor-specific anti-HLA antibodies (DSA and HLA non-DSA) with peripheral blood NK-cell subsets and clinical features in 393 renal allograft recipients. Multivariate analysis indicated that retransplantation and pretransplant sensitization were associated with detection of posttransplant DSA. Recipient female gender, DR mismatch and acute rejection were significantly associated with posttransplant DSA compared to HLA non-DSA. In contrast with patients without detectable anti-HLA antibodies, DSA and HLA non-DSA patients displayed lower proportions of NK-cells, associated with increased CD56(bright) and NKG2A(+) subsets, the latter being more marked in DSA cases. These differences appeared unrelated to retransplantation, previous acute rejection or immunosuppressive therapy. Although preliminary and observational in nature, our results suggest that the assessment of the NK-cell immunophenotype may contribute to define signatures of alloreactive humoral responses in renal allograft recipients.

Number of Antihypertensive Drugs at 1 Year After Kidney Transplantation

High blood pressure (BP) affects up to 90% of kidney transplant recipients and is associated with lower patient and graft survival rates. Kidney Disease/Improving Global Outcomes (KDIGO) guidelines suggest maintaining BP at lower than 130/80 mm Hg. Multidrug therapy is usually required for the control of BP in this population. Our aim was to analyze the number of antihypertensive drugs used in our kidney transplantation population at 1 year after transplantation and their influence on graft and patient outcome. We included 411 deceased-donor kidney transplantation cases; data were obtained from a prospectively maintained institutional database. BP was measured at the outpatient clinic. Approximately 97 patients were not under antihypertensive therapy, whereas 130, 119, 52, and 13 received 1, 2, 3, or 4 antihypertensive drugs, respectively. The number of antihypertensive drugs was significantly related to lower patient survival rates independently of a previous diagnosis of hypertension and diabetes, recipient age and sex and renal function at 1-year. After multivariate linear regression analysis high body mass index, male gender of recipients, donor hypertension, previous acute rejection, and cyclosporine therapy were risk factors independently related to a higher number of antihypertensive drugs. To conclude, the number of antihypertensive drugs is an objective and easy-to-measure marker related to lower patient survival rates. Recipient body mass index, type of calcineurin inhibitor, and acute rejection are modifiable risk factors whose control can help to reduce the number of antihypertensive drugs needed to treat high BP in the kidney transplantation population.

Histoplasmosis in Renal Transplant Patients in an Endemic Area at a Reference Hospital in Medellin, Colombia

BackgroundHistoplasmosis is an uncommon systemic fungal infection, but it is potentially fatal in immunosuppressed populations. In Latin America, which is considered an endemic area for this mycosis, there have been no published reports regarding the incidence, clinical presentation, morbidity, and mortality of histoplasmosis in renal transplant patients. The objective of this study was to describe cases of histoplasmosis in renal transplant patients treated at the Pablo Tobon Uribe Hospital (Medellin, Colombia) between 2006 and 2013. MethodsThis is a descriptive, retrospective study. ResultsThe incidence of histoplasmosis in our renal transplant population was 1.1%. The ages of the 9 patients (4 men and 5 women) ranged between 27 and 59 years. In 2 of these patients, histoplasmosis appeared during the first year after transplantation. At the time of transplantation, 66% of patients received induction with alemtuzumab; 88% had a prior rejection episode and required increased immunosuppressive medication; 88% had renal graft dysfunction with creatinine levels >1.5 mg/dL; and the primary clinical presentation was disseminated histoplasmosis followed by the pulmonary form of the disease. Diagnoses were performed by histology in 6 patients, blood culture in 2 patients, and antigenuria in 1 patient. Three patients required treatment with amphotericin B for the severity of their infection, and 2 of these patients died before receiving the cumulative dose of amphotericin B. The 7 remaining patients received itraconazole for 12 months and had a successful treatment response. Regarding complications, 2 patients had hemophagocytic syndrome. At the 1-year follow-up appointment, renal function remained stable in all patients, and no patients had acute rejection or required renal replacement therapy. Thus, the overall mortality rate observed was 22.2%. ConclusionsIn this series, histoplasmosis in renal transplant patients presented as an aggressive opportunistic infection with a higher incidence than that previously reported in the literature. The following risk factors have been associated with histoplasmosis: renal graft dysfunction, previous acute rejection, immunosuppression with tacrolimus-mycophenolate, and induction with alemtuzumab. The clinical presentation of histoplasmosis was nonspecific, which complicated disease diagnosis, and the treatment regimens were highly toxic and associated with significant morbidity and mortality rates.

Cardiovascular MRI Predicts 5-Year Adverse Clinical Outcome in Heart Transplant Recipients

Imaging recommendations for the follow-up of heart transplant recipients (HTRs) lack evidence justifying their prognostic value. Cardiovascular magnetic resonance imaging (CMRI) can characterize heart structure and function and has prognostic value in many myocardial diseases. We hypothesized that CMRI evaluation of cardiac allografts would predict adverse events. We performed CMRI on 60 HTRs evaluating biventricular size, function and myocardial scar. We performed survival analysis to identify independent predictors of cardiovascular (CV) death or hospitalization. Participants had a mean age of 51 ± 14 years, mean graft age of 3.5 years (±4) and 75% are male. Median follow-up time was 4.9 years with 22 CV hospitalizations and 7 CV deaths. A multivariable survival analysis of imaging and clinical variables identified myocardial scar (hazard ratio [HR] of 10.7, p = 0.005), right ventricular end- diastolic volume index (RVEDVI; 1.1/mL/m(2) , p = 0.001), graft age (HR = 1.2/year, p = 0.004) and previous allograft rejection (HR = 4.4, p = 0.006) as predictive of time to CV death or hospitalization. CMRI-derived myocardial scar and RVEDVI are independently associated with CV outcomes in HTRs.

Delayed-Onset Cytomegalovirus Disease Coded During Hospital Readmission After Kidney Transplantation

Use of prophylactic anti-CMV therapy for 3 to 6 months after kidney transplantation can result in delayed-onset CMV disease. We hypothesized that delayed-onset CMV disease (occurring >100 days posttransplant) occurs more commonly than early-onset CMV disease and that it is associated with death. We assembled a retrospective cohort of 15,848 adult kidney transplant recipients using 2004 to 2010 administrative data from the California and Florida Healthcare Cost and Utilization Project State Inpatient Databases. We identified demographic data, comorbidities, CMV disease coded during readmission, and inpatient death. We used multivariate Cox proportional hazards modeling to determine risk factors for delayed-onset CMV disease and inpatient death. Delayed-onset CMV disease was identified in 4.0%, and early-onset CMV disease was identified in 1.2% of the kidney transplant recipients. Risk factors for delayed-onset CMV disease included previous transplant failure or rejection (HR 1.4) and residence in the lowest-income ZIP codes (HR 1.2). Inpatient death was associated with CMV disease occurring 101 to 365 days posttransplant (HR 1.5), CMV disease occurring greater than 365 days posttransplant (HR 2.1), increasing age (by decade: HR 1.5), nonwhite race (HR 1.2), residence in the lowest-income ZIP codes (HR 1.2), transplant failure or rejection (HR 3.2), previous solid organ transplant (HR 1.7), and several comorbidities. These data showed that delayed-onset CMV disease occurred more commonly than early-onset CMV disease and that transplant failure or rejection is a risk factor for delayed-onset CMV disease. Further research should be done to determine if delayed-onset CMV disease is independently associated with death.

High Dose Intravenous Immunoglobulin Therapy for Donor-Specific Antibodies in Kidney Transplant Recipients With Acute and Chronic Graft Dysfunction

Postkidney transplant donor-specific antibodies (DSA) have been identified as important contributors to graft loss. Few therapeutic options exist and have been met with limited success. We report outcomes in patients with de novo DSA and graft damage treated with a protocol of high-dose intravenous immunoglobulin (IVIG). Retrospective analysis of 28 kidney transplant recipients with de novo DSA and graft damage in the form of either chronic graft dysfunction (group 1, n=20) or a recent previous acute antibody-mediated rejection (AMR) episode (group 2, n=8) prescribed a standard regimen of high-dose (5 g/kg) IVIG dosed over 6 months. Mean fluorescence intensity (MFI) of 70 total DSA decreased by 12%at the end of treatment (T1, P=0.14) and by 18%at last follow up (T2, P=0.035) compared with treatment initiation (T0) MFI. The most robust effect was seen in class I DSA (37% decrease at T2 versus T0, P=0.05) and in DSA from patients in group 2 (52% decrease at T2 versus T0, P=0.008). Graft function stabilized in patients in group 2 but continued to decline in those in group 1. High-dose IVIG resulted in modest DSA MFI reductions in patients with previous graft damage, with a larger effect occurring in class I DSA in patients with a previous acute AMR. There was no clinical treatment benefit in patients with ongoing chronic graft damage, whereas high-dose IVIG may reduce the risk of chronic graft dysfunction in those with an acute AMR event.

Outlier detection based on the neural network for tensor estimation

Rationale and objectivesDiffusion weighted imaging (DWI) is always influenced by both thermal noise and spatially/temporally varying artifacts such as subject motion and cardiac pulsation. Motion artifacts are particularly prevalent, especially when scanning an uncooperative population with several disorders. Some motion between acquisitions can be corrected by co-registration approaches. However, automated and accurate motion outlier detection of brain DWIs is an integral component of the analysis and interpretation of tensor estimation. Many different and innovative methods have been proposed to improve upon this technology. In this study, we proposed a classifier work frame, which can classify DWIs as normal images or motion artifacts. Materials and methodsThe procedure contains the following stages: first, we used the wavelet transform to extract features from the original DWIs; second, the principle component analysis was used to reduce the features; third, the forward neural network (FNN) was employed to construct the classifier; fourth, a Rossler-based chaotic particle swarm optimization method was proposed to train the FNN; fifth, the cost matrix was determined as the false negative (FN) which was 10 times larger than the false position (FP); and finally, the K-fold cross validation was chosen to avoid overfitting. We applied this method on 60 DWI datasets, including 50 training datasets and 10 test datasets. ResultsThe experimental results based on our DWI database showed that the proposed method can effectively extract the global feature from images and achieve better performance in tensor estimation by automatic unvoxelwise outlier rejection compared with manual and visual inspection, and previous voxelwise outlier rejection methods. We found that the motion artifact detection accuracy on both the training and test datasets was over 95.8%, while the computation time per DWI slice was only 0.0149s. ConclusionThe proposed method could potentially remove the influence of unexpected motion artifacts in DWI acquisitions and should be applicable to other magnetic resonance imaging.

Efficacy of a reduced pill burden on therapeutic adherence to calcineurin inhibitors in renal transplant recipients: an observational study

PurposeThe aim of this study was to determine the prevalence of nonadherence in a cohort of renal transplant recipients (RTRs) and to evaluate prospectively whether more intense clinical surveillance and reduced pill number enhanced adherence.Patients and methodsThe study was carried out in 310 stable RTRs in whom adherence, life satisfaction, and transplant care were evaluated by specific questionnaires (time 0). The patients under tacrolimus (TAC; bis in die [BID]) were then shifted to once-daily TAC (D-TAC) to reduce their pill burden (Shift group) and were followed up for 6 months to reevaluate the same parameters. Patients on cyclosporin or still on BID-TAC constituted a time-control group.ResultsThe prevalence of nonadherence was 23.5% and was associated with previous rejection episodes (P<0.002), and was inversely related to Life Satisfaction Index, anxiety, and low glomerular filtration rate (minimum P<0.03). Nonadherent patients were significantly less satisfied with their medical care and their relationships with the medical staff. A shift from BID-TAC to D-TAC was performed in 121 patients, and the questionnaires were repeated after 3 and 6 months. In the Shift group, a reduction in pill number was observed (P<0.01), associated with improved adherence after 3 and 6 months (+36%, P<0.05 versus basal), with no change in controls. Decreased TAC trough levels after 3 and 6 months (−9%), despite a slight increase in drug dosage (+6.5%), were observed in the Shift group, with no clinical side effects.ConclusionThe reduced pill burden improves patients’ compliance to calcineurin-inhibitors, but major efforts in preventing nonadherence are needed.

Conversion to mTOR-inhibitor-based immunosuppression: which patients and when?

Mammalian target of rapamycin (mTOR) inhibitors are currently considered an alternative immunosuppressive treatment that can prevent the nephrotoxicity, viral infections and malignancies that are associated with calcineurin inhibitor-based immunosuppressive regimens. However, the side effects of mTOR-inhibitor-based regimens lead to frequent treatment discontinuations, and not all patients seem to have the same benefits from conversion to mTOR inhibitors. This review focuses on long-term results of trials that have assessed early and late conversion to sirolimus or everolimus. The renal benefit of late conversion (≥1 year post transplantation) is limited, except in patients with good renal function and without proteinuria. Early conversion to mTOR inhibitors in the first 6 months, in combination with mycophenolate mofetil, could be an appropriate strategy for maintenance therapy in renal transplant recipients with a low immunological risk after careful screening at the time of conversion. Good renal function (glomerular filtration rate >40 ml/ minute), weak proteinuria (<1 g/day), an absence of previous acute rejection and subclinical rejection, and appearance of donor-specific anti-human leukocyte antigen antibodies appear to be the most important criteria in identifying patients for whom conversion to an mTOR inhibitor may improve renal function at 5 years.

Operational Tolerance in Kidney Transplantation—Improved Terminology May Enable More Precise Investigation

Operational Tolerance in Kidney Transplantation—Improved Terminology May Enable More Precise Investigation

Graft Rejection and Graft Failure After Penetrating Keratoplasty or Posterior Lamellar Keratoplasty for Fuchs Endothelial Dystrophy

To compare the frequency of rejection episodes and graft failure because of surgical complications or rejection after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK) for Fuchs endothelial dystrophy. A total of 201 eyes of 201 consecutive patients with Fuchs endothelial dystrophy undergoing keratoplasty were included. One hundred two patients underwent DSAEK and 99 PK in the period January 1, 2000, to December 31, 2010. Postoperative topical steroid treatment was similar in the 2 groups. Most patients in the PK group received a short course of oral prednisolone, which was not prescribed for patients undergoing DSAEK. Patient records were retrospectively reviewed; rejection episodes and causes of graft failures were recorded, and Kaplan-Meier survival curves up to 5 years after surgery were computed and compared. All rejection episodes and most graft failures occurred during the first 2 years after surgery. In this period, rejection episodes were noted in 16% of PK and in 5% of DSAEK-treated eyes (P = 0.03). During the first 5 years, significantly more DSAEK grafts than PK grafts had failed (P = 0.04) but only 2 PK-treated and no DSAEK-treated grafts failed because of rejection. The frequency of graft rejection episodes is higher after PK than DSAEK for primary endothelial disease, despite the use of oral prednisolone in the PK group. Early graft failure is more common after DSAEK than after PK, whereas graft failure because of previous rejection episodes is uncommon after DSAEK and PK.

하이사이드와 로우사이드 LO 신호를 동시에 적용하는 새로운 이미지 제거 수신기 구조

본 논문에서 높은 주파수 LO 신호와 낮은 주파수 LO신호를 동시에 사용하는 새로운 구조의 이미지 제거 수신기 구조를 제안하였다. 제안된 구조는 기존의 하나의 LO 신호를 사용하는 경우보다 저 잡음 지수 성능과 높은 선형성 특성을 갖는다. 또한 제안된 수신기는 기존의 Weaver 이미지 제거 수신기 구조 보다 같은 이득 error와 위상 error가 존재할 때도 6dB 이상의 높은 이미지 제거 특성을 보인다. 제안된 수신기 구조의 특성을 증명하기 위하여 이득 및 위상 error가 존재할 때의 이미지 제거 특성 공식을 유도하였다. 그리고 이 공식의 유용성을 시스템 시뮬레이션을 통하여 증명하였다. 따라서 높은 이미지 제거 특성 때문에 제안된 새로운 수신기 구조가 이미지 제거 수신기로써 널리 사용이 가능할 것으로 기대한다. In this paper, we propose a new image rejection receiver architecture using simultaneously the high-side and low-side injected LO signals. The proposed architecture has a lower noise figure (NF) performance and a higher linearity characteristic than the previous receiver architecture using a single LO signal. Also, the proposed receiver shows a higher IRR performance about 6dB than that of the previous Weaver image rejection architecture even though the same gain and phase errors between I-path and Q-path exist. To verify these characteristics, we derive an IRR formular of the proposed architecture as a function of mismatch parameters. And we demonstrate its formular's usefulness through the system simulation. Therefore, the proposed architecture will be widely used to implement the image rejection receiver due to its higher IRR performance.

Cholestatic hepatitis C following liver transplantation: An outcome-based histological definition, clinical predictors, and prognosis

Cholestatic hepatitis C virus (HCV) is a rare form of recurrent HCV following liver transplantation (LT) without specific diagnostic criteria. An outcome-based method to improve its diagnosis and a description of its prognosis are needed. All 1-year post-LT protocol liver biopsy samples and biopsy samples initially reported to show cholestatic HCV from patients transplanted with HCV between February 2002 and December 2009 were reviewed for the inflammation grade, the fibrosis stage, and 4 cholestatic HCV features: ductular proliferation, canalicular cholestasis with or without intracellular cholestasis, hepatocyte swelling with or without lobular disarray, and sinusoidal/pericellular fibrosis. We used patient and graft survival to define histological criteria for cholestatic HCV, and compared the clinical features of these patients to those of patients with minimal or significant post-LT fibrosis. One hundred seventy-nine patients were analyzed, the median age was 56 years, and 73% were male. Patients with 3 or more of the 4 cholestatic HCV criteria had significantly worse survival (log-rank P < 0.001) regardless of the fibrosis stage, and this was used as our novel definition of cholestatic HCV. Using this definition, we found that 27 patients (15%) had cholestatic HCV, 53 (30%) had significant fibrosis (stage ≥ 2/4), and 99 (55%) had minimal fibrosis (stage < 2/4). The final model for clinical predictors of cholestatic HCV included donor age [odds ratio (OR) = 1.37 per decade, P = 0.04] and previous rejection (Banff grade ≥ 5; OR = 4.19, P = 0.002). Total bilirubin was the strongest laboratory predictor of cholestatic HCV (area under the curve = 0.93), whereas the HCV viral load was not a significant predictor. The final model of post-LT survival included the pathology group {cholestatic HCV [hazard ratio (HR) = 6.07, P < 0.001] and significant fibrosis (HR = 2.53, P = 0.02)}, donor age (HR = 1.49 per decade, P < 0.001), and cold ischemia time (HR = 1.11 per hour, P = 0.02). In conclusion, we propose diagnostic criteria for cholestatic HCV that include specific criteria (the presence of at least 3 of the 4 histopathological features on biopsy) and other supportive and exclusionary criteria. Older donor age and rejection increase the risk of cholestatic HCV, and an elevation in the total bilirubin level may help to identify these patients. These criteria must be validated prospectively.

Switch from Prograf® to Advagraf® in Kidney Transplantation. Long Term Follow-Up

Introduction: Advagraf is a new modified-release once-daily formulation of tacrolimus. The aim of this study was to define the efficacy and safety of switching from Prograf to Advagraf immunosuppression in kidney transplant recipients. Methods: Forty-one patients (34 men, 7 women, mean age: 43.9±12.7 years), all treated with Prograf and mycophenolic acid (except one patient in Prograf monotherapy) were switched at 36.6 ± 16.1 months after kidney transplantation; 27 of them were treated also with steroids. The switched dose ratio of Prograf to Advagraf was 1:1. We evaluated the dose, the tacrolimus blood levels and renal function at 1, 3, 6, 12, 24 and 30 months from the switch. Results: The average follow-up from the switch was 32±6 months. Blood levels of tacrolimus showed a statistic significant reduction in the first three months post-conversion (average from the baseline 6.9 ng/ml to 3 months 4.7 ng/ml - p=0.0001) and then regularized at month 12. In our report the drug dose was increased from the third month after the switch to month 6, in order to reach adequate blood levels. The creatinine values remained stable throughout the follow-up. In none of the 14 steroid-free patients at the time of the switch was necessary to switch back to steroids. Regarding the subgroup of patients treated with steroids (n=27), in 19 cases it was possible to discontinue steroids at the time of stabilization of Advagraf dose (11.5±5.2 months after the switch), without worsening of renal function. One patient presented dizzines and tinnitus after the switch, requiring the reintroduction of Prograf; one other patient who had two previous acute rejection episodes, had a new acute rejection on chronic rejection after 8 months from the switch; likewise a second patient, with a previous acute rejection episode, had a new acute rejection after 10 months from the switch. Conclusion: Conversion from Prograf to Advagraf in a 1:1 ratio results in a significant reduction in tacrolimus blood levels at months 3 and 6 which requires an adjustment of the dose. The switch to Advagraf is safe in low-risk patients and also in patients on maintenance therapy without steroids. Moreover steroids suspension is feasible and safe after the switch to Advagraf when patients achieve adequate tacrolimus blood levels. Finally in patients with previous acute rejection episodes or in high risk patients, it is recommended a close follow up in order to rapidly achieve adequate and stable drug blood levels with Advagraf.

Conversion from Tacrolimus (TAC) to Sirolimus(SRL)-Based Immunosuppressive Regimen in Kidney Transplant Recipients: 1 Year Results

Introduction: This multicenter prospective study evaluates renal function of kidney transplant recipients who underwent planned conversion from TAC to SRL-based regimen 3 months after transplantation. Methods: Low risk recipients of first kidney transplant receiving TAC, mycophenolate sodium (MPS) and prednisone showing good renal function, no proteinuria and no previous severe acute rejection at 3 months were randomized after the transplant surgery to be converted from TAC to SRL. The primary outcome is calculated glomerular filtration rate (cGFR, Cockroft-Gault) at 24 months using intention-to-treat analysis. Here we show results observed at 12 months. Results: Of 296 patients enrolled in this study and reaching 12 months, 277 were randomized to be converted to SRL (n=136) or to stay on TAC (n=141). The mean age of this population was 45.0 ± 13.3 years; 55.4% caucasian, 70.9 % male and 46.4% RKT from deceased donor. During the first 3 months 14 (5%) patients discontinued the study. Of 263 patients reaching month 3, 58 (22%) did not meet criteria for intervention, 110 were converted to SRL and 95 were maintained on TAC. At 3 months, TAC mean trough blood concentration was 7.1 ng/mL, mean MPS dose was 1349.3±244.4 mg/day and mean prednisone dose 8.0±4.9 mg/day. No differences were observed in mean cGFR at 3 months (64.4±19.8 and 66.2±19.5 ml/min) and 12 months (74.8±25.7 vs. 70.2±19.1 ml/min), respectively. The incidence of biopsy proven acute rejection (BCAR) was comparable at 3 months (15% vs. 17%), but higher in patients on SRL (5.2% vs. 1.8%) between 3 and 12 months. At month 12, patients receiving SRL showed mean trough blood concentrations of 8.5±3.1 ng/ mL and mean MPS dose of 1316.8±234.8 mg/day while patients receiving TAC showed mean trough blood concentration of 5.8±2.7ng/mL and mean MPS dose of 1365.2 ± 213.3 mg/day. There were no differences in the incidence of treatment discontinuation (7.4% vs. 5.4%), graft loss (1.1% vs. 0.9%) or death (0.9% vs. 1.8%), respectively. Conclusions: This preliminary analysis indicates that 78% of KTR reaching 3 months fulfilled the criteria to undergo conversion from TAC to SRL. Conversion was associated with increased risk of acute rejection, comparable tolerability but no difference in cGFR at 12 months compared to patients maintained on TAC.

Impact of Early Conversion From Tacrolimus to Sirolimus on Chronic Allograft Changes in Kidney Recipients on Rapid Steroid Withdrawal

Calcineurin-inhibitor therapy is a contributing factor to the origin of interstitial fibrosis and tubular atrophy (IFTA). We conducted a prospective randomized trial of conversion of tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal. We compared the chronic changes (IFTA and sum of Banff chronic scores--Total Score) on protocol biopsies at 1 month, 1 year, and 2 years in all randomized patients. We compared the outcomes between treatment groups and analyzed the impact of previous rejection on the chronic changes. We randomized 122 patients, 62 to sirolimus and 60 to tacrolimus. The 1-year biopsy was performed in 54 patients (90%) of the tacrolimus group and 56 patients (90%) of the sirolimus group. The proportion of biopsies with IFTA more than or equal to 2 and the Total Score more than 2 increased over the 2 years but were not different between the study groups at any time point. On the 1-year biopsy, there was more IFTA, and the fraction with Total Score more than 2 was higher in the tacrolimus group with previous rejection. In the cohort without rejection, there was a significant progression of the IFTA and Total Score between 1 and 2 years in both the sirolimus and tacrolimus groups. Conversion from tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal does not decrease the progression of chronic changes on protocol biopsies during the first 2 years even in those patients without previous acute rejection.

Changes of Progesterone-Induced Blocking Factor in Patients After Kidney Transplantation

The prediction of graft rejection can play an important part in graft survival. Analysis of immune reactions has shown that graft rejection shares mechanisms with recurrent abortions during pregnancy. Progesterone-induced blocking factor (PIBF), a mediator of progesterone that blocks natural killer cell activity in peripheral blood, produces antiabortive effects. The aim of this study was to examine the PIBF concentration in the urine of transplanted recipients. The study included 116 white adults (70 men and 46 women) of median age 49.3 years, who had undergone kidney transplantations. The median duration after transplantation was 3.46 years. The average period between renal disease and our measurement was 12.3 years, and the median interval between graft rejection and our study was 1.75 years. Urine samples were used to measure PIBF concentrations by an enzyme-linked immunsorbent assay. PIBF urinary concentrations decreased significantly in patients who experienced ≥1 rejection episode (31.8 ± 2.2 ng/mL) compared with those without any episode (22.7 ± 1.2 ng/ml; P < .01). Moreover, the urinary PIBF level was significantly lower among patients who had increased creatinine and urea nitrogen levels in blood samples ( P < .05 and P < .01, respectively). Decreased PIBF values in kidney transplant patients followed previous rejection episodes. A close negative correlation was observed between urinary PIBF concentrations and blood levels of creatinine and urea nitrogen. These findings suggested that PIBF detection may predict graft rejection in transplant recipients.

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Novel therapeutic strategies for the induction of tolerance in cornea transplantation

AbstractPurpose With more than 60,000 procedures per year, the cornea is the most commonly transplanted solid tissue. However, immunologic rejection is still the leading cause of corneal allograft failure, especially in high‐risk recipients with a history of previous graft rejection, inflammation or neovascularization. Therefore, novel treatment protocols are desirable.Methods The genetic engineering of tissues prior to transplantation is an attractive approach to protect the graft from allogeneic rejection. Here the role of lentivirus mediated overexpression of Programmed Death‐Ligand 1 (PD‐L1) to prevent corneal graft rejection will be discussed. Moreover the injection of regulatory cell populations to modulate immune‐mediated rejection will be discussed in this presentation.Results Overexpression of PD‐L1 in ex‐vivo cultured corneas prior to transplantation significantly prevents corneal allograft rejection by modulating both innate and adaptive intragraft allo‐immune responses. Moreover, injection of regulatory cells is able to prolong corneal allograft survival.Conclusion Local overexpression of immunomodulatory molecules is a promising approach to prevent corneal graft rejection. In addition treatment of transplanted animals with regulatory cells also modulates graft rejection. These novel therapies may have the potential to be further developed towards a clinical application. [Supported by Science Foundation of Ireland (SFI 07/IN.1/B925). TR is supported by a Travel Grant from Millennium Research Funds, National University of Ireland, Galway]

Editorial

The OES Conferences have produced collections of state-ofthe- technology papers that could transition to full-fledged peerreviewed articles or technical communications in the JOURNAL. To facilitate this process, in 2010, I have launched an initiative to encourage authors of meritorious papers presented at OES Conferences to submit their work for peer review and publication in the JOURNAL. The JOURNAL is experiencing an increasing number of ethics problems such as simultaneous submission of papers to multiple Journals, republication of papers, and plagiarism. These offenses are serious. The policy is quite clear. One can avoid the appearance of impropriety simply by informing the Editor of previous publication or rejection of the paper. The Editor can thus decide whether the paper should be considered for peer review and any misunderstanding can be avoided. Also, it is the responsibility of the authors to determine whether proprietary or classified restrictions apply, and to obtain prior consent. The strength of our JOURNAL rests on the quality of the papers submitted, the quality of the peer review, and the diligent efforts of our Associate Editors.