Late Graft Dysfunction Research Articles

Evaluation of Indication Biopsies ≥5 Years After Kidney Transplant: A Single-Center Experience.

Rejection is a common cause of late graft dysfunction seen on biopsy studies. The aim of this study was to evaluate indication biopsy findings ? 5 years after kidney transplant and to assess the effectiveness of applied treatments. Between January 2013 and December 2015, 30 patients who underwent renal transplant indication biopsies and were followed up for ≥ 6 months were evaluated retrospectively. A >30% increase in serum creatinine and/or development of > 1 g/day proteinuria was considered an acceptable indication for biopsy. Of the 156 indication biopsies obtained within a 3-year period, 30 of them were indication biopsies performed ≥ 5 years after transplant. Twenty patients (67%) demonstrated late graft rejection, 6 patients (20%) had recurrent or de novo glomerulonephritis, and 4 patients (13%) were diagnosed with idiopathic chronic allograft nephropathy. The mean total histologic score was 6.2 ± 2.6, and the chronicity rate was 70%. For patients with late rejection, treatment consisted of pulse steroids in 11, intravenous immunoglobulin in 5, plasmapheresis in 4, antithymocyte globulin in 3, and rituximab in 2 cases. Five patients with glomerulonephritis received pulse steroids, 1 received rituximab therapy, and 3 were treated with cyclophosphamide. The mean follow-up after indication biopsy was 16 ± 11 months. Eleven patients (37%) had a progressive disease course and 7 patients (23%) resumed hemodialysis. Of the 30 patients, the 15 whose glomerular filtration rate was < 30 mL/min/1.72 m² at biopsy were more likely to have a progressive disease course (53% vs. 20%; P = .05) and more commonly resumed dialysis (40% vs. 7%; P = .03). Rejection was the most common cause of graft dysfunction long term. Chronic histologic changes predominated in indication biopsies ≥ 5 years posttransplant. Regardless of diagnosis, a low glomerular filtration rate at biopsy was closely associated with poor renal outcomes.

Impact of Antibodies That React With Liver Tissue and Donor-Specific Anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis.

BackgroundThe cause of late graft dysfunction has not been elucidated. Although an antibody-mediated reaction is suspected as a potential mechanism, the target antigens have not been clarified.MethodsTo clarify the etiology of idiopathic posttransplantation hepatitis (IPTH), we simultaneously examined the presence of antibodies that react with liver tissue (ARLT) by means of indirect immunofluorescence staining, as well as the presence of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA). A subanalysis of the IPTH group was also performed. Within the IPTH group, the correlation between ARLT titer and clinical data were analyzed.ResultsIn the sera of patients with IPTH (30 patients), ARLT were found at a significantly higher frequency than in patients without IPTH (42 patients; P < 0.001). Moreover, the ARLT titer appeared to be correlated with the severity of hepatitis or hepatic injury. In contrast, the frequency of HLA-DSA was significantly lower in patients with IPTH than in patients without IPTH (P = 0.001).ConclusionOur findings indicate that ARLT, and not HLA-DSA, profoundly influence the etiology of IPTH.

Histology Utility in Liver Graft Surveillance: What About Normal Liver Tests?

In liver transplantation, late graft dysfunction can have several causes, particularly rejection, infection, vascular, biliary complications, and others, usually suspected by abnormal liver tests. However, normal liver tests do not confirm a normal graft and liver biopsy could identify unexpected features with repercussions in immunosuppressive therapy. The aim of this study was to determinate the histological abnormalities in patients 10 years after liver allograft transplantation with sustainably normal liver tests and evaluate the changes in immunosuppressive therapy triggered by histological data. A retrospective analysis of liver allograft recipients was performed in an adult liver transplantation center with graft histological characterization 10 years after transplantation. Patients with abnormal liver tests and retransplantation were excluded. We evaluated 39 patients with repeatedly normal liver tests. Familial amyloid polyneuropathy (n= 27) was the mainly indication for liver transplantation. Allograft histological dysfunction was observed in 13 (21.7%) patients. In 3 patients we observed chronic hepatitis, signs of cellular rejection in another 3 patients, and histological features suggesting autoimmune hepatitis in 7 patients. The diagnosis of de novo autoimmune hepatitis was proposed according to contemporaneous positive autoantibodies. Changes in immunosuppressive treatment were proposed in 7 patients. Allograft histological dysfunctions 10 years after liver transplantation were observed in 21.7% of patients despite normal liver tests. Although the histological features led to alterations of immunosuppressive therapy in half of the cases, the absence of enzymatic tests changes makes monitoring a challenging process.

The effect of timing and graft dysfunction on survival and cardiac allograft vasculopathy in antibody-mediated rejection

Antibody-mediated rejection (AMR) has been associated with increased death and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction, whereas recent reports have demonstrated an association with increased mortality. We investigated the timing of AMR and its association with graft dysfunction, death, and CAV. This retrospective cohort study identified all adult orthotopic heart transplant (OHT) recipients (N = 689) at Columbia University Medical Center from 2004 to 2013. There were 68 primary cases of AMR, which were stratified by early (< 1 year post-OHT) or late (> 1 year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. From January 1, 2004, through October 1, 2015, early AMR (median 23 days post-OHT) occurred in 43 patients and late AMR (median 1,084 days post-OHT) occurred in 25. Graft dysfunction was less common with early compared with late AMR (25.6% vs 56%, p = 0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1 year: 80% vs 93%, 5 years: 51% vs 73%, p < 0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30 days: 79%, 1 year: 64%, 5 years: 36%; p < 0.006). The association remained irrespective of age, sex, donor-specific antibodies, left ventricular assist device use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de novo CAV (50% at 1 year; hazard ratio, 5.42; p = 0.009), whereas all other groups were all similar to the general transplant population. Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR, there is an early and sustained increased risk of death and rapid development of de novo CAV despite aggressive treatment.

The Prognostic Value of Late Kidney Transplant Rejection Pathology Characteristics

Renal allograft rejection, represented by the wide spectrum of lesions with different pathogenesis, pathology patterns, clinical course and prognosis, still remains the most often cause of late graft dysfunction. Moreover, a combination of several factors, either of which may impact the post-transplant course, generally take place. We aimed to analyze the incidence of late renal allograft rejection variants, and to determine clinical factors and pathology features, influencing prognosis in the specific types of late renal allograft rejection. The data obtained from 361 patients with acute (n=227) or chronic (n=134) late allograft rejection (mean time after kidney transplantation 48.8 ± 46.1 months) were analyzed retrospectively. C4d expression was found in 34% cases of acute rejection and in 58% cases of chronic rejection (64% in chronic transplant glomerulopathy and 52% in transplant vasculopathy). 5-year graft survival comprised 48% and 24% for acute and chronic transplant rejection respectively (Р<0.01). Combination of acute cell-mediated rejection with chronic transplant rejection did not influence significantly the prognosis for the latter. Diffuse C4d expression on peritubular capillaries turned to be an independent prognostic factor regardless the pathology variant of renal allograft rejection. In contrast, focal C4d expression had no impact on the prognosis, which did not differ significantly from C4d-negative type. On the other hand, in acute rejection prognosis for C4dpositive forms was worse compared to C4d-negative (55% vs 25%; P <0.01), while in chronic rejection there was no difference between C4d-positive and C4d-negative forms (26% vs 24%; P=NS). In multivariate Cox-model analysis, the following factors appeared to influence the prognosis: presence of chronic transplant glomerulopathy, features of vasculitis, severity of tubulitis, presence of thrombotic micrioangiopathy and prominence of interstitial fibrosis.

Chronische Abstoßung

In this paper, chronic rejections after transplantation of the lungs, heart, liver, and kidney are described. Chronic allograft dysfunction (CAD) plays an important role in all of these transplantations and has a significant influence on patient survival. The pathophysiological reasons for CAD varies greatly in the various organs.Chronic lung allograft dysfunction (CLAD) is the most important determinant of survival and quality of life after lung transplantation. Diagnosis is based on lung function, especially forced expiratory flow in 1 s (FEV1) decline. Prevention, early detection, and rapid treatment are extremely important. Azithromycin and extracorporeal photopheresis are commonly used for treatment because they usually positively influence the progression of lung remodeling.The expression for chronic rejection of the heart is cardiac allograft vasculopathy (CAV). Immunological and nonimmunological factors are important for its development. Due to limited therapeutic options, prevention is of utmost importance (administration of mTOR inhibitors and minimizing cardiovascular risk factors).The mid- and long-term survival rates after liver transplantation have hardly changed in recent decades, which is an indication of the difficulty in diagnosing chronic graft dysfunction. Chronic ductopenic rejection accounts for a small proportion of late graft dysfunction. Idiopathic posttransplant hepatitis and de novo autoimmune hepatitis are important in addition to recurrence of the underlying disease that led to transplantation.Chronic allograft nephropathy is the result of severe rejection which cumulates in increasing fibrosis with remodeling. The earliest possible diagnosis and therapy is currently the only option. Diagnosis is based on evidence of donor-specific antibodies and histological findings.

Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody-Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients.

Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

Influence of Selected Factors on Long-Term Kidney Graft Survival—A Multivariable Analysis

BackgroundLong-term function of transplanted kidney is the factor determining quality of life for transplant recipients. The aim of this study was to evaluate the effect of selected factors on time of graft function after renal transplantation within 15 years of observation. MethodsPreoperative and intraoperative factors were analyzed in 232 kidney recipients within a 15-year observation period. Analysis included age, sex, cause of recipient's renal failure, length of hemodialyses before transplantation, peak panel reactive antibodies test, human leukocyte antigen compatibility, cold ischemia time, delayed graft function occurrence, length and time of hemodialyses after transplantation, early graft rejection, creatinine level at days 1, 3, 7, 30, 90, and 180 after transplantation, and influence of these factors on the time of graft function. Statistical analysis was performed with the use of univariate and multivariate Kaplan-Meier test and Cox regression proportional hazards model, with P < .05 considered to be significant. ResultsUnivariate analysis showed significantly shorter renal graft function in the group of recipients with higher creatinine levels in all of the analyzed time periods and in patients experiencing delayed graft function. Length of time of hemodialyses after transplantation and number of dialyses had significant impact on worsening of late transplant results. Multivariate analysis reported that early graft rejection in the postoperative period is an independent factor improving late graft function: P = .002; hazard ratio (HR), 0.49 (95% confidence interval [CI], 0.31–0.78). Higher creatinine level at day 90 after kidney transplantation is a predictive factor of late graft dysfunction: P = .002; HR, 1.68 (95% CI 1.2–2.35). ConclusionsCreatinine level at day 90 after renal transplantation is the prognostic factor of long-term kidney function. Early transplant rejection leads to introduction of more aggressive immunosuppression protocol, which improves long-term transplant results.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Chronic Renal Allograft Dysfunction Antibody-Mediated: An Update

This paper reviews the most important studies on chronic antibody-mediated rejection (cABMR), which is an important cause of late graft dysfunction after renal transplantation. Several antibodies seem to be responsible for chronic rejection; new techniques have allowed us to identify these antibodies in circulation. The pathogenetic role of the antibodies generally includes the complement pathway, but may also be complement-independent. This paper also examines the pathogenesis of chronic endothelial lesions, as well as the histopathological aspects. Antibodies responsible for chronic rejection may preexist before transplantation or may develop after transplantation. The possible therapeutic approaches are poor and principally based on early identification and desensitisation techniques. New B cell targeting drugs are aimed at an improved control of the relevant condition.

CMV Drives Expansion of Cytotoxic CD4+CD27nullCD28null T Cells in Renal Transplant Recipients Resulting in NKG2D Dependent Endothelial Stress, Apoptosis and Late Graft Dysfunction.

CMV Drives Expansion of Cytotoxic CD4+CD27nullCD28null T Cells in Renal Transplant Recipients Resulting in NKG2D Dependent Endothelial Stress, Apoptosis and Late Graft Dysfunction.

Prospective Randomized Study of Low Level CNI vs SRL @ 6 Mos Posttx, While Pred (P)-Free.

Late posttx kidney graft dysfunction has been attributed to CNI toxicity. We studied late (>6 mos) low level CNI vs conversion to sirolimus (SRL) in recipients on a rapid discontinuation of P (RDP) protocol (Ab, CNI, MMF, P stopped at 6 days postop). 532 1st and 2nd tx recipients (325 LD; 207 DD) on RDP were randomized to CSA (n= 271) (targeted levels, Table 1) vs TAC (n=261). Exclusion criteria: simultaneous or previous extra-renal tx; DSA).Table 1: Targeted LevelsAt 6 mos posttx, each grp was re-randomized to low level CNI (levels, Table 1) vs SRL. Exclusion criteria: >1 AR; AR in mos 5-6; hx of BK; DSA. Recips signed consent for the double randomization pre-tx. We studied post-randomization outcomes.Phase 1 - There was no diff in demographics between groups. At 6 mos posttx, there was no signif diff in patient survival (PS) graft survival (GS), AR-free GS, CMV-free and BK-free survival, NODM, and renal function. Phase 2 - Only 191 of 397 (48%) eligible recipients re-consented at 6 mos (58 CSA; 87 TAC). Major reason for not re-consenting: not willing to be re-randomized. Comparing low level CNI (both CNIs) vs SRL @ 60 mos post re-randomization, there were no significant differences in actuarial outcomes for PS, GS, death-censored GS, AR-free GS, CMV- and BK-free survival, renal function and malignancy rates (Table 2).Table 2: Outcomes (Phase 1)Also, there were no diff in outcomes between each CNI and SRL (data not shown). We conclude: 1) in a study, it is difficult to convert stable tx recipients posttx; only 48%, who consented at tx, re-consented. 2) There were no differences in actuarial 60 month outcomes after randomization to low level CNI vs conversion to SRL. DISCLOSURES:Matas, A.: Grant/Research Support, sanofi, astellas, BMS, Pfizer, Novartis.

Using Markers of Endothelial to Mesenchymal Transition to Detect Endothelial Activation in Kidney Recipients With Antibody Mediated Rejection.

Introduction: Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. The efficacy of treatment depends on an accurate diagnosis at an early stage. Sensitive and reliable markers are still lacking. Methods: Using immunohistochemistry, we retrospectively studied the diagnostic value of endothelial-to-mesenchymal transition (EndMT) markers for ABMR in 53 renal transplant biopsies including 20 ABMR, 24 with cell-mediated rejection and 9 normal grafts. We validated our results in a second independent set of 72 non-selective biopsies. Results: The markers of EndMT were very strongly expressed in the endothelial cells of peritubular capillaries in grafts with ABMR, and absent in normal renal grafts. The level of expression of EndMT markers was significantly associated with current ABMR criteria such as capillaritis (rho=0.6, p<0.0001), glomerulitis (rho=0.5, p=0.0002), peritubular capillary c4d deposition (mean of EndMT score=3.44±0.18 vs 1.8±0.24 for c4d+ for c4d- groups respectively, p=0.0019), but not with T cell mediated rejection Banff scores “i” and “t”. In addition, EndMT markers allowed us to identify ABMR at an early stage (i.e. before any clinical or histological features of ABMR), as well as C4d-negative ABMR. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR, predicting late (up to 4 years post biopsy) renal graft dysfunction (rho=-0.66, p<0.0001) and proteinuria (rho=0.414, p=0.023). A prolonged cold ischemia time and a history of delayed graft function were the main risk factors associated with the occurence of EndMT markers. In the second independent set of 72 renal graft biopsies, the diagnostic value of EndMT markers for ABMR was confirmed and showed a sensitivity of 85.7% and a specificity of 96.7%. Conclusion: EndMT markers are a sensitive and reliable diagnostic tool for ABMR, and predict late allograft function loss.

LATE RENAL GRAFT REJECTION: PATHOLOGY AND PROGNOSIS

Rejection has always been one of the most important cause of late renal graft dysfunction. Aim of the study was to analyze the prevalence of different clinico-pathological variants of rejection that cause late graft dysfunction, and evaluate their impact on long-term outcome. Materials and methods. This is a retrospective study that analyzed 294 needle core biopsy specimens from 265 renal transplant recipients with late (48,8 ± 46,1 months after transplantation) allograft dysfunction caused by late acute rejection (LAR, n = 193) or chronic rejection (CR, n = 78) or both (n = 23). C4d staining was performed by immunofl uorescence (IF) on frozen sections using a standard protocol. Results. Peritubular capillary C4d deposition was identifi ed in 36% samples with acute rejection and in 62% cases of chronic rejection (including 67% cases of transplant glomerulopathy, and 50% – of isolated chronic vasculopathy). 5-year graft survival for LAR vs CR vs their combination was 47, 13 and 25%, respectively. The outcome of C4d– LAR was (p &lt; 0,01) better than of C4d+ acute rejection: at 60 months graft survival for diffuse C4d+ vs C4d − was 33% vs 53%, respectively. In cases of chronic rejection C4d+ vs C4d– it was not statistically signifi cant (34% vs 36%). Conclusion. In long-term allograft biopsy C4d positivity is more haracteristic for chronic rejection than for acute rejection. Only diffuse C4d staining affects the outcome. C4d– positivity is associated with worse allograft survival in cases of late acute rejection, but not in cases of chronic rejection.

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vβ repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8(+) T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vβ diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA(+)CCR7(-)CD27(-)CD28(-)) CD8(+) T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8(+) T cells to secrete TNF-α and IFN-γ. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8(+) T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8(+) T cells may improve the early identification of at-risk patients.

Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase I-II of clinical trials. Thus the pipeline for the near future appears almost empty.

Late Kidney Dysfunction in a Kidney Transplant Recipient

Late kidney transplant dysfunction may be a harbinger of graft failure. For many years, calcineurin inhibitor toxicity was felt to be the main cause for graft dysfunction with fibrosis and transplant loss. Recently this idea has come into question. With the observation that peritubular capillary C4d staining in kidney allografts may indicate antibody-mediated injury in conjunction with biopsy study findings, an appreciation for antibody-mediated rejection as a major cause of late graft dysfunction and loss has emerged. Twenty percent to 30% of patients develop de novo donor-specific antibodies after kidney transplantation. There are no US Food and Drug Administration-approved treatments for antibody-mediated rejection, nor have any randomized controlled trials assessed efficacy. Off-label treatment strategies include some combination of plasma exchange, intravenous immunoglobulin, and rituximab. Other approaches, including splenectomy, bortezomib, and eculizumab, have also been tried.

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Introduction: Chronic allograft nephropathy is the primary cause of late graft dysfunction in the renal transplant population. The causes are multi-factorial including calcineurin inhibitor nephrotoxicity. Calcineurin inhibitors (CNI), such as tacrolimus and cyclosporine are commonly used in solid organ transplant patients to prevent allograft rejection. They contribute to chronic allograft nephropathy and cause nephrotoxicity in all solid organ transplant populations via afferent arteriolar vasoconstriction. Fenoldopam is a dopamine receptor-1 agonist, which causes vasodilatation in the proximal tubule, and theoretically will directly antagonize the deleterious effects of CNI induced renal failure; with in-vitro data to suggest its efficacy in preventing CNI induced renal failure. Methods: A retrospective chart review was performed on transplant patients, in acute renal failure, admitted to the University of Kentucky medical center from 2004- 2011. Our primary objective was to compare changes in renal function values: serum creatinine (Scr) and urine output (UOP) of patients admitted with acute renal failure due to CNI who received either fenoldopam or no drug. Patient data was collected at baseline (time 0) and then for 4 continuous days upon admission (non-fenoldopam group) or at the point of initiation of fenoldopam (time 1) until day 5, or the end of the infusion. Demographic data were analyzed using either a two sample T-test or Mann-Whitney U test, when appropriate. Repeated measures ANOVA with and without adjustment for covariates for the outcomes of Scr and UOP were performed using SAS version 9.3 by SAS Institute (Cary, NC). Results: A total of 87 patients were analyzed (36 non-fenoldopam; 51 fenoldopam). Differences in demographics were significant for a higher SOFA score in the fenoldopam group, (4.8 ± 2.77 vs 2.97 ± 1.68 p=0.0005) After controlling for confounders, the effect of fenoldopam on urine output (UOP) was not statistically significant (p=0.08771) at any time point throughout the infusion time (days 1-4, or end of infusion, day 5) compared to the non-drug group. The non-drug group saw a statistically significant decrease in Scr over the 4 days (-1.0173 ± 0.2143 p= <0.001). The fenoldopam group saw a decrease in Scr from time 1 (start of infusion) over the 4 time points, however this effect did not reach statistical significance (-0.13 ± 0.2 p=0.5194). Conclusions: Although in-vitro data exist to suggest fenoldopam's efficacy in preventing CNI induced renal failure, fenoldopam was not associated with improvement in renal function parameters in this transplant population. As this is the first reported use of fenoldopam for this indication in humans, there is an opportunity for a randomized trial to determine the utility in CNI induced renal failure.

Zurich University Hospital lung transplantation programme: update 2012

Lung transplantation is an established therapeutic option for end-stage lung disease in selected patients. During the last 30 years more than 34,000 transplantations have been performed worldwide. Emphysema, pulmonary fibrosis, cystic fibrosis and primary pulmonary hypertension are the most common indications. This type of surgical treatment is increasingly successful, with better early and late survival rates. However, lung transplantation is still hampered by persisting problems such as donor organ shortage, primary graft dysfunction, late graft dysfunction and morbidity related to long-term immunosuppression. The first lung transplantation in Switzerland was performed the 10th November 1992 at Zurich University Hospital. Since then the lung transplant programme has progressively increased its yearly transplant volume. Since the beginning of our lung transplantation programme, overall patient survival has increased steadily and has been at benchmark levels since the year 2000. The most important factors influencing this result are presumably good teamwork among all involved specialists, improved surgical techniques, and close and long-term patient follow-up by the transplant pulmonologists. In this paper we present our programme structure, managing strategies for some specific problems and outcome after lung transplantation. The results presented here are from recipients who underwent lung transplantation up to the end of 2011.

Epstein-Barr Virus DNAemia Is an Early Surrogate Marker of the Net State of Immunosuppresion in Solid Organ Transplant Recipients

Epstein-Barr virus (EBV) DNAemia (EBVd) may be a surrogate marker of the net state of immunosuppression after solid organ transplantation (SOT). A sample of 81 SOT recipients (53 renal, 21 liver, and 7 cardiac) from our institution (2003-2004) surviving more than 180 days was analyzed. EBVd was monitored in whole blood within the first 6 months using a real-time polymerase chain reaction assay. Using a Cox proportional hazards model, duration and magnitude of EBVd were assessed as potential surrogate markers for the occurrence of late adverse events (>6 months): graft dysfunction, graft loss, death, and immunosuppression-related adverse events (IRAE), defined by the occurrence of solid organ tumor and opportunistic and severe infections. A median of 10 blood samples per patient was screened. A total of 68 (84%) patients had detectable EBVd. Persistent EBVd (>30 days) was found in 40 (49.4%) and high EBVd (>1500 copies/mL) in 35 (43.3%). Multivariate analyses showed that persistent EVBd and high EBVd levels were independently related to the development of IRAE (hazard ratio, 2.95 and 4.32, respectively), whereas no significant associations were observed with late graft dysfunction or graft loss. Persistent and high levels of EBVd within the first 6 months after SOT are surrogate markers of increased risk of IRAE.