Rejection Episodes In Patients Research Articles

P2.03: Dynamic Kidney Rejection Risk Prediction Using Serial Donor Derived Cell Free DNA.

Background: Donor-derived cell free DNA (ddcfDNA) has evolved as a non-invasive biomarker for monitoring kidney transplant patients for rejection. Trends in ddcfDNA over time may help predict important outcomes for the allograft. We examined samples from subjects enrolled in the CTOT08 clinical trial (NCT01289717) to determine the ability of joint modeling to dynamically predict rejection episodes (clinical and subclinical) in kidney transplant recipients. Methods: Serial blood samples collected in the first two years post-transplant were analyzed for ddcfDNA using the TRAC test (Eurofins – Viracor, Lees Summit, MO). We used the joint modeling method to model the trend of serial ddcfDNA scores to predict the 2-year rejection-free probability. We pre-defined 4 time points post-transplant and dynamically plotted two illustrative patient’s 2-year event-free probability via the joint modeling method. Results: The figures depicting the predicted event-free probability are presented as below. The two patients have very similar predicted 2-year event-free probability based on their serial TRAC score up to 0.17-years post transplant. Moving forward in time, the predicted probability starts to diverge for these two patients. One patient has stable ddcfDNA scores below 0.5% up to year 0.75. The patient’s predicted 2-year event-free probability increases over time. At 0.5-year post transplant, the predicted event-free probability is 0.621 [0.503, 0.737]. While for the other patient, their ddcfDNA score is relatively high and continues to increase. The second patient has a lower 2-year event-free probability. At 0.5-year post transplant, the predicted event-free probability is 0.548 [0.360, 0.702]. The second patient went on to have a rejection episode at 0.86 months post-transplant. Discussion: Plasma ddcfDNA is evolving as both a diagnostic and a prognostic biomarker in the management of kidney transplant recipients. Using joint modeling, we were able to develop a dynamic risk prediction model for future rejection episodes in patients. Future applications include further validation and eventually defined interventions such as immunosuppression titration to reduce the risk of future rejection episodes.

11-year experience of kidney retransplantation in elderly recipients in Sklifosovsky Research Institute for Emergency Medicine

Introduction. In spite of improvements in quality of life and lifetime of kidney transplant recipients the limited time of kidney transplant survival dictate the need for returning back to dialysis or repeat kidney transplantation. In respect that the need of repeat kidney transplantation usually observed in elderly recipients we attach importance in the analysis of outcomes of kidney retransplantation in patients over 60-s. Aim: to analyse the early outcomes of kidney re-transplantations in middle-aged and elderly recipients. Material and methods : the retrospective analysis of outcomes of 124 repeat kidney transplantations was made (16 transplantations in elderly recipients -Group I; 108 transplantations in recipients aged 20-59 yrs - Group II). The recovery of kidney transplants, acute rejection rates, the causes and the rate of kidney transplant dysfunction and failure, early patient’s and kidney transplant’ survival rates were analyzed. We used clinical, laboratory, histological and instrumental diagnostics. Results : in both groups there were no differences in kidney transplant recovery rates (p = 0,546), kidney transplant function (normal function 81,2% vs 86,1%, dysfunction 6,3% vs 4,3%, graft failure 12,5% vs 9,3% (p = 0,876), recipient 100% vs 99,1% (p = 0,34) and graft survival rates 87,5% vs 90,7% (p = 0,30). There were no episodes of acute rejection in patients of group I (0% vs 30,6% (p = 0,006). The reason of graft failure in group I - the graft’s pathology (nephroangiosclerosis (12,5%), group II - intractable acute rejection (4,6%), graft’s pathology (3,7%), patient’s death with functioning graft (0,9%). Conclusion: there were similar recipient and graft survival rates in both groups. We observed lower acute rejection rate in patients of group I using sufficient immunosuppressive regimens.

Liver transplantation for critically Ill patients with secondary sclerosing cholangitis: Outcome and complications.

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a destructive cholangiopathy with a poor prognosis. Liver transplantation (LT) is an established therapeutic option in end-stage liver disease but is insufficiently evaluated in patients with SSC-CIP. Our aim was the retrospective analysis of the outcome and complications of patients with SSC-CIP undergoing LT between 2002 and 2012. Demographic characteristics, laboratory, transplantation, and follow-up data were compared to sex- and age-matched patients undergoing LT because of other reasons. Quality of life (QoL) before and after LT was assessed in a retrospective telephone interview. LT was performed in 21 patients with SSC-CIP. The main causes for intensive care unit admission comprised cardiothoracic surgery interventions (10/21, 48%), polytrauma (6/21, 29%), and pneumonia (3/21, 14%). Median follow-up period after LT was 82 months (interquartile range [IQR], 37-129) for patients with SSC-CIP and 83 months (IQR, 55-104) for control patients. Biopsy-proven rejection episodes in patients with SSC-CIP (4/21, 19%) were similar compared to control patients (12/60, 20%; P = 0.93). Cytomegalovirus infections were equal in both groups (10/21, 48% versus 25/60, 42%; P = 0.64). The 1-, 3-, and 5-year survival rates of patients with SSC-CIP versus control patients were 100% versus 98%, 86% versus 92%, and 76% versus 87%, respectively (P > 0.05). The QoL improved significantly after LT in SSC-CIP. In conclusion, LT is a valid option for patients with SSC-CIP with excellent long-term outcome and improvement of QoL.

Strain and strain rate imaging using speckle tracking in acute allograft rejection in children with heart transplantation.

Acute allograft rejection is a major cause of morbidity and mortality following heart transplantation. There is no reliable noninvasive test to diagnose rejection. We aimed to investigate the accuracy of strain by speckle tracking echocardiography in the detection of acute rejection. We identified acute rejection episodes in patients followed at a single transplant center. Data were collected at baseline, during rejection and two follow-up points. Peak systolic radial and circumferential strain at the level of papillary muscles and peak systolic longitudinal strain from apical four-chamber view were analyzed offline. ANOVA was used for comparison between groups. p value ≤0.05 was considered significant. Fifteen rejection episodes were identified. There were no differences in the fractional shortening, LV posterior wall thickness, E/A, septal E/E', septal S', lateral E/E', lateral S', or MPI during rejection, compared to baseline. There was a significant increase in the LV mass during a rejection episode (47.5 vs. 34.4 g/ht(2.7) [p = 0.03]). The peak systolic radial strain (18.3 vs. 26.5; p = 0.03), longitudinal strain (-11.7 vs. -14.6; p = 0.05), and circumferential strain (-14.4 vs. -21.7; p = 0.05) declined significantly during rejection. In conclusion, peak systolic radial, longitudinal and circumferential strain decline and LV mass increases during an episode of rejection.

Clinicopathologic study on complications of orthotopic liver transplantation in 54 patients with chronic hepatitis B viral infection.

To study the complication incidence of 54 patients with chronic HBV infection following orthotopic liver transplantation (OLT) and risk factors associated with HBV recurrence and hepatocellular carcinoma (HCC) recurrence or metastasis post-OLT. The light-microscopic appearance of hepatic allograft biopsies in 54 patients with chronic HBV infection following OLT was examined. The related clinical data were analyzed. The incidence and occurrence time of post-OLT complications were studied. Furthermore, the relationship between hepatitis B virus recurrence and acute rejection and the relationship among HCC recurrence/metastasis, acute rejection, tumor diameter, and portal vein invasion were particularly studied. Frequent complications of patients with chronic HBV infection following OLT were acute rejection [38 (70.4%); occurrence time: 5-365 days], chronic rejection [1 (1.9%); occurrence time: 10.7months], bile duct complications [24 (44.4%);occurrence time: 7-940days], HBV recurrence [7 (13.0%); occurrence time: 1-540days], HCV infection [3 (5.6%); occurrence time: 60days, 60days, 33months], CMV infection [8 (14.8%); occurrence time: 67-90days], and HCC recurrence or metastasis [17 (31.5%); occurrence time: 2-41months]. At the end of 1year post-OLT, 95% of patients with post-hepatitis B cirrhosis were alive. At the end of 3years post-OLT, 85% of patients with post-hepatitis B cirrhosis were alive. However, at the end of 1year post-OLT, 67.6% of patients with post-hepatitis B HCC were alive. At the end of 3years post-OLT, 50% of patients with post-hepatitis B HCC were alive. The number of acute rejection episodes in patients with recurrent HBV infection and in those without recurrent HBV infection was 0.86±1.46 times/patient and 1.07±0.90 times/patient, respectively (p>0.05); the number of moderate acute rejection episodes (RAI score ≥4) in patients with recurrent HBV infection and in those without recurrent HBV infection was 0.29±0.49 times/patient and 0.50±0.63 times/patient (p>0.05). Incidence of patients with ≥3 episodes of acute rejection in patient with recurrent HBV infection and in those without recurrent HBV infection was 14.3 and 10.6% (p>0.05). Furthermore, the number of acute rejection episodes in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 1.12±0.93 times/patient and 1.06±1.39 times/patient, respectively (p>0.05). The number of moderate acute rejection episodes (RAI score ≥4) in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 0.65±0.79 times/patient and 0.65±1.06 times/patient, respectively (p>0.05). Incidence of patients with ≥3 episodes of acute rejection in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 5.9 and 17.6%, respectively (p>0.05). The tumor diameter in patients with HCC recurrence or metastasis was 6.72±3.40 cm; however, that in patients without HCC recurrence or metastasis was 3.55±2.17 cm (p=0.0047). The incidence of portal vein invasion in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 68.75 and 33.3%, respectively (p=0.006). There was no significant difference between HBV recurrence and acute rejection post-liver transplantation in patients with chronic HBV infection. There was no significant difference between HCC recurrence and acute rejection. The tumor diameter in patients with HCC recurrence or metastasis was significantly greater than that in patients with no HCC recurrence or metastasis. Portal vein invasion was significantly more frequent in patients with HCC recurrence or metastasis than in those with no HCC recurrence or metastasis.

Belatacept in kidney transplantation

In June 2011 the US Food and Drug Administration approved belatacept (Nulojix; Bristol-Myers Squibb, Princeton, New Jersey, USA) for the prophylaxis of organ rejection in adult kidney transplant recipients. This review will discuss the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase 3 trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Overall, there seemed to be an improvement in cardiometabolic parameters in patients treated with belatacept compared with cyclosporine. There was a trend toward higher rates of early rejection episodes in patients treated with belatacept. One safety issue that must be considered when using belatacept is the potential for increased risk of posttransplant lymphoproliferative disease, especially in Epstein-Barr virus-seronegative recipients or patients treated with lymphocyte-depleting agents. Belatacept is the first new agent available in kidney transplant that may achieve the goal of improved long-term renal function.

Risk of Corneal Transplant Rejection Significantly Reduced with Descemet's Membrane Endothelial Keratoplasty

To evaluate the relative risk of immunologic rejection episode in patients who underwent Descemet's membrane endothelial keratoplasty (DMEK), Descemet's stripping endothelial keratoplasty (DSEK), and penetrating keratoplasty (PK). Comparative case series. One hundred forty-one eyes treated with DMEK at Price Vision Group, Indianapolis, Indiana. The patients in the DMEK group were compared retrospectively with cohorts of DSEK (n = 598) and PK (n = 30) patients treated at the same center, with similar demographics, follow-up duration, and indications for surgery. The postoperative steroid regimen and rejection criteria were identical in the 3 groups. Kaplan-Meier survival analysis, which takes varying length of follow-up into consideration, was performed to determine the cumulative probability of a rejection episode 1 and 2 years after surgery. Proportional hazards analysis was used to determine the relative risk of rejection episodes between the 3 groups. P<0.05 was considered significant and calculated using the log-rank test. Rejection-free survival and cumulative probability of a rejection episode. The mean recipient age was 66 years (56% females and 94% Caucasian) and median follow-up duration was 13 months (range, 3-40) in the DMEK group. Fuchs' dystrophy was the most common indication for surgery (n = 127; 90%) followed by pseudophakic bullous keratopathy (n = 4; 4%) and regrafts (n = 9; 6.4%). Only 1 patient (0.7%) had a documented rejection episode in the DMEK group compared with 54 (9%) in the DSEK and 5 (17%) in the PK group. The Kaplan-Meier cumulative probability of a rejection episode at 1 and 2 years was 1% and 1%, respectively, for DMEK; 8% and 12%, respectively, for DSEK; and 14% and 18%, respectively, for PK. This was a highly significant difference (P = 0.004). The DMEK eyes had a 15 times lesser risk of experiencing a rejection episode than DSEK eyes (95% confidence limit [CL], 2.0-111; P = 0.008) and 20 times lower risk than PK eyes (95% CL, 2.4-166; P = 0.006). Patients undergoing DMEK had a significantly reduced risk of experiencing a rejection episode within 2 years after surgery compared with DSEK and PK performed for similar indications using the same corticosteroid regimen.

Fetuin-A Pretransplant Serum Levels, Kidney Allograft Function and Rejection Episodes: A 3-Year Posttransplantation Follow-Up

Background: Fetuin-A is a negative acute-phase protein, which acts as a potent calcification inhibitor and an antagonist of transforming growth factor-β. Thus, fetuin-A levels are influenced by chronic inflammation and actively affect fibrosis and calcification processes, respectively. Graft rejection, interstitial fibrosis and tubular atrophy, chronic inflammation and calcification are common causes for kidney allograft loss. This study evaluated whether pretransplant fetuin-A levels predict long-term graft survival and rejection episodes in patients after kidney transplantation. Methods: In 206 renal transplant recipients pretransplant fetuin-A levels were measured in serum by ELISA. During the 36 months’ active follow-up (median 1,249 days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). Results: Pretransplant fetuin-A levels did not differ among patients with incident graft failures as compared to patients with functional graft after long-term follow-up or rejection episodes (fetuin-A: 393.6 ± 46 vs. 384.4 ± 69 vs. 405 ± 27.4 µg/ml). In logistic regression analysis, pretransplant fetuin-A levels did not correlate with graft failure after 3 years’ follow-up (p = 0.895). In COX regression analysis, fetuin-A levels were not associated with the time to graft loss. Moreover, fetuin-A levels correlated neither with renal and metabolic parameters nor with cellular or humoral rejection episodes. Conclusion: Pretransplant levels of fetuin-A are not a predictor for renal allograft loss or rejection episodes after 36 months’ follow-up in transplant recipients.

Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India

The present study investigated pharmacogenetic associations of common cytochrome P450 3A (CYP3A5 and CYP3A4) polymorphisms with dose requirements of calcineurin inhibitors, cyclosporine (CsA) and tacrolimus (Tac) in renal transplant recipients of North India. Two hundred twenty four patients on CsA and 73 patients on Tac-based immunosuppression regimen were genotyped for CYP3A5*3 (6986A>G) and CYP3A4*1B (-290A>G) and correlated with CsA/Tac dose requirement (mg/kg/day) and dose-adjusted CsA (C(2))/Tac (T (0)) blood levels (concentration/dose ratio) at 1 month and 3 months posttransplantation. The dose-adjusted levels were significantly lower in CYP3A5 expressers for CsA (p = 0.037; 3 months) and Tac (p < 0.001; 1 month and p < 0.001; 3 months) compared to the non-expressers, suggesting that for a given dose their CsA/Tac blood concentration is lower. The CYP3A5 non-expresser genotype was associated with reduced risk for allograft rejection (HR-0.18, 95% CI 0.03-0.99). No influence of CYP3A4*1B on CsA/Tac pharmacokinetics was observed. CYP3A5 expressers were associated with significantly lower dose-adjusted CsA/Tac concentrations and higher allograft rejection episodes in patients on Tac therapy.

Cardiovascular magnetic resonance in the diagnosis of acute heart transplant rejection: a review.

BackgroundScreening for organ rejection is a critical component of care for patients who have undergone heart transplantation. Endomyocardial biopsy is the gold standard screening tool, but non-invasive alternatives are needed. Cardiovascular magnetic resonance (CMR) is well suited to provide an alternative to biopsy because of its ability to quantify ventricular function, morphology, and characterize myocardial tissue. CMR is not widely used to screen for heart transplant rejection, despite many trials supporting its use for this indication. This review summarizes the different CMR sequences that can detect heart transplant rejection as well as the strengths and weaknesses of their application.ResultsT2 quantification by spin echo techniques has been criticized for poor reproducibility, but multiple studies show its utility in screening for rejection. Human and animal data estimate that T2 quantification can diagnose rejection with sensitivities and specificities near 90%. There is also a suggestion that T2 quantification can predict rejection episodes in patients with normal endomyocardial biopsies.T1 quantification has also shown association with biopsy proven rejection in a small number of trials. T1 weighted gadolinium early enhancement appeared promising in animal data, but has had conflicting results in human trials. Late gadolinium enhancement in the diagnosis of rejection has not been evaluated.CMR derived measures of ventricular morphology and systolic function have insufficient sensitivity to diagnose mild to moderate rejection. CMR derived diastolic function can demonstrate abnormalities in allografts compared to native human hearts, but its ability to diagnose rejection has not yet been tested.There is promising animal data on the ability of iron oxide contrast agents to illustrate the changes in vascular permeability and macrophage accumulation seen in rejection. Despite good safety data, these contrast agents have not been tested in the human heart transplant population.ConclusionT2 quantification has demonstrated the best correlation to biopsy proven heart transplant rejection. Further studies evaluating diastolic function, late gadolinium enhancement, and iron oxide contrast agents to diagnose rejection are needed. Future studies should focus on combining multiple CMR measures into a transplant rejection scoring system which would improve sensitivity and possibly reduce, if not eliminate, the need for endomyocardial biopsy.

Hepatic parenchymal changes and histologic eosinophilia as predictors of subsequent acute liver allograft rejection

During the first episode of acute cellular rejection (ACR) after liver transplantation, centrilobular changes in liver biopsy specimens may be possible indicators of subsequent episodes of ACR, early chronic rejection, or acute graft loss. The purpose of this study was to identify differences between the histopathological findings in liver biopsy specimens obtained during the first rejection episode in patients who subsequently developed further episodes of ACR and those who did not. The histopathological findings in 22 patients who had a single episode of acute rejection (group 1) were compared with those in 23 patients who had multiple episodes of acute rejection (group 2). Only the first liver biopsy samples of the latter group were taken into consideration. We assessed the predictive value of centrilobular necrosis, central vein endothelialitis, pericentral inflammation, hepatocellular ballooning, cholestasis, hepatocellular apoptosis, lobular inflammation, the degree of portal eosinophilia, and characteristic portal tract features in poor responders to antirejection treatment. The time to the first episode of ACR and the rejection activity index were similar in patients in both groups. Hepatocellular apoptosis, hepatocellular ballooning, and central vein endothelialitis were common features of both groups. The incidences of pericentral inflammation, centrilobular necrosis, and portal eosinophilia were significantly higher in patients in group 2 than in those in group 1 (P < 0.05). Patients with pericentral inflammation, centrilobular necrosis, and marked portal eosinophilia during an initial episode of acute rejection may be more likely to develop subsequent episodes of ACR.

240: Matrix metalloprotease (MMP)-1 Serum levels correlate with incidence of acute graft rejection episodes in patients undergoing cardiac transplantation

240: Matrix metalloprotease (MMP)-1 Serum levels correlate with incidence of acute graft rejection episodes in patients undergoing cardiac transplantation

Characterization of rejection episodes in patients following positive crossmatch and ABO-incompatible live donor renal transplantation

For kidney transplant recipients with donor-specific antibody (DSA) to HLA- (+XM) or ABO-antigens (ABOI), there is a need to improve detection and treatment of antibody-mediated rejection (AMR). The methods included a retrospective review of consecutive patients that received plasmapheresis and immune globulin (PPIVIg) to abrogate +XM or ABOI. Twelve patients were transplanted after PPIVIg (+XM = 9, ABOI = 2, +XM/ABOI = 1). No hyperacute rejections occurred. Rejection occurred in seven patients [four AMR, three acute cellular rejection (ACR)]. In four +XM patients, DSA was detected during graft dysfunction despite lack of histologic and C4d features of AMR. In one patient, DSA preceded the histologic and immunofluorescent features of AMR. In another patient with borderline changes and DSA, graft function improved after PPIVIg, despite lack of histologic or immunofluorescent evidence of AMR. One patient with Banff IIA ACR and DSA treated with antithymocyte antibody but not PPIVIg had recurrent rejections and poor graft function. In +XM and ABOI recipients with graft dysfunction: (i) DSA may represent AMR in the absence of C4d or histologic features of AMR; (ii) DSA can precede C4d or light microscopic features of AMR; (iii) A poor outcome may result if DSA or continued allograft dysfunction is present and not treated despite a negative biopsy.

Rejection after simultaneous pancreas–kidney transplantation

Simultaneous pancreas-kidney (SPK) transplantation is an accepted therapy for type 1 diabetic patients with end-stage renal disease. This study analyses the occurrence of rejection episodes in patients undergoing SPK. The study population was obtained from 205 patients enrolled in the Euro-SPK 001 study and randomized to receive tacrolimus- (n = 103) or cyclosporin microemulsion (ME)-based (n = 102) immunosuppressive therapy. All patients received concomitant antibody induction therapy, mycophenolate mofetil and short-term corticosteroids. After 3 years of follow-up, rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving cyclosporin-ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93 and 90%, respectively) and in most cases were treated with corticosteroids alone (88 vs 90%). Actuarial rejection-free kidney and/or pancreas graft survival was similar for tacrolimus (54%) and cyclosporin-ME (44%). Human leukocyte antigen (HLA) compatibility (P = 0.003) and graft vessel extension (P = 0.000001) had a significant influence on rejection-free graft survival. Also, rejection influenced pancreas graft survival (P = 0.01), and pancreas graft loss due to rejection influenced patient survival (P = 0.02). In the intent-to-treat analysis of early rejection, significantly fewer tacrolimus- than cyclosporin-ME-treated patients had (i) more than one rejection episode (11 out of 40 vs 24 out of 47; P = 0.03); (ii) first moderate to severe rejection (one out of 40 vs 12 out of 47; P = 0.004); and (iii) refractory rejection (two out of 40 vs 10 out of 47; P = 0.03). Pancreas survival was lower in late rejectors (53%) than non-rejectors (86%; P = 0.002). Also, serum creatinine was highest in late rejectors. Tacrolimus-based immunosuppressive therapy demonstrates significant advantages over cyclosporin-ME in terms of the severity of acute rejection in SPK transplant patients.

VIRAL LOAD MONITORING IN PATIENTS WITH POLYOMAVIRUS NEPHROPATHY WHO HAVE BEEN TREATED FOR REJECTION EPISODES

P823 Aims: Rejection occurring after reduction of immunosuppression for treatment of polyomavirus nephropathy (PVN) is a difficult clinical problem, as an increase in immunosuppression could result in a worsening of PVN. Recent anecdotal literature has suggested that treatment of rejection episodes followed by a rapid reduction of immunosuppression may prevent a relapse of PVN. The aim of this study was to determine the effects of a transient increase in immunosuppression for the treatment of acute rejection on viral load monitoring parameters in renal transplant recipients diagnosed with PVN. Methods: Four patients experienced six rejection episodes post PVN. BKV serum and urine viral loads were analyzed by Taqman PCR and anti-BKV antibody titers (ab) were analyzed by hemagglutination assay at the time of rejection, and at 8 and 24 weeks post rejection episode. Results: Four patients experienced six rejection episodes (multiple episodes in two patients) post PVN. Median time to acute rejection post PVN was 18 (2-60) weeks. Four of the rejections were mild, 1 was moderate and one patient developed humoral rejection after multiple acute cellular rejection episodes. Rejection treatment consisted of: none in 1, increased tacrolimus in 2, IVIG and increased tacrolimus in 1, leflunomide in 1 and IVIG alone in 1. Median BKV serum and urine viral loads did not deteriorate following the treatment of rejection (BKV serum viral load 5.04 x 10 4 at rejection vs 7.70 x 10 2 copies/mL post-rejection) and (BKV urine viral load 1.22 x 10 6 at rejection vs 1.52 x 10 4 copies/mL post-rejection). Median anti-BKV antibody titers were higher in patients post rejection (8192 at rejection vs 32968 HA units post rejection) and median serum creatinine values were not worse post rejection treatment followed by a reduction of immunosuppression (median serum creatinine at rejection 2.6 vs 2.1 mg/dL post rejection) Of patients who experienced post PVN rejection episodes, graft loss occurred in one patient (25%) who experienced multiple acute rejection episodes followed by humoral rejection and worsening PVN. Conclusions: 1) Transient increases in immunosuppression for the successful treatment of acute rejection episodes, in patients with PVN does not result in an increase in BKV viral loads. 2) Graft loss occurred only in 1 out of 4 patients experiencing rejection following diagnosis of PVN 3) Our results suggest that transient increases in immunosuppression for the treatment of rejection episodes in patients with PVN is indicated for the optimal management of these complex patients.

Effect of immunosuppressive regimen on acute rejection and liver graft function

Despite the use of modern immunosuppressive drugs, acute liver rejection (AR) continues to affect up to 70% of transplant recipients. The aim of this retrospective study was to assess the incidence of acute rejection episodes in patients treated with different immunosuppressive protocols. In our series, 37.3% of patients developed a clinical episode of AR. Analysis of immunosuppression has shown that the most effective immunosuppressive protocols, with regard to prevention of AR, include: antibody anti–IL-2R (anti–IL-2R) + tacrolimus (Tac) + mycophenolate mofetil (MMF) + prednisolone (Pred); anti–IL-2R + tacrolimus (Tac) + Pred; or Tac + Pred (25% vs 28.6% vs 30.4%, respectively). The highest rate of AR (66.6%) was observed among patients with anti–IL-2R and Tac but no steroid treatment, mostly (77.7%) in the initial period after liver transplantation. There were no statistical differences in liver function tests between the group treated with a CsA-based versus a Tac-based therapy. Strong immunosuppression contributed to a relatively low incidence of clinical AR in our series. The lowest rate of AR was observed among patients treated with anti–IL-2R antibody. Tac, and Pred. Deprivation of steroids in the early phase after liver transplantation substantially increased the risk of acute rejection episodes despite the use of anti–CD25. There were no statistically significant differences in liver function tests among those treated with Tac versus CsA in the short-term follow-up.

Daclizumab (humanized anti-IL2Ralpha mAb) prophylaxis for prevention of acute rejection in renal transplant recipients with delayed graft function.

The purpose of this retrospective study was to determine the benefits of daclizumab, (Zenapax, Roche Pharmaceuticals) a humanized anti-interleukin-2Ralpha (IL-2Ralpha) monoclonal antibody, for prevention of acute rejection in renal transplant recipients with delayed graft function (DGF). Data from two multicenter randomized placebo-controlled trials were pooled. DGF was defined by urine output <30 cc/hour, decline in serum creatinine of <0.5 mg/dl, or the need for dialysis within the first 24 hours after transplantation. At one year posttransplantation, the incidence of biopsy-proven acute rejection in patients with DGF was reduced from 44% in the placebo group to 28% in the daclizumab group. (P=0.03) Prophylaxis with daclizumab also delayed the onset of the first biopsy-proven acute rejection episode in patients with DGF from 29+/-43 days in the placebo group to 73+/-70 days in the daclizumab group. (P=0.004) The graft survival rates in patients with DGF at 1 year posttransplantation were 78% in the placebo group and 82% in the daclizumab treated group. (P=ns) Three patients in the placebo-treated group with DGF experienced graft loss due to acute rejection, whereas no patients in the daclizumab-treated group with DGF had graft loss due to acute rejection. The 1-year patient survival rate in those with DGF in the placebo and daclizumab groups were 93% and 98%, respectively. (P=ns) Daclizumab effectively reduced the incidence and delayed the onset of biopsy-proven acute rejection in this high-risk subgroup of patients with DGF after renal transplantation. Graft and patient survival rates were similar between placebo- and daclizumab-treated patients with DGF.

Weekly protocol renal transplant biopsies allow detection of sub-clinical acute rejection episodes in patients with delayed graft function

Weekly protocol renal transplant biopsies allow detection of sub-clinical acute rejection episodes in patients with delayed graft function

Monitoring of anti-HLA class I and II antibodies by flow cytometry in patients after first cadaveric kidney transplantation.

While the relevance of pre-formed anti-human leukocyte antigen (HLA) antibodies has been studied extensively, the role of anti-HLA class I and II antibodies produced after cadaveric kidney transplantation is still a matter of discussion. As it has been proposed that they are involved in a considerable number of cases, it should be investigated whether a post-transplant monitoring is a sensitive parameter for the early diagnosis of acute rejection episodes. Additionally, it has been suggested that antibodies are a major cause for chronic rejection; thus, it would be of interest to correlate antibody detection and graft survival. We retrospectively investigated 59 patients after a first cadaveric kidney transplantation without known anti-HLA antibodies (complement-dependent cytotoxicity [CDC] testing). The panel reactivity was determined with a new highly sensitive and specific flow-cytometric technique (Flow-PRA Screening Test, One Lambda, Canoga Park, USA) in sequentially collected serum samples pre- and post-transplant. In patients with acute rejection episodes during the clinical course, the last sample prior to rejection, and in patients without rejection, the last sample prior to discharge, was analyzed. Furthermore, we analyzed 3-yr graft survival and several clinical parameters such as cold ischemia time (CIT). Twenty-four of 59 patients (41%) experienced acute rejections during the clinical course. Five of 59 died with a functioning graft within the first 3 yr. Seven of 54 patients, still alive after 3 yr, lost their graft. Anti-HLA antibodies were detectable in only 7/59 patients and a correlation between antibody positivity and acute rejections (p = 0.32 and 0.54 for anti-HLA class I and II, respectively) could not be identified (sensitivity 12.5 and 8.3%). However, we found a significant correlation between the detection of anti-HLA class II and graft loss within 3 yr (p = 0.005, specificity 97.9%). Additionally, anti-HLA class II positive patients had significantly longer CIT (p = 0.003). Whether the detection of anti-HLA class II antibodies in the early post-transplant phase is of great value for the identification of patients at high risk for early graft loss needs additional investigation. However, we found that anti-HLA antibodies are detectable only in a minority of unsensitized patients and we conclude that flow-cytometric monitoring with Flow PRA is not a sensitive parameter for the early diagnosis of acute rejection episodes in patients after first cadaveric kidney transplantation.

Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation

Background The aim of the study was to assess the impact of mycophenolate mofetil (MMF) on the early phase after lung transplantation. Patients and methods Thirty-eight consecutive patients between November 1994 and January 1997 were treated with cyclosporine, prednisolone, antithymocyte globuline induction therapy, and either MMF (n = 21) or azathioprine (Aza) (n = 17). Four patients from the MMF group and 2 patients from the Aza group were intubated and in the ICU prior to transplantation. Demographic data and primary diagnosis were comparable. MMF was administered at a dosage of 2 gm/day whereas Aza was initiated at 2 mg/kg/day and adapted by leukocyte count. Three-month survival and incidence of rejections and infections were compared. Results Six-month survival in the MMF group was 76% compared to 65% in the Aza group (n.s.). The mean number of acute rejection episodes in the MMF and Aza group were 0.29 ± 0.10 and 1.53 ± 0.29 ( p < 0.01) respectively. Transbronchial biopsy (TBB) results ≥ grade 2 ISHLT were seen in 10% of MMF and in 43% of Aza-treated patients; completely free from rejection were 17 MMF and 3 Aza patients. The mean number of infections per patient in the MMF and Aza group were 1.57 ± 0.29 and 2.29 ± 0.40 respectively, bacterial (1.10 vs 1.71), viral (0.35 vs 0.33), and fungal (0.14 vs 0.24) infections were the same in both groups. Conclusions These data result suggest that mycophenolate mofetil therapy is more effective in preventing rejection episodes in patients early after lung transplantation than therapy with azathioprine. We therefore conclude that MMF is a safe and effective drug to optimize immunosuppressive therapy in the early phase after lung transplantation.