Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results.

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections.

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Kidney graft survival of >25 years: a single center report including associated graft biopsy results.

Only few centers have reported their observations on patients with very long-term kidney graft survival of more than 25 years. Eighty-six subjects were identified in our center with graft survival of >25 years. Donor age was 31.3 ± 18.5 years. Mean duration of transplantation was 30.3 ± 3.6 years. At last follow-up, the cystatin C clearance was 47 ± 23 ml/min. Transplant biopsies for cause were performed in 30 subjects at a median of 28.4 years (19.1-40.3) after transplantation. Acute or chronic active T cell-mediated rejection was present in five cases and histological characteristics of acute or chronic active humoral rejection in eight cases. More than 80% of biopsies had inflammatory infiltrates in nonatrophic or atrophic cortical areas. The number of HLA mismatches were higher in biopsied subjects (3.0 ± 1.8 vs. 2.2 ± 1.7 without biopsy). Immunosuppressive therapy was adapted in most biopsied subjects; impaired graft function and proteinuria was unchanged at last follow-up. Sixty percent of all subjects had hyperparathyroidism (iPTH of the whole group: 132 ± 157 pg/ml), which was predominantly secondary, as judged by serum calcium and graft function. Young donor age was certainly a prerequisite of longterm graft survival. Nonetheless, inflammation or rejection in most biopsied patients suggests an important role of alloreactivity even in this late course.

Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy.

HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m2 , P < .001) or low CNI (difference 7.6 mL/min/1.73 m2 , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m2  and 10.1 mL/min/1.73 m2 , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account.

Hepatocyte-induced CD4+ T cell alloresponse is associated with major histocompatibility complex class II up-regulation on hepatocytes and suppressible by regulatory T cells.

Hepatocyte transplantation is a promising therapeutic approach for various liver diseases. Despite the liver's tolerogenic potential, early immune-mediated loss of transplanted cells is observed, and longterm acceptance has not been achieved yet. Patients deemed tolerant after liver transplantation presented an increased frequency of regulatory T cells (Tregs), which therefore also might enable reduction of posttransplant cell loss and enhance longterm allograft acceptance. We hence characterized hepatocyte-induced immune reactions and evaluated the immunomodulatory potential of Tregs applying mixed lymphocyte cultures and mixed lymphocyte hepatocyte cultures. These were set up using peripheral blood mononuclear cells and primary human hepatocytes, respectively. Polyclonally expanded CD4+ CD25high CD127low Tregs were added to cocultures in single-/trans-well setups with/without supplementation of anti-interferon γ (IFNγ) antibodies. Hepatocyte-induced alloresponses were then analyzed by multicolor flow cytometry. Measurements indicated that T cell response upon stimulation was associated with IFNγ-induced major histocompatibility complex (MHC) class II up-regulation on hepatocytes and mediated by CD4+ T cells. An indirect route of antigen presentation could be ruled out by use of fragmented hepatocytes and culture supernatants of hepatocytes. Allospecific proliferation was accompanied by inflammatory cytokine secretion. CD8+ T cells showed early up-regulation of CD69 despite lack of cell proliferation in the course of coculture. Supplementation of Tregs effectively abrogated hepatocyte-induced alloresponses and was primarily cell contact dependent. In conclusion, human hepatocytes induce a CD4+ T cell alloresponse in vitro, which is associated with MHC class II up-regulation on hepatocytes and is susceptible to suppression by Tregs. Liver Transplantation 24 407-419 2018 AASLD.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Assessment of liver ischemia reperfusion injury in mice using hepatic T2 mapping: Comparison with histopathology.

BACKGROUND: Liver ischemia reperfusion injury (IRI) occurs during liver surgery or transplantation resulting in an inflammatory response, tissue damage, and functional impairment of the organ. PURPOSE: To assess the feasibility of T2 mapping for noninvasive quantification of liver edema after partial liver IRI in mice. STUDY TYPE: Prospective, experimental study. ANIMAL MODEL: Partial liver IRI was induced in C57BL/6-mice by transient clamping of the left lateral and median liver lobes for 35 (n = 8), 45 (n = 6), 60 (n = 17), or 90 minutes (n = 5). For comparison, healthy C57BL/6-mice were examined as controls (n = 9). FIELD STRENGTH/SEQUENCE: Functional liver MRI was performed on a 7T scanner using a respiratory-triggered multiecho spin-echo sequence. ASSESSMENT: Healthy control mice and mice with partial liver IRI on day 1 after surgery, and additionally on day 7 in a subgroup with 60 minutes IRI (n = 8) were examined. Maps of T2 relaxation time of liver tissue were used to assess distribution, severity of tissue edema (mean T2 time), and the percentage of edematous liver tissue. STATISTICAL TEST: One-way analysis of variance (ANOVA) with Tukey's honest significant difference (HSD), paired t-tests, Pearson's test for correlation of MRI parameters with levels of liver enzymes, and histopathology, receiver operating characteristic (ROC) analysis. RESULTS: Significant tissue edema induced by liver IRI as compared to the control group was detected by increased mean T2 times in groups with 60 minutes (P < 0.001) and 90 minutes IRI (P < 0.001). The percentage of edematous liver tissue significantly increased with longer ischemia times (controls 3.4 ± 0.4%, 35 minutes 5.3 ± 0.6%, 45 minutes 23.3 ± 7.6%, 60 minutes 39.7 ± 3.6%, 90 minutes 51.3 ± 4.5%). Mean T2 times and the percentage of edematous liver tissue significantly correlated with elevation of liver enzymes (P < 0.001), histological evidence of liver injury (r = 0.80 and r = 0.82, P < 0.001), and neutrophil infiltration (r = 0.70 and r = 0.74, P < 0.001). In the subgroup with follow-up, the severity (P < 0.01) and extent of liver edema decreased significantly over time (P < 0.01). DATA CONCLUSION: T2 mapping allows quantification and follow-up of liver injury in mice. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1586-1594.

Assessment of acute kidney injury with T1 mapping MRI following solid organ transplantation.

OBJECTIVES: To evaluate T1 mapping as a non-invasive, functional MRI biomarker in patients shortly after solid organ transplantation to detect acute postsurgical kidney damage and to correlate T1 times with renal function. METHODS: 101 patients within 2 weeks after solid organ transplantation (49 kidney transplantation, 52 lung transplantation) and 14 healthy volunteers were examined by MRI between July 2012 and April 2015 using the modified Look-Locker inversion recovery (MOLLI) sequence. T1 times in renal cortex and medulla and the corticomedullary difference were compared between groups using one-way ANOVA adjusted for multiple comparison with the Tukey test, and T1 times were correlated with renal function using Pearson's correlation. RESULTS: Compared to healthy volunteers T1 times were significantly increased after solid organ transplantation in the renal cortex (healthy volunteers 987 ± 102 ms; kidney transplantation 1299 ± 101 ms, p < 0.001; lung transplantation 1058 ± 96 ms, p < 0.05) and to a lesser extent in the renal medulla. Accordingly, the corticomedullary difference was diminished shortly after solid organ transplantation. T1 changes were more pronounced following kidney compared to lung transplantation, were associated with the stage of renal impairment and significantly correlated with renal function. CONCLUSIONS: T1 mapping may be helpful for early non-invasive assessment of acute kidney injury and renal pathology following major surgery such as solid organ transplantation. KEY POINTS: • Renal cortical T1 relaxation times are prolonged after solid organ transplantation. • Cortical T1 values increase with higher stages of renal function impairment. • Corticomedullary difference decreases with higher stages of renal function impairment. • Renal cortical T1 relaxation time and corticomedullary difference correlate with renal function. • T1 mapping may be helpful for non-invasive assessment of post-operative renal pathology.

Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study.

Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 µg/L over the year) was lower than aspired (2 µg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.

Renal cell cancer after kidney transplantation.

PURPOSE: This study aims to identify modifiable risk factors for de novo renal cell carcinoma (RCC) after kidney transplantation in a matched-pair approach matching for unmodifiable factors. PATIENTS AND METHODS: One thousand six hundred fifty-five adults who underwent kidney transplantation in the period 1 January 2000 to 31 December 2012 were analyzed. Patients with RCC after kidney transplantation were matched in a 1:2 ratio with those without RCC using the indication for transplantation, age at transplantation (± 10 years), recipient sex (male/female), number of received transplants, living organ donor transplantation (yes/no), and time of follow-up in days as matching criteria. The paired t test was used to compare continuous variables and the Cochran-Mantel-Haenszel test for categorical variables. Multivariable conditional logistic regression modeling was used to identify independent risk factors for RCC. RESULTS: In matched-pair analysis, a total number of 26 incident cases with RCC after kidney transplantation could be matched. Post-transplant RCC was significantly associated with longer durations of pre-transplant hemodialysis (p = 0.007) and post-transplant immunosuppression with cyclosporine (p = 0.029) and/or mycophenolate mofetil (p = 0.020) and with larger proportions of post-transplant time on mycophenolate mofetil (p = 0.046) and/or prednisolone medication (p = 0.042). Multivariable conditional logistic regression modeling revealed a significant risk increasing multiplicative factor interaction between the duration of pre-transplant dialysis (years) and the time of prednisolone usage (percent/100). Cyclosporine A usage and mycophenolate mofetil usage were also revealed as independent, significant risk factors for RCC development. CONCLUSIONS: Longer pre-transplant dialysis, cyclosporine-based protocols and/or intensified immunosuppression with additional mycophenolate mofetil, and larger proportions of time of prednisolone treatment during follow-up increase de novo RCC risk.

Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials.

BACKGROUND: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes. METHODS: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497). RESULTS: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes). CONCLUSIONS: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes. TRIAL REGISTRATION: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 ).

Histological findings to five years after early conversion of kidney transplant patients from cyclosporine to everolimus: an analysis from the randomized ZEUS study.

BACKGROUND: Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation. METHODS: Biopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids. RESULTS: At least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively. CONCLUSIONS: This analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00154310 . Date of registration: September 12, 2005.

Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation.

BACKGROUND & AIMS: The shortage of liver donations demands the use of suboptimal grafts with steatosis being a frequent finding. Although ≤30% macrovesicular steatosis is considered to be safe the risk for primary non-function (PNF) and outcome after re-transplantation (re-OLT) is unknown. METHODS: Among 1205 orthotopic liver transplantations performed at our institution the frequency, survival and reason of re-OLT were evaluated. PNF (group A) cases and those with initial transplant function but subsequent need for re-OLT (group B) were analysed. Histopathology and clinical judgement determined the cause of PNF and included an assessment of hepatic steatosis. Additionally, survival of fatty liver allografts (group C) not requiring re-OLT was considered in Kaplan-Meier and multivariate regression analysis. RESULTS: A total of 77 high urgency re-OLTs were identified and included 39 PNF cases. Nearly 70% of PNF cases were due to primary fatty liver allografts. The 3-month in-hospital mortality for PNF cases after re-OLT was 46% and the mean survival after re-OLT was 0.5 years as compared to 5.2 and 5.1 years for group B, C, respectively, (P<.008). In multivariate Cox regression analysis only hepatic steatosis was associated with an inferior survival (HR 4.272, P=.002). The MELD score, donor BMI, age, cold ischaemic time, ICU stay, serum sodium and transaminases did not influence overall survival. CONCLUSIONS: Our study highlights fatty liver allografts to be a major cause for PNF with excessive mortality after re-transplantation. The findings demand the development of new methods to predict risk for PNF of fatty liver allografts.

Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial.

BACKGROUND.: Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain. METHODS.: In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514). RESULTS.: The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively. CONCLUSIONS.: Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged-release tacrolimus plus mycophenolate mofetil or sirolimus.

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged-release tacrolimus-based immunosuppressive regimens. On Days 0-27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolonged-release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m2 ; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged-release tacrolimus plus MMF (Arm 1) versus lower dose prolonged-release tacrolimus plus sirolimus (Arm 2).

Patterns and challenges of treatment sequencing in patients with hepatocellular carcinoma: Experience from a German referral center.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Several local and systemic therapies are available for patients with HCC depending on the stage of the disease. In clinical practice, treatment decision-making, and sequencing may be very heterogeneous. METHODS: In this study, we retrospectively analyzed treatment algorithms in 2101 patients with HCC treated from 2000 to 2015 at Hannover Medical School, Germany. RESULTS: Transarterial chemoembolization was the most common initial treatment (n = 545; 25.9%), followed by resection (n = 435, 20.7%), local-ablative procedures (n = 283, 13.5%), systemic therapies (n = 275, 13.1%), and liver transplantation (n = 52; 2.5%). Most patients were treated only once (n = 960; 59.6%). A total of 433 (26.9%) and 160 (9.9%) patients received a second line and third line treatment after recurrent or progressive disease. Patients with more than one treatment line were diagnosed at significantly earlier disease stages (P < 0.001). Using binary logistic regression, AFP ≤ 200 µg/L, albumin > 36 g/L, and small tumor size (≤50 mm) were identified as predictors of achieving more than one treatment line. Subsequent treatment stage migration to a therapy suggested for the next advanced stage occurred only in 56.9%, whereas 43.1% received treatments suggested for earlier disease stages. Only 16% of all treated patients received systemic therapy in the salvage setting. CONCLUSION: Most patients were treated only once, and only a minority of patients received systemic treatment. The high dropout rate for subsequent therapies needs to be considered within therapy decision-making. There is an urgent need for prospective studies to define the best time point when to switch patients from local to systemic therapies.

Short- and long-term effects of the use of RAAS blockers immediately after renal transplantation.

BACKGROUND: The efficacy and safety of renin angiotensin aldosterone system blockers (RAASB's) if introduced immediately after renal transplantation have not been extensively investigated. METHODS: The medical charts of 142 kidney transplant recipients who received a RAASB in the early postoperative period and of 114 matched controls were analyzed. The RAASB was given primarily for blood pressure control. RESULTS: 117 patients continued to receive and 50 controls remained continuously free of the RAASB in the first year. The RAASB was added on average at postoperative day 8 and the mean duration of follow-up was 5.4 years. Systolic, blood pressure at treatment initiation was increased in the RAASB group (150 ± 17 vs. 141 ± 16, p < 0.001). At discharge from hospital and during follow-up blood pressure was similar in both groups, without differences in GFR, potassium and proteinuria. The endpoints "graft failure" and "graft failure or death from any cause" were significantly better in patients treated with RAASB's (p = 0.03 and p = 0.04, respectively). The treatment effects in the RAASB group persisted even after adjustment for demographic parameters, immunological risk factors, peritransplant risk factors, duration of dialysis prior to transplantation and medical comorbidities. CONCLUSIONS: Thus, RAASB's can be used effectively and safely to treat hypertension in the early postoperative period after kidney transplantation and are renoprotective in the long term.

Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts.

Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4(+) cells, an increasing CD4(+) /CD8(+) ratio, and an increasing CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cell (Treg)/CD8(+) ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4(+) FOXP3(+) Tregs. Liver Transplantation 22 943-955 2016 AASLD.

Diffusion-Weighted imaging and diffusion tensor imaging detect delayed graft function and correlate with allograft fibrosis in patients early after kidney transplantation.

PURPOSE: To combine diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) for detection of allograft dysfunction in patients early after kidney transplantation and to correlate diffusion parameters with renal function and renal histology of allograft biopsies. MATERIALS AND METHODS: Between day 4 and 11 after kidney transplantation 33 patients with initial graft function and 31 patients with delayed graft function (DGF) were examined with a 1.5T magnetic resonance imaging (MRI) scanner. DTI and DWI sequences were acquired and fractional anisotropy (FA), apparent diffusion coefficient (ADCmono), pure diffusion (ADCdiff ), and the perfusion fraction (Fp) were calculated. Kidney biopsies in 26 patients were analyzed for allograft pathology, ie, acute tubular injury, inflammation, edema, renal fibrosis, and rejection. Histological results were correlated with MRI parameters. RESULTS: In the renal medulla FA (0.25 ± 0.06 vs. 0.29 ± 0.06, P < 0.01) and ADCmono (1.73 ± 0.13*10(-3) vs. 1.93 ± 0.16*10(-3) mm(2) /s, P < 0.001) were significantly reduced in DGF patients compared with patients with initial function. For ADCdiff and Fp similar reductions were observed. FA and ADCmono significantly correlated with renal function (r = 0.53 and r = 0.57, P < 0.001) and were inversely correlated with the amount of renal fibrosis (r = -0.63 and r = -0.65, P < 0.05). CONCLUSION: Combined DTI and DWI detected allograft dysfunction early after kidney transplantation and correlated with allograft fibrosis. J. Magn. Reson. Imaging 2016;44:112-121.

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.