BackgroundLiver transplantation is the only curative therapy for end-stage liver disease (ESLD). Sarcopenia is often defined as the loss of muscle quantity (skeletal muscle index [SMI]), but muscle... Show moreBackgroundLiver transplantation is the only curative therapy for end-stage liver disease (ESLD). Sarcopenia is often defined as the loss of muscle quantity (skeletal muscle index [SMI]), but muscle attenuation (MA), a surrogate marker of muscle quality, is also decreased in ESLD. We assessed pre-liver transplant SMI and MA and their association with post-transplant mortality, complications, and length of intensive care unit (ICU) and hospital stay. MethodsIn 169 consecutive patients with ESLD who underwent a liver transplantation between 2007 and 2014, SMI and MA were measured on computed tomography scans at time of placement on the waiting list for liver transplantation. The primary outcome of interest was 1-year post-transplant mortality. Secondary posttransplantation outcomes of interest were complications within 30 days and length of stay in the ICU > 3 days and in the hospital >3 weeks. Logistic and Cox regression analyses were performed. ResultsMA was associated with 1-year post-transplant mortality rate (hazard ratio=0.656, 95% CI=0.464-0.921, P = 0.015). The highest quartile of SMI had a lower odds for the total length of stay in the hospital lasting >3 weeks (odds ratio=0.211, 95% CI=0.061-0.733, P = 0.014). MA was associated with a prolonged ICU stay; this was, however, not statistically significant after adjustment for age, sex, and Model for ESLD score. ConclusionLower MA is associated with a longer length of ICU stay and 1-year mortality after liver transplantation, whereas low SMI was associated with a total length of hospital stay. Show less
BackgroundThe aim of this study was to analyze the value of the unadjusted CUSUM graph of liver surgical injury and discard rates in organ procurement in the Netherlands. MethodsUnadjusted CUSUM... Show moreBackgroundThe aim of this study was to analyze the value of the unadjusted CUSUM graph of liver surgical injury and discard rates in organ procurement in the Netherlands. MethodsUnadjusted CUSUM graphs were plotted for surgical injury (C event) and discard rate (C2 event) from procured livers accepted for transplantation for each local procurement team compared with the total national cohort. The average incidence for each outcome was used as benchmark based on procurement quality forms (Sep 2010-Oct 2018). The data from the five Dutch procuring teams were blind-coded. ResultsThe C and C2 event rate were 17% and 1.9%, respectively (n = 1265). A total of 12 CUSUM charts were plotted for the national cohort and the five local teams. National CUSUM charts showed an overlapping "alarm signal." This overlapping signal for both C and C2, albeit a different time period, was only found in one local team. The other CUSUM alarm signal went off for two separate local teams, but only for C events or C2 events respectively, and at different points in time. The other remaining CUSUM charts showed no alarm signaling. ConclusionThe unadjusted CUSUM chart is a simple and effective monitoring tool in following performance quality of organ procurement for liver transplantation. Both national and local recorded CUSUMs are useful to see the implication of national and local effects on organ procurement injury. Both procurement injury and organ discard are equally important in this analysis and need to be separately CUSUM charted. Show less
Ruijter, B.N.; Tushuizen, M.E.; Moes, D.J.A.R.; Klerk, B.M. de; Hoek, B. van 2022
Background After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration-dependent, chronic kidney disease. Monitoring ciclosporin with two-hour levels... Show moreBackground After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration-dependent, chronic kidney disease. Monitoring ciclosporin with two-hour levels reduced overexposure and led to better renal function than trough-monitoring (C0). For tacrolimus, a 4-hour level (C4) can give a reasonable approximation of total drug exposure. We evaluated whether monitoring tacrolimus in stable patients after LT by C4 was superior to C0 regarding renal function, rejection and metabolic parameters. Methods This open label randomized controlled trial compared C4 monitoring of tacrolimus BID (Prograft) to trough (C0) monitoring in stable LT recipients. The target range for C4 of 7.8-16 ng/ml was calculated to be comparable with target C0 of 4-8 ng/ml. Primary endpoint was the effect on renal function and secondary endpoints were the occurrence of treated biopsy-proven acute rejection, blood pressure and metabolic parameters, during 3 months of follow-up. Results Fifty patients were randomized to C0 (n = 25) or C4 (n = 25) monitoring. There was no difference in renal function between the C0 and the C4 group (p = .98 and p = .13 for CG and MDRD at 3 months). Also, the amount of proteinuria was similar (p = .59). None of the patients suffered from graft loss or was treated for rejection. Metabolic parameters did not differ between the two groups. Conclusion Tacrolimus 4-hour monitoring in stable LT patients is not superior to trough monitoring, regarding the effect on renal function, but is safe for use to facilitate tacrolimus monitoring in an afternoon outpatient clinic. Show less
Schurink, I.J.; Goeij, F.H.C. de; Habets, L.J.M.; Leemkolk, F.E.M. van de; Dun, C.A.A. van; Oniscu, G.C.; ... ; Jonge, J. de 2022
Objective: This study investigates whether liver grafts donated after circulatory death (DCD) that are declined by the entire Eurotransplant region can be salvaged with abdominal normothermic... Show moreObjective: This study investigates whether liver grafts donated after circulatory death (DCD) that are declined by the entire Eurotransplant region can be salvaged with abdominal normothermic regional perfusion (aNRP). Background: aNRP is increasingly used for DCD liver grafts because it prevents typical complications. However, it is unclear whether aNRP is capable to rescue pretransplant declined liver grafts by providing the opportunity to test function during donation. Methods: Donor livers from DCD donors, declined by all centers in the Eurotransplant region, were included for this study. The comparator cohort included standard DCD livers and livers donated after brain death, transplanted in the same time period. Results: After the withdrawal of life-sustaining treatment, 28 from the 43 donors had a circulatory death within 2 hours, in which case aNRP was initiated. Of these 28 cases, in 3 cases perfusion problems occurred, 5 grafts were declined based on liver assessment, and 20 liver grafts were transplanted. The main differences during aNRP between the transplanted grafts and the assessed nontransplanted grafts were alanine transaminase levels of 53 U/L (34-68 U/L) versus 367 U/L (318-488 U/L) (P=0.001) and bile production in 100% versus 50% of the grafts (P=0.024). The 12-month graft and patient survival were both 95%, similar to the comparator cohort. The incidence of ischemic cholangiopathy was 11%, which was lower than in the standard DCD cohort (18%). Conclusion: aNRP can safely select and thus is able to rescue DCD liver grafts that were deemed unsuitable for transplantation, while preventing primary nonfunction and minimizing ischemic cholangiopathy. Show less
Montano-Loza, A.J.; Ronca, V.; Ebadi, M.; Hansen, B.E.; Hirschfield, G.; Elwir, S.; ... ; Int Autoimmune Hepatitis Grp IAIHG 2022
Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a... Show moreBackground & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.Methods: We included 736 patients (77% female, mean age 42 +/- 1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis.Results: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT <= 42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001).Conclusion: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH.Lay summary: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition. (C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Show less
Moolenaar, L.R.; Waard, N.E. de; Heger, M.; Haan, L.R. de; Slootmaekers, C.P.J.; Nijboer, W.N.; ... ; Golen, R.F. van 2022
The obesity epidemic has caused a surge in the use of bariatric surgery. Although surgery-induced weight loss is an effective treatment of nonalcoholic fatty liver disease, it may precipitate... Show moreThe obesity epidemic has caused a surge in the use of bariatric surgery. Although surgery-induced weight loss is an effective treatment of nonalcoholic fatty liver disease, it may precipitate severe hepatic complications under certain circumstances. Acute liver injury (ALI) and acute liver failure (ALF) following bariatric surgery have been reported in several case series. Although rare, ALI and ALF tend to emerge several months after bariatric surgery. If so, it can result in prolonged hospitalization, may necessitate liver transplantation, and in some cases prove fatal. However, little is known about the risk factors for developing ALI or ALF after bariatric surgery and the mechanisms of liver damage in this context are poorly defined. This review provides an account of the available data on ALI and ALF caused by bariatric surgery, with emphasis on potential injury mechanisms and the outcomes of liver transplantation for ALF after bariatric surgery. Show less
Objective: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody... Show moreObjective: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19. Design: Prospective multicentre case-control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT). Results: Overall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, p<0.001). When analysing anti-S antibody response, no difference in positivity rate was found between the COVID-19-LT and COVID-19-immunocompetent cohorts (97.1% vs 100%, p=0.314). Functional antibody testing showed neutralising activity in 82.9% of LT recipients (vs 100% in COVID-19-immunocompetent cohort, p=0.024). Conclusions: Our findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability. Show less
Background & aims: Acute-on-chronic liver failure (ACLF) is usually associated with a precipitating event and results in the failure of other organ systems and high short-term mortality.... Show moreBackground & aims: Acute-on-chronic liver failure (ACLF) is usually associated with a precipitating event and results in the failure of other organ systems and high short-term mortality. Current prediction models fail to adequately estimate prognosis and need for liver transplantation (LT) in ACLF. This study develops and validates a dynamic prediction model for patients with ACLF that uses both longitudinal and survival data.Methods: Adult patients on the UNOS waitlist for LT between 11.01.2016-31.12.2019 were included. Repeated model for end-stage liver disease-sodium (MELD-Na) measurements were jointly modelled with Cox survival analysis to develop the ACLF joint model (ACLF-JM). Model validation was carried out using separate testing data with area under curve (AUC) and prediction errors. An online ACLF-JM tool was created for clinical application.Results: In total, 30,533 patients were included. ACLF grade 1 to 3 was present in 16.4%, 10.4% and 6.2% of patients, respectively. The ACLF-JM predicted survival significantly (p <0.001) better than the MELD-Na score, both at baseline and during follow-up. For 28- and 90-day predictions, ACLF-JM AUCs ranged between 0.840-0.871 and 0.833-875, respectively. Compared to MELD-Na, AUCs and prediction errors were improved by 23.1%-62.0% and 5%-37.6% respectively. Also, the ACLF-JM could have prioritized patients with relatively low MELD-Na scores but with a 4-fold higher rate of waiting list mortality.Conclusions: The ACLF-JM dynamically predicts outcome based on current and past disease severity. Prediction performance is excellent over time, even in patients with ACLF-3. Therefore, the ACLF-JM could be used as a clinical tool in the evaluation of prognosis and treatment in patients with ACLF.Lay summary: Acute-on-chronic liver failure (ACLF) progresses rapidly and often leads to death. Liver transplantation is used as a treatment and the sickest patients are treated first. In this study, we develop a model that predicts survival in ACLF and we show that the newly developed model performs better than the currently used model for ranking patients on the liver transplant waiting list. (C) 2021 The Author(s). Published by Elsevier B.V. Show less
Hepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral... Show moreHepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral hepatitis). In this situation, hematopoietic stem cell transplantation (HSCT) might be a curative option. Here the authors report on 6 patients who received HSCT after LT for nonviral HAAA hepatitis. The outcomes were interpreted in the context of recently reported immune suppressive therapy (IST) outcomes in 8 patients with HAAA and to HSCT outcomes in patients with HAAA who recovered from hepatitis without undergoing LT. All patients transplanted by using HLA-identical sibling donors (3 of 6) were alive and had normal liver function and hematopoiesis without graft versus host disease. Both patients receiving bone marrow from a matched unrelated donor (MUD) experienced extensive graft versus host disease that was fatal for one patient. Thereby, the authors conclude that HSCT can be considered as a first-choice treatment for this category of patients when HLA-identical donors are available. When no HLA-identical donor is available, IST should be applied as HSCT with other donor sources might be reserved for IST nonresponders or poor responders. Show less
Liver function is measured regularly in liver transplantation (LT) candidates. Currently, these previous disease development data are not used for survival prediction. By constructing and... Show moreLiver function is measured regularly in liver transplantation (LT) candidates. Currently, these previous disease development data are not used for survival prediction. By constructing and validating joint models (JMs), we aimed to predict the outcome based on all available data, using both disease severity and its rate of change over time. Adult LT candidates listed in Eurotransplant between 2007 and 2018 (n = 16 283) and UNOS between 2016 and 2019 (n = 30 533) were included. Patients with acute liver failure, exception points, or priority status were excluded. Longitudinal MELD(-Na) data were modeled using spline-based mixed effects. Waiting list survival was modeled with Cox proportional hazards models. The JMs combined the longitudinal and survival analysis. JM 90-day mortality prediction performance was compared to MELD(-Na) in the validation cohorts. MELD(-Na) score and its rate of change over time significantly influenced patient survival. The JMs significantly outperformed the MELD(-Na) score at baseline and during follow-up. At baseline, MELD-JM AUC and MELD AUC were 0.94 (0.92-0.95) and 0.87 (0.85-0.89), respectively. MELDNa-JM AUC was 0.91 (0.89-0.93) and MELD-Na AUC was 0.84 (0.81-0.87). The JMs were significantly (p < .001) more accurate than MELD(-Na). After 90 days, we ranked patients for LT based on their MELD-Na and MELDNa-JM survival rates, showing that MELDNa-JM-prioritized patients had three times higher waiting list mortality. Show less
Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear.... Show moreLiver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4-18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9-9.1) and patient survival (HR 2.3; 95% CI 1.5-3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7-4.8). PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival. Show less
Biewenga, M.; Verhelst, X.P.D.M.J.; Baven-Pronk, M.A.M.C.; Putter, H.; Berg, A.P. van den; Nieuwkerk, K.C.M.J. van; ... ; Dutch Autoimmune Hepatitis Study G 2021
Background No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic... Show moreBackground No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. Methods The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. Results In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). Conclusions A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated. Show less
Bruggenwirth, I.M.A.; Reeven, M. van; Vasiliauskaite, I.; Helm, D. van der; Hoek, B. van; Schaapherder, A.F.; ... ; Porte, R.J. 2020
With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post... Show moreWith the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes. From a national cohort of adult liver transplant recipients (1996-2016), all recipients transplanted with a liver from a DM donor (n = 69) were matched 1:2 with recipients of livers from non-DM donors (n = 138). The primary end-point included early post-transplant outcome, such as the incidence of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analysis was used to analyze the impact of donor DM on graft failure. PNF was observed in 5.8% of grafts from DM donors versus 2.9% of non-DM donor grafts (P = 0.31). Recipients of grafts derived from DM donors had a higher incidence of HAT (8.7% vs. 2.2%, P = 0.03) and decreased 90-day graft survival (88.4% [70.9-91.1] vs. 96.4% [89.6-97.8], P = 0.03) compared to recipients of grafts from non-DM donors. The adjusted hazard ratio for donor DM on graft survival was 2.21 (1.08-4.53, P = 0.03). In conclusion, donor DM is associated with diminished outcome early after liver transplantation. The increased incidence of HAT after transplantation of livers from DM donors requires further research. Show less
The MELD score is used in the Eurotransplant (ET) region to allocate liver grafts. Hyponatremia in cirrhotic patients is an important predictor of death but is not incorporated in MELD. This study... Show moreThe MELD score is used in the Eurotransplant (ET) region to allocate liver grafts. Hyponatremia in cirrhotic patients is an important predictor of death but is not incorporated in MELD. This study investigated the performance of the MELD-Na score for the ET region. All adult patients with chronic liver disease on the ET liver transplantation waiting list (WL) allocated through lab MELD scores were included. The MELD-corrected effect of serum sodium (Na) concentration at listing on the 90-day WL mortality was calculated using Cox regression. The MELD-Na performance was assessed with c-indices, calibration per decile and Brier scores. The reclassification from MELD to MELD-Na score was calculated to estimate the impact of MELD-Na-based allocation in the ET region. For the 5223 included patients, the risk of 90-day WL death was 2.9 times higher for hyponatremic patients. The MELD-Na had a significantly higher c-index of 0.847 (SE 0.007) and more accurate 90-day mortality prediction compared to MELD (Brier score of 0.059 vs 0.061). It was estimated that using MELD-Na would reduce WL mortality by 4.9%. The MELD-Na score yielded improved prediction of 90-day WL mortality in the ET region and using MELD-Na for liver allocation will very likely reduce WL mortality. Show less
Reeven, M. van; Leeuwen, O.B. van; Helm, D. van der; Murad, S.D.; Berg, A.P. van den; Hoek, B. van; ... ; Porte, R.J. 2020
Due to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD... Show moreDue to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD), especially donation after circulatory death (DCD), for reLT are lacking. We aimed to assess the outcome of patients undergoing reLT using a DCD graft in the Netherlands between 2001 and July 2018. Propensity score matching was used to match each DCD-reLT with three DBD-reLT cases. Primary outcomes were patient and graft survival. Secondary outcome was the incidence of biliary complications, especially nonanastomotic strictures (NAS). 21 DCD-reLT were compared with 63 matched DBD-reLTs. Donors in the DCD-reLT group had a significantly lower BMI (22.4 vs. 24.7 kg/m(2), P-value = 0.02). Comparison of recipient demographics and ischemia times yielded no significant differences. Patient and graft survival rates were comparable between the two groups. However, the occurrence of nonanastomotic strictures after DCD-reLT was significantly higher (38.1% vs. 12.7%, P-value = 0.02). ReLT with DCD grafts does not result in inferior patient and graft survival compared with DBD grafts in selected patients. Therefore, DCD liver grafts should not routinely be declined for patients awaiting reLT. Show less
TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1)... Show moreTRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) mL/min per 1.73 m(2) was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = -0.3, 8.7; P = .006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m(2)) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R- high-risk group (P < .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. Clinicaltrials.gov number: NCT01950819. Show less
Goet, J.C.; Hansen, B.E.; Tieleman, M.; Hoek, B. van; Berg, A.P. van den; Polak, W.G.; ... ; Vries, A.C. de 2018