Patients awaiting heart transplantation in Eurotransplant are prioritized by waiting time and medical urgency. To reduce mortality, the introduction of post-transplant survival in an allocation model ...based on the concept of survival benefit might be more appropriate. The aim of this study was to assess the prognostic accuracy of the heart failure survival score (HFSS), the Seattle heart failure model (SHFM), the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) model, and the index for mortality prediction after cardiac transplantation (IMPACT) score for predicting mortality.
The HFSS, SHFM, the adapted SHFM, and the INTERMACS model were evaluated for predicting waiting list mortality among heart transplant candidates, and the IMPACT score was tested for predicting post-transplant mortality in separate Cox regression models. Included were the 448 adult heart transplant candidates listed for an urgent status between October 2010 and June 2011 in Eurotransplant. A cardiac allocation score (CAS) was calculated based on the estimated survival times as predicted by the scores. All analyses were performed for the total cohort and separately for ventricular assist device (VAD) and non-VAD patients.
Mortality on the waiting list could significantly be predicted in the non-VAD cohort by HFSS (p = 0.005) and SHFM (p < 0.0001) and after transplant by IMPACT (p < 0.0001). None of the tested scores could predict mortality among VAD-supported patients.
In non-VAD patients, the HFSS, SHFM, and IMPACT provide accurate risk stratification. Further studies will reveal whether these models should be considered as the basis for a new heart allocation policy in Eurotransplant.
A roundtable meeting to discuss the use of therapeutic drug monitoring (TDM) to guide immunosuppression with mycophenolate mofetil was held in New York in December 2004. Existing recommendations for ...the initial months after transplantation were updated. After ensuring adequate levels of mycophenolic acid (MPA, the active metabolite of mycophenolate mofetil) immediately after transplantation, optimal efficacy may require only a few dose adjustments, because intrapatient variability in exposure seems low. Recommendations based on current knowledge were made for posttransplantation sampling time points and for target MPA concentrations. Algorithms for estimating MPA exposure using limited sampling strategies were presented, and a new assay for MPA discussed. It was agreed that because of interpatient variability and the influence of concomitant immunosuppressants, TDM might help optimize outcomes, especially in patients at higher risk of rejection. The value of TDM in the general transplant population will be assessed from large, ongoing, randomized studies.
The purpose of the study was to investigate the impact of the lung allocation score (LAS) on mortality among highly urgent (HU) and urgent (U) lung transplant (LTx) candidates in Eurotransplant (ET) ...and to identify useful additional parameters (LASplus).
All adult LTx candidates for whom a first request for HU or U status was made in 2008 in ET were included (N = 317). Patients were followed until LTx, death on the waiting list (WL), delisting, or closure date (i.e., January 10, 2010). The relationship between the LAS/LASplus and waiting list, post-transplant, and overall mortality was assessed with a multivariate regression model. The LAS and LASplus were decomposed into their basic waitlist and post-transplant components.
Waiting list mortality rate was 22% and 1-year post-transplant mortality rate was 34%. The waitlist component of the LASplus was significantly associated with waiting list mortality (hazard ratio HR 1.91, p = 0.021), whereas the LAS was not (p = 0.063). The post-transplant components of both scores were significantly associated with 1-year post-transplant mortality (LAS: HR 2.69, p = 0.005; LASplus: HR 2.55, p = 0.004). Both scores strongly predicted overall mortality (LAS: HR 1.65, p = 0.008; LASplus: HR 1.72, p = 0.005).
LAS accurately predicts overall mortality in critically ill transplant candidates and should therefore be considered as the basis for a new lung allocation policy in ET. An adjustment of the original LAS may be indicated to accurately predict waiting list mortality.
This retrospective single-center study aimed to analyze transfusion requirements, coagulation parameters, and outcome parameters in patients undergoing lung transplantation (LuTx) with intraoperative ...extracorporeal circulatory support, comparing cardiopulmonary bypass (CPB), and extracorporeal membrane oxygenation (ECMO).
Over a 3-year period, 49 of a total of 188 LuTx recipients were identified being set intraoperatively on either conventional CPB (n = 22) or ECMO (n = 27). Intra- and postoperative transfusion and coagulation factor requirements as well as early outcome parameters were analyzed.
LuTx patients on CPB had significantly higher intraoperative transfusion requirements when compared with ECMO patients, that is, packed red cells (9 units 5-18 vs. 6 units 4-8, p = 0.011), platelets (3.5 units 2-4 vs. 2 units 0-3, p = 0.034), fibrinogen (5 g 4-6 vs. 0 g 0-4, p = 0.013), prothrombin complex concentrate (3 iU 2-5 vs. 0 iU 0-2, p = 0.001), and tranexamic acid (2.5 mg 2-5 vs. 2.0 mg 1-3, p = 0.002). Also, ventilator support requirements (21 days 7-31 vs. 5 days 3-21, p = 0.013) and lengths of ICU stays (36 days 14-62 vs. 15 days 6-44, p = 0.030) were markedly longer in CPB patients. There were no differences in 30-day and 1-year mortality rates.
These data indicate a perioperative advantage of ECMO usage with low-dose heparinization over conventional CPB for extracorporeal circulatory support during LuTx. Long-term outcome is not affected.
The calcineurin inhibitor tacrolimus, which is available as an immediate- or extended-release formulation, is the standard-of-care immunosuppression after kidney transplantation with low rejection ...rates, especially in the first year after transplantation. However, its highly variable metabolism rate, narrow therapeutic window, and nephrotoxic side effects require close drug monitoring and individual dosing. Here, we describe first the application of extended-release tacrolimus (ER-Tac) twice daily with beneficial effects in a kidney transplant recipient under extensive therapeutic drug monitoring. A 47-year-old female kidney transplant recipient, who was identified as a fast metabolizer for tacrolimus, presented with declining allograft function and low tacrolimus through levels over time and 8 years after a second kidney transplantation despite the administration of high doses of ER-Tac once daily. Therefore, the area under the concentration–time curve (AUC) showed exceedingly high blood levels of ER-Tac. The latest biopsy of the kidney transplant showed arteriolar hyalinosis with pole vessel stenosis as a sign of chronic transplant vasculopathy and transplant glomerulopathy as a sign of chronic humoral rejection. After the exclusion of other options for immunosuppressive therapy due to the patient’s high immunological risk, the patient was switched from ER-Tac once daily to ER-Tac twice daily. After switching to ER-Tac twice daily, the AUC for oral tacrolimus decreased and the transplant function improved despite higher tacrolimus trough levels and a lower total dose administered. This case highlights the importance of careful therapeutic drug monitoring with the performance of an AUC in the follow-up management of kidney transplant recipients.
Immunosuppressants and antifibrotics are currently used to treat patients with various interstitial lung diseases, which may undergo lung transplantation (LTx). The retrospective study aimed to ...evaluate the potential effects of therapeutic regimen on the perioperative course in patients with idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF) undergoing LTx. All patients with IPF and PPF undergoing LTx between January 2014 and December 2021 were included. We retrospectively screened for previous use of immunosuppressants and antifibrotic therapy. We analyzed perioperative courses, short-term outcomes, and safety retrospectively. In total, 286 patients with diagnosis of IPF or PPF were analyzed. According to the treatment regimen before LTx, the study cohort was divided into four groups and compared. No differences between antifibrotic monotherapy, combined antifibrotic and immunosuppressive therapy with regard to postoperative complications were observed. Length of mechanical ventilation was shorter in patients with antifibrotics prior to LTx. Pretreatment with antifibrotic monotherapy and a combination of antifibrotic drugs with immunosuppressive therapy, lower body mass index (BMI) and lower blood loss, were independently associated with primary graft dysfunction grades 0-3 72 hours after LTx (
< 0.001). Finally, patients with antifibrotic monotherapy developed significantly less de novo donor-specific antibodies (DSA) (
= 0.009). Higher intraoperative blood loss, etiology of interstitial lung disease (ILD) and older age were independently associated with shorter survival after LTx. Use of antifibrotic monotherapy and a combination of antifibrotic drugs with immunosuppressive therapy in IPF/PPF patients undergoing LTx, proved to be safe and might lead to beneficial effects after LTx.
Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation (HTx). This study investigates the impact of PPI use on mycophenolate acid (MPA) ...pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) and tacrolimus (Tac).
MPA post-dose plasma concentrations at 0 to 2 hours were obtained by high-performance liquid chromatography (HPLC) in 21 patients on pantoprazole 40 mg/day (PPI group) and 12 patients not on pantoprazole (control group). In a subgroup, MPA plasma concentrations at 0 to 12 hours were measured to evaluate full MPA area-under-the-curve (AUC) measurements.
In the PPI group, the mean daily MMF dose was 1,912 +/- 1,023 mg with mean pre-dose serum concentrations (C(0)) of 1.9 +/- 1.4 mg/liter, without a significant difference from controls. Mean post-dose MPA concentrations at 30 minutes (C(0.5h)) were significantly higher in the control group (control, 17.9 +/- 11.5 mg/liter; PPI, 6.7 +/- 4.6 mg/liter; p < 0.001). One- and 2-hour (C(1h, 2h)) MPA concentrations were persistently higher in the control group (1 hour: control, 13.8 +/- 9.1 mg/liter; PPI, 7.7 +/- 4.1 mg/liter; 2 hours: control, 7.6 +/- 4.2; PPI, 5.0 +/- 2.8 mg/liter; p < 0.05). In the subgroup with full AUC measurements, the control group had higher MPA levels 12 hours after dosing (C(12h): control, 3.3 +/- 2.4 mg/liter; PPI, 1.6 +/- 1.3 mg/liter; p < 0.05) and a significantly higher dose-adjusted AUC C(0-3h) (control, 59.5 +/- 20.7 mg/liter; PPI, 41.7 +/- 23.4 mg/liter; p < 0.05). In the subgroup, the maximum plasma concentration of mycophenolic acid (MPA C(max)) in the PPI group was significantly lower (10.1 +/- 4.7 mg/liter) than in the control group (45.5 +/- 53.5 mg/liter, p < 0.0001), whereas t(max) revealed no differences (control: 1.1 +/- 0.77 hours; PPI: 1.1 +/- 0.97 hours). Furthermore, a clear trend for more acute rejection episodes (AREs) and more transplant vasculopathy (TVP) was found in the PPI group.
Patients with PPI co-medication show significantly lower MPA plasma concentrations, possibly due to decreased absorption. Therapeutic drug monitoring allows identification of patients with decreased MMF drug exposure who might be at risk for acute rejection.
This observational study focuses on the characteristics and survival of patients taken off of the liver transplant waiting list. Assessment of post-delisting survival and a frequent follow-up of ...patients after delisting are important keys to improve the survival rate of patients with liver failure after being delisted. Within this study, delisted liver transplant candidates were divided into the following groups: (1) “too good” (54%) or (2) “too sick” (22%) for transplantation, (3) adherence issues (12%) or (4) therapy goal changed (11%). The 5-year survival after delisting within these groups was 84%, 9%, 50%, and 68%, respectively. Less than 3% of the delisted patients had to be relisted again. The clinical expert decision of the multidisciplinary transplant team was sufficiently accurate to differentiate between patients requiring liver transplantation and those who were delisted after a stable recovery of liver function. The assessment of post-delisting survival may serve as a complementary metric to assess differences in center practices and to estimate cumulative post-delisting mortality risk.
OBJECTIVES
This study was designed to assess the association between 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition, coronary endothelial function and cytokine activation in ...heart transplant recipients without angiographically detectable disease.
BACKGROUND
Coronary endothelial dysfunction contributes to cardiac allograft vasculopathy. The vasoprotective effects of statins in heart transplant recipients may include restoration of endothelial function and suppression of allograft inflammatory activity.
METHODS
Heart transplant recipients (one to three years after heart transplant) were divided into three groups based on the total cholesterol levels: group 1 (n = 21), patients with a history of hypercholesterolemia adequately controlled with simvastatin; group 2 (n = 19), patients with hypercholesterolemia not adequately treated with simvastatin; and group 3 (n = 40), patients without hypercholesterolemia. Coronary vasomotor function and intimal thickness as well as coronary sinus and aortic cytokine concentrations (tumor necrosis factor TNF-α, interleukin IL-6 and soluble IL-2 receptor) were investigated. In a prospective one-year follow-up study, changes in coronary endothelial function and cytokine levels were compared between 11 hypercholesterolemic patients treated with simvastatin and 9 controls.
RESULTS
Epicardial and microvascular endothelial functions were better in groups 1 and 3 than they were in group 2 (p < 0.01 and p < 0.05). Transcardiac IL-6 and TNF-α gradients were significantly increased in groups 2 and 3 compared with group 1 (IL-6: p < 0.05; TNF-α: p < 0.01). Plaque areas were significantly increased in groups 1 and 2 (p < 0.05 vs. group 3), whereas lumen area was increased in group 2 compared with group 1 (p < 0.05), demonstrating adaptive vascular remodeling. In patients treated with simvastatin, coronary endothelial function and cardiac cytokine activity significantly improved during the one-year follow-up.
CONCLUSIONS
Inhibition of allograft inflammatory activity and attenuation of the coronary endothelial dysfunction observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of cardiac allograft vasculopathy.
Despite improvements in immunosuppressive therapy, the most advantageous combination for cardiac transplant recipients has not been established. This randomized controlled trial was performed to ...evaluate the efficacy and safety of 3 immunosuppressive protocols.
Between 2003 and 2005, 78 de novo cardiac transplant recipients were randomized 2:2:1 to receive steroids and tacrolimus plus mycophenolate mofetil (TAC/MMF; n = 34), TAC and sirolimus (TAC/SRL; n = 29), or SRL and MMF (SRL/MMF) plus anti-thymocyte globulin (ATG; n = 15). Steroids were withdrawn after 6 months.
The 5-year survival was 85.3% for TAC/MMF, 93.1% for TAC/SRL, and 86.7% for SRL/MMF (p = 0.31 for TAC/MMF vs TAC/SIR; p = 0.47 for TAC/MMF vs SIR/MMF and p = 0.86 for TAC/SIR vs SIR/MMF). Despite the use of ATG, patients in the SRL/MMF group revealed numerically fewer freedom from acute rejection episodes: TAC/MMF, 82.4%; TAC/SRL, 85.2%; SRL/MMF, 73.3% (p = 0.33). Mean creatinine at 5 years revealed preservation of renal function in the SRL/MMF vs the TAC/MMF group (p = 0.045): TAC/MMF, 1.70±0.91 mg/dl; TAC/SRL, 1.44±0.65 mg/dl; and SRL/MMF, 1.25±0.46 mg/dl. Freedom from cardiac allograft vasculopathy was improved in the SRL/MMF group (93.3%) compared with TAC/MMF (73.5%) and TAC/SRL (80.8%) groups, reaching no statistical significance. Freedom from cytomegalovirus infection was TAC/MMF, 72.2%; TAC/SRL, 89.7%; and SRL/MMF, 86.7%. There was a trend toward improved freedom from cytomegalovirus infection with TAC/SRL vs TAC/MMF (p = 0.076). More frequent discontinuations of study medication occurred in SRL-based immunosuppression protocols (TAC/SRL vs TAC/MMF, p = 0.034; SRL/MMF vs TAC/MMF, p = 0.003).
The 3 strategies yield no survival advantage at 5 years, with higher numeric rates of rejection and adverse effects in the calcineurin inhibitor-free arm. A trend was observed in favor of freedom from cardiac allograft vasculopathy and preservation of renal function in the calcineurin inhibitor-free arm. However, the clinical relevance on outcomes is unclear because only few patients were receiving the assigned treatment protocols.
PDF