De novo donor‐specific antibodies in belatacept‐treated vs cyclosporine‐treated kidney‐transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT‐EXT studies

Donor‐specific antibodies (DSAs) are associated with an increased risk of antibody‐mediated rejection and graft failure. In BENEFIT and BENEFIT‐EXT, kidney‐transplant recipients were randomized to receive belatacept more intense (MI)–based, belatacept less intense (LI)–based, or cyclosporine‐based immunosuppression for up to 7 years (84 months). The presence/absence of HLA‐specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid‐phase flow‐cytometry screening. Samples from anti‐HLA‐positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan‐Meier analysis, de novo DSA incidence was significantly lower in belatacept‐treated vs cyclosporine‐treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept‐based immunosuppression was associated with numerically lower MFI vs cyclosporine‐based immunosuppression. Although derived post hoc, these data suggest that belatacept‐based immunosuppression suppresses de novo DSA development more effectively than cyclosporine‐based immunosuppression.     

Donor‐Specific HLA Antibodies in a Cohort Comparing Everolimus With Cyclosporine After Kidney Transplantation

Donor‐specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody‐mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3–4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow‐up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log‐rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log‐rank: p = 0.036). Four of 10 patients with AMR—all in the everolimus group—lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus‐based immunosuppression is associated with an increased risk for the development of DSA and AMR.     

Renal function preservation with the mTOR inhibitor,Everolimus, after lung transplant

Chronic kidney disease (CKD) is a common complication of calcineurin inhibitors (CNIs) in solid organ transplantation. Previous data suggest that the use of everolimus as an immunosuppressant drug leads to improvement in renal function. The aim of our study was to establish the effect of everolimus in combination with lower doses of CNIs on renal function among lung transplant recipients. Data regarding renal function and pulmonary function were collected from 41 lung transplanted patients in whom treatment was converted to a combination of everolimus with lower doses of CNIs. Patients transferred to everolimus and low dose CNIs showed an improvement in renal function. Patients who continued treatment with everolimus showed improvement in renal function, as opposed to patients who discontinued the treatment. Subjects without proteinuria at baseline showed a better improvement compared with subjects with proteinuria. The incidence of graft rejection did not increase. We concluded that a protocol that includes everolimus and lower doses of CNIs is effective for preserving renal function in lung transplant recipients with CKD. We also believe that an early implementation of everolimus, before proteinuria occurs or creatinine clearance is reduced, could lead to better outcomes.     

Impact of Early Blood Transfusion After Kidney Transplantation on the Incidence of Donor‐Specific Anti‐HLA Antibodies

Little is known about the impact of posttransplant blood transfusion on the sensitization of anti‐HLA antibodies and the formation of donor‐specific antibodies (DSAs). The aims of our study were to determine the 1‐year incidence of DSAs (assessed using a solid‐phase assay) and antibody‐mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non–HLA‐sensitized patients who had received an ABO‐compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1‐year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.     

Posttransplant reduction in preexisting donor‐specific antibody levels after belatacept‐ versus cyclosporine‐based immunosuppression: Post hoc analyses of BENEFIT and BENEFIT‐EXT

BENEFIT and BENEFIT‐EXT were phase III studies of cytotoxic T‐cell crossmatch–negative kidney transplant recipients randomized to belatacept more intense (MI)‐based, belatacept less intense (LI)‐based, or cyclosporine‐based immunosuppression. Following study completion, presence/absence of HLA‐specific antibodies was determined centrally via solid‐phase flow cytometry screening. Stored sera from anti‐HLA–positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of donor‐specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present. The effect of belatacept‐based and cyclosporine‐based immunosuppression on MFI was explored post hoc in patients with preexisting DSAs enrolled to BENEFIT and BENEFIT‐EXT. In BENEFIT, preexisting DSAs were detected in 4.6%, 4.9%, and 6.3% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 6.0%, 5.7%, and 9.2%. In both studies, most preexisting DSAs were of class I specificity. Over the first 24 months posttransplant, a greater proportion of preexisting DSAs in belatacept‐treated versus cyclosporine‐treated patients exhibited decreases or no change in MFI. MFI decline was more apparent with belatacept MI‐based versus belatacept LI‐based immunosuppression in both studies and more pronounced in BENEFIT‐EXT versus BENEFIT. Although derived post hoc, these data suggest that belatacept‐based immunosuppression decreases preexisting DSAs more effectively than cyclosporine‐based immunosuppression.     

De novo donor‐specific anti‐HLA antibodies mediated rejection in liver‐transplant patients

The incidence and consequences of de novo donor‐specific anti‐HLA antibodies (DSAs) after liver transplantation (LT) are not well known. We investigated the incidence, risk factors, and complications associated with de novo DSAs in this setting. A total of 152 de novo liver‐transplant patients, without preformed anti‐HLA DSAs, were tested for anti‐HLA antibodies, with single‐antigen bead technology, before, at transplantation, at 1, 3, 6 and 12 months after transplantation, and thereafter annually and at each time they presented with increased liver‐enzyme levels until the last follow‐up, that is, 34 (1.5–77) months. Twenty‐one patients (14%) developed de novo DSAs. Of these, five patients had C1q‐binding DSAs (24%). Younger age, low exposure to calcineurin inhibitors, and noncompliance were predictive factors for de novo DSA formation. Nine of the 21 patients (43%) with de novo DSAs experienced an acute antibody‐mediated rejection (AMR). Positive C4d staining was more frequently observed in liver biopsies of patients with AMR (9/9 vs. 1/12, P < 0.0001). Eight patients received a B‐cell targeting therapy, and one patient received polyclonal antibodies. Only one patient required retransplantation. Patient‐ and graft‐survival rates did not differ between patients with and without DSAs. In conclusion, liver‐transplant patients with liver abnormalities should be screened for DSAs and AMR.     

Neurological complications after liver transplantation as a consequence of immunosuppression: univariate and multivariate analysis of risk factors

Neurological complications (NCs) can frequently and significantly affect morbidity and mortality of liver transplant (LT) recipients. We analysed incidence, risk factors, outcome and impact of the immunosuppressive therapy on NC development after LT. We analysed 478 LT in 440 patients, and 93 (19.5%) were followed by NCs. The average LOS was longer in patients experiencing NCs. The 1‐, 3‐ and 5‐year graft survival and patient survival were similar in patients with or without a NC. Multivariate analysis showed the following as independent risk factors for NC: a MELD score ≥20 (OR = 1.934, CI = 1.186–3.153) and an immunosuppressive regimen based on calcineurin inhibitors (CNIs) (OR = 1.669, CI = 1.009–2.760). Among patients receiving an everolimus‐based immunosuppression, the 7.1% developed NCs, vs. the 16.9% in those receiving a CNI (P = 0.039). There was a 1‐, 3‐ and 5‐year NC‐free survival of 81.7%, 81.1% and 77.7% in patients receiving a CNI‐based regimen and 95.1%, 93.6% and 92.7% in those not receiving a CNI‐based regimen (P < 0.001). In patients undergoing a LT and presenting with nonmodifiable risk factors for developing NCs, an immunosuppressive regimen based on CNIs is likely to result in a higher rate of NCs compared to mTOR inhibitors.     

Late conversion of tacrolimus to sirolimus in a prednisone‐free immunosuppression regimen in renal transplant patients

Chhabra D, Grafals M, Cabral B, Leventhal J, Parker M, Gallon L. Late conversion of tacrolimus to sirolimus in a prednisone‐free immunosuppression regimen in renal transplant patients.
Clin Transplant 2009: DOI: 10.1111/j.1399‐0012.2009.01047.x
© 2009 John Wiley & Sons A/S. Abstract: Background: One of the most important causes of graft loss is chronic nephrotoxicity from calcineurin inhibitors. The aim of this study was to evaluate the feasibility and to assess the impact on rejection risk, graft loss and renal allograft function of converting patients from tacrolimus (Tac) to sirolimus (SRL) at one yr post‐transplantation (Tx) using a prednisone‐free immunosuppressive regimen. Methods: Two hundred fifty‐five kidney transplant patients were induced with Alemtuzumab and maintained on a steroid‐free regimen with Tac and mycophenolate mofetil. Thirty‐seven stable patients (14%) were converted from Tac to SRL at one yr post‐Tx. Results: The two groups were demographically similar. Mean post‐tx follow‐up was 2.8 ± 0.2 yr. Patient and graft survival were not statistically different. There was no significant difference in acute rejection episodes between the SRL and Tac groups (21% vs. 15%, p = 0.2). Calculated glomerular filtration rate (GFR), in the SRL group at 2.8 yr post‐tx, was 69 ± 13 mL/min from the one month post‐tx GFR of 53 ± 19 and 59 ± 23 mL/min from the one month post‐tx GFR of 56 ± 21 mL/min in the Tac group. Conclusions: Using a prednisone‐free regimen, the conversion of Tac to SRL at one yr post‐Tx was not associated with an increased risk of acute rejection or graft loss.     

Clinical Significance of Pretransplant Donor‐Specific Antibodies in the Setting of Negative Cell‐Based Flow Cytometry Crossmatching in Kidney Transplant Recipients

Antibodies to donor‐specific HLA antigens (donor‐specific antibodies [DSA]) detected by single‐antigen bead (SAB) analysis prior to kidney transplant have been associated with inferior graft outcomes. However, studies of pretransplant DSA, specifically in the setting of a negative flow cytometry crossmatch (FCXM) without desensitization therapy, are limited. Six hundred and sixty kidney and kidney–pancreas recipients with a negative pretransplant FCXM from September 2007 to August 2012 without desensitization therapy were analyzed with a median follow‐up of 4.2 years. All patients underwent cell‐based FCXM and SAB analysis on current and historic sera prior to transplantation. One hundred and sixty‐two patients (24.5%) had DSA detected prior to transplant. One‐year acute rejection rates were similar in DSA‐positive versus DSA‐negative patients (15.4% vs. 11.4%, respectively; p = 0.18) and were higher in those with DSA mean fluorescence intensity (MFI) greater than or equal to 3000 in multivariable analysis (p = 0.046). The estimated glomerular filtration rate (eGFR) at 3 and 4 years was lower in the DSA(+) versus the DSA(?) group (p = 0.050 at 3 years) without an impact on 5‐year death‐censored graft survival (89.0% vs. 90.6%, respectively; p = 0.53). Timing (current or historic) of DSA detection did not alter these findings. In conclusion, pretransplant DSA in the setting of a negative FCXM confers minimal immunologic risk in the intermediate term, does not necessitate desensitization therapy and should not represent a barrier to renal transplant.     

A Randomized,Controlled Study to Assess the Conversion From Calcineurin‐Inhibitors to Everolimus After Liver Transplantation—PROTECT

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal‐sparing alternative. In this randomized 1‐year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post‐LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft‐Gault formula (?2.9 mL/min in favor of EVR, 95%‐CI: [?10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (?7.8 mL/min, 95%‐CI: [?14.366; ?1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy‐proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI‐based to EVR‐based immunosuppression proved to be a safe alternative post‐LTx that deserves further investigation in terms of nephroprotection.     

CD25 blockade in kidney transplant patients randomized to standard‐dose or high‐dose basiliximab with cyclosporine,or high‐dose basiliximab in a calcineurin inhibitor‐free regimen

An increased basiliximab dose may saturate T‐cell CD25 receptors in kidney transplant patients receiving calcineurin inhibitor (CNI)‐free immunosuppression. In a 12‐week study, 16 de novo kidney transplant patients were randomized to (i) 40 mg basiliximab with cyclosporine [n = 3] (controls), (ii) 80 mg basiliximab with cyclosporine [n = 6], or (iii) 80 mg basiliximab with everolimus (CNI‐free) [n = 7], all with mycophenolic acid and steroids. Recruitment was stopped prematurely due to increased biopsy‐proven acute rejection (BPAR) in the basiliximab 80 mg CNI‐free group. BPAR occurred in 1/3, 1/6, and 4/7 patients in the three treatment groups, respectively. The primary endpoint, area under the effect curve of CD25 saturation to week 12, was 8.4(1.6) % × weeks in the control group, 11.1(1.1) % × weeks with basiliximab 80 mg + cyclosporine, and 9.7(0.7) % × weeks in the basiliximab 80 mg CNI‐free group (P = 0.020 for basiliximab 80 mg + cyclosporine versus controls; P = 0.119 for basiliximab 80 mg CNI‐free versus controls). Although small patient numbers prohibit robust conclusions, these results suggest that doubling the cumulative basiliximab dose to 80 mg does not provide adequate immunosuppression during the first 3 months after kidney transplantation in the absence of CNI therapy (ClinicalTrials.gov number: NCT01596062).     

Acquisition of C3d‐Binding Activity by De Novo Donor‐Specific HLA Antibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients

Alloantibody‐mediated graft injury is a major cause of kidney dysfunction and loss. The complement‐binding ability of de novo donor‐specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement‐fixing dnDSAs and their role in antibody‐mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q⁺ and C3d⁺ in 25 and nine patients, respectively. At follow‐up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d‐fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10‐year graft survival probability was lower in patients with C3d‐binding dnDSA than in those without dnDSAs or with C1q⁺/C3d^? or non‐complement‐binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics.     

De novo mTOR inhibitor‐based immunosuppression in ABO‐incompatible kidney transplantation

ABO‐incompatible (ABOi) kidney transplantation (KTx) has become an accepted therapeutic option in renal replacement therapy for patients without a blood group‐compatible living donor. Using different desensitization strategies, most centers apply B‐cell depletion with rituximab and maintenance immunosuppression (IS) with tacrolimus and mycophenolic acid. This high load of total IS leads to an increased rate of surgical complications and virus infections in ABOi patients. Our aim was to establish ABOi KTx using an immunosuppressive regimen, which is effective in preventing acute rejection without increasing the risk for viral infections. Therefore, we selected a de novo immunosuppressive protocol with low‐dose calcineurin inhibitor and the mTOR inhibitor everolimus for our ABOi program. Here, we report the first 25 patients with a complete three‐yr follow‐up treated with this regimen. Three‐yr patient survival and graft survival were 96% and 83%. The rate of acute T‐cell‐mediated rejections was low (12%). Cytomegalovirus (CMV) infection was evident in one patient only (4%). Surgical complications were common (40%), but mild in 80% of cases. We demonstrate that ABOi KTx with a de novo mTOR inhibitor‐based regimen is feasible without severe surgical or immunological complications and a low rate of viral infections.     

Pilot conversion trial from mycophenolic acid to everolimus in ABO‐incompatible kidney‐transplant recipients with BK viruria and/or viremia

Immunosuppression using everolimus (EVR) plus low‐dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long‐term outcomes and impacts of Tac‐EVR on the BK virus are reported in ABO‐incompatible kidney‐transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34–529) days post‐transplantation, seven stable ABO‐incompatible kidney‐transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO‐incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow‐up, clinical and biological parameters were monitored. The median time from conversion to the last follow‐up was 784 (398‐866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti‐HLA antibodies). At last follow‐up, median eGFR was similar in the Tac‐MPA versus Tac‐EVR group (40 [range: 14–56] vs. 54.5 ml/min/1.73 m² [range: 0–128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO‐incompatible kidney‐transplant recipients with an active BK virus infection may benefit from conversion to EVR.     

Conversion from calcineurin inhibitor–based immunosuppression to mammalian target of rapamycin inhibitors or belatacept in renal transplant recipients

The calcineurin inhibitors (CNIs) remain the standard of care for maintenance immunosuppression following renal transplantation. CNIs have demonstrated their effectiveness in reducing acute cellular rejection; however, some evidence suggests that these compounds negatively affect native renal function and are associated with allograft injury in renal transplant recipients. CNIs have also been linked with hypertension, new‐onset diabetes after transplantation, tremor, and thrombotic microangiopathy, which have significant consequences for long‐term allograft function and patient health overall. Thus, converting patients to a non‐CNI‐based regimen may improve renal function and also provide extrarenal benefits. A number of studies have been conducted that explore CNI conversion strategies in renal transplant recipients in an effort to improve long‐term allograft function and survival. These include converting to alternative, non‐nephrotoxic, maintenance immunosuppressants, such as the mammalian target of rapamycin inhibitors (sirolimus and everolimus) and the costimulation blocker belatacept. In this review of literature, evidence for the potential renal and extrarenal benefits of conversion to these non‐CNI‐based regimens is evaluated. Clinical challenges, including the adverse event profiles of non‐CNI‐based regimens and the selection of candidates for conversion, are also examined.     

Eculizumab Salvage Therapy for Antibody‐Mediated Rejection in a Desensitization‐Resistant Intestinal Re‐Transplant Patient

The presence of elevated calculated panel reactive antibody (cPRA) and anti‐HLA donor specific antibodies (DSA) are high risk factors for acute antibody‐mediated rejection (AAMR) in intestinal transplantation that may lead to graft loss. Eculizumab has been used for the treatment of AAMR in kidney transplantation of sensitized patients that do not respond to other treatment. Here, we report a case where eculizumab was used to treat AAMR in a desensitization‐resistant intestinal re‐transplant patient. A male patient lost his intestinal graft to AAMR 8.14 years after his primary transplant. He received a second intestinal graft that had to be explanted a month later due to refractory AAMR. The patient remained highly sensitized despite multiple treatments. He received a multivisceral graft and presented with severe AAMR on day 3 posttransplantation. The AAMR was successfully treated with eculizumab. The patient presently maintains an elevated cPRA level above 90% but his DSAs have decreased from 18 000 MFI (mean fluorescent intensity) to below the positive cut‐off value of 3000 MFI and remains rejection free with a 2‐year follow‐up since his multivisceral transplant. Eculizumab offers an alternative to treat AAMR in intestinal transplantation in desensitization‐resistant patients.     

Experience with belatacept rescue therapy in kidney transplant recipients

In kidney transplant recipients with chronic graft dysfunction, long‐term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy‐nine kidney transplant recipients treated with CNI‐based or mTORi‐based maintenance immunosuppression who had CNI‐induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26.1 ± 15.0 ml/min/1.73 m², increasing to 34.0 ± 15.2 ml/min/1.73 m² at 12 months postconversion (P < 0.0005). Renal function improvements were also seen in patients with low eGFR (<25 ml/min/1.73 m²) or high proteinuria (>500 mg/l) at conversion. The Kaplan–Meier estimates for patient and graft survival at 12 months were 95.0% and 85.6%, respectively. The discontinuation rate due to adverse events was 7.9%. One case of post‐transplant lymphoproliferative disorder occurred at 17 months postconversion. For comparison, a historical control group of 41 patients converted to mTORi‐based immunosuppression because of biopsy‐confirmed CNI‐induced toxicity was examined; eGFR increased from 27.6 ± 7.2 ml/min/1.73 m² at baseline to 31.1 ± 11.9 ml/min/1.73 m² at 12 months (P = 0.018). Belatacept‐based immunosuppression may be an alternative regimen for kidney transplant recipients with CNI‐ or mTORi‐induced toxicity.     

Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review

Calcineurin inhibitors (CNIs) have been associated in a dose‐dependent fashion with an increased risk of post‐transplant hepatocellular carcinoma (HCC) recurrence. The mammalian target of rapamycin inhibitors (mTORi) (sirolimus/everolimus) might represent an alternative immunosuppressive regimen with antineoplastic effect. In the present systematic review, the association between mTORi and HCC recurrence after liver transplantation (LT) was evaluated and compared against that of CNIs‐treated patients. In total, 3666 HCC liver transplant recipients from 42 studies met the inclusion criteria. Patients under CNIs developed HCC recurrence significantly more frequently, compared with patients under mTORi (448/3227 or 13.8% vs. 35/439 or 8%, P < 0.001), although patients treated with CNIs had a higher proportion of HCC within Milan criteria (74% vs. 69%) and lower rates of microvascular invasion, compared with mTORi‐treated patients (22% vs. 44%) (P < 0.05). Patients on everolimus had significantly lower recurrence rates of HCC, compared with those on sirolimus or CNIs (4.1% vs. 10.5% vs. 13.8%, respectively, P < 0.05), but everolimus‐treated recipients had shorter follow‐up period (13 vs. 30 vs. 43.2 months, respectively) and more frequently been transplanted for HCC within Milan criteria (84% vs. 60.5% vs. 74%, respectively, P < 0.05). Our findings favor the use of mTORi instead of CNIs to control HCC recurrence after LT, but comparative studies with longer follow‐up are needed for final conclusions.     

Preformed donor‐specific antibodies do not affect the 1‐year allograft survival in living donor liver transplantation

The effect of preformed donor‐specific antibodies (DSAs) on liver transplantation (LT) remains unclear, especially in the field of living donor LT (LDLT). Herein, we evaluated the prevalence of preformed DSAs and their effect on graft outcome in LDLT in the first year following surgery. Using the Luminex^® Single Antigen assay, we analyzed the preoperative sera of 61 adult LDLT recipients between 2014 and 2015. Clinical outcomes and pathologic findings including complement component 4d (C4d) expression in the first year after LT were retrospectively reviewed. Regardless of the class of DSA, DSAs with mean fluorescence intensity (MFI) ≥1000 were defined as positive and preformed DSA with MFI ≥5000 was defined as strongly positive. Fifteen patients (24.6%) had preformed DSAs, and 8 patients (13.1%) showed strongly positive preformed DSAs. Among 15 DSA positive patients, 2 (13.3%) showed persistent DSAs after LDLT. No de novo DSAs were noted in patients without preformed DSAs. Preformed DSAs were not related to graft dysfunction, laboratory values, or C4d expression or other pathologic findings in the first year of LDLT. In conclusion, preformed DSAs persisted during follow‐up in 13.3% of cases and did not have adverse effect on histologic or clinical outcomes in the first year of LDLT.     

Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score–matched cohort analysis

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low‐dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard‐dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3‐year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3 months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n = 128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P = .007) and biopsy‐proven acute rejections (15 [23.4%] vs 31 [48.4%], P = .002). These results were confirmed in the overall cohort (n = 213), after multivariable and inverse probability score weighting analyses. Renal function and donor‐specific HLA‐antibodies remained similar in both groups. Low‐dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy.