Lower Incidence Of Acute Rejection Research Articles

#2649 INFECTIOUS COMPLICATIONS AFTER KIDNEY TRANSPLANTATION IN RELATION TO INDUCTION IMMUNOSUPPRESSIVE THERAPY

Abstract Background and Aims Infections are the most common non-cardiac cause of death after kidney transplantation (KT). The main goal of immunosuppressive therapy is to find a balance between the low incidence of acute rejection and infectious complications. Method We conducted a retrospective, monocentric analysis of transplant patients at the Transplant Center University Hospital Martin from 2011 to 2020 with various induction immunosuppressive therapies. We monitored the incidence of infections in terms of etiology, localization and severity at different intervals after KT. Results Our study included 39 patients on induction therapy with basiliximab to whom we paired 39 patients with induction therapy with thymoglobulin based on gender and age, in total our population consisted of 78 patients (56 men, 22 women), the mean age was 45 years. In the group of patients with induction therapy with thymoglobulin, we noted a higher proportion of fungal (P=0.0409), urogenital infections (P=0.0384), sepsis (P=0.0497) and leukopenia (0.0384) from 1st to 6th month after KTx, higher incidence of skin infections (P= 0.0218) and serious infections requiring hospitalization (P = 0.0269) from 6th-12th months to TO. On the other hand, in the basiliximab patient group, we identified a higher incidence of acute humoral and cellular rejection (P=0.0218) after 6 months of TO. From the perspective of recurrent infections, in the Thymoglobulin induction group, we noted a higher incidence of infections by localization, etiology and severity. Risk factors for recurrent bacterial infections from 1st to 6th month after KT are: history of respiratory diseases (P = 0.0108), thrombocytopenia (P = 0.0104) and infections caused by multi-resistant bacteria (P = 0.0003). Conclusion Patients on inductive immunosuppressive therapy with thymoglobulin are at a higher risk of recurrent, multidrug-resistant and severe infections after KT compared to induction with basiliximab with identical maintenance immunosuppressive therapy. On the other hand, patients on induction therapy with basiliximab have a higher risk of developing acute rejection. Therefore, it is essential to identify risk groups of patients benefiting from milder or more intensive inductive immunosuppressive therapy without a concomitant increased risk of infectious complications or acute graft rejection

Tacrolimus time-in-therapeutic range is associated with freedom from acute rejection and graft failure following intestinal transplantation.

Trough-adjusted tacrolimus is commonly prescribed following intestinal transplantation to prevent allograft rejection. Despite established practice, there remains limited direct evidence linking tacrolimus levels with improved clinical outcomes. This was a single-center review of all adult non-liver containing intestinal allograft recipients from 2011 to 2018. Patients received lymphocyte depleting induction and maintenance immunosuppression consisting of tacrolimus and a corticosteroid taper. Tacrolimus time-in-therapeutic range (TAC-TTR) was calculated for all patients from the date of transplant until 1-year post-transplant using Rosendaal's method. Cox-Proportional hazards modeling was utilized to assess freedom from acute rejection and graft failure stratified by TAC-TTR quartile. 47 patients were included in the review. Mean TAC-TTR for the cohort was 30.2% ± 11.4. Fifteen episodes of acute rejection were observed, 8 of which were severe. Patients in the highest TAC-TTR quartile >36% had a lower incidence of acute rejection and graft failure relative to patients with a TAC-TTR <20%. Cox-Proportional hazards modeling found a 10% decrease in TAC-TTR was associated with an increased hazard for acute rejection (2.03), severe acute rejection (2.19), and graft loss (3.33). The results of this study suggest that decreasing TAC-TTR is a risk factor for both acute rejection as well as intestinal allograft failure.

Intra-operative kinetics of anti-HLA antibody in simultaneous liver-kidney transplantation

During simultaneous liver-kidney transplantation (SLK) in highly sensitized patients, donor specific anti-human leukocyte antigen antibodies (DSA, HLA) can be present prior to transplant leading to positive crossmatch, yet these recipients have relatively low incidences of acute rejection. The mechanisms and timing underlying immunologic changes that occur intra-operatively remain largely unknown. Therefore, we measured the intra- and peri-operative kinetics of anti-HLA antibodies in highly sensitized SLK recipients. In this study, pre- and post-operative blood samples were obtained from sensitized SLK candidates with documented DSA. Intra-operative samples were obtained from a sub-group of SLK recipients. Pretransplant anti-HLA antibody profiles were created and flow cytometry and anti-human globulin complement-dependent cytotoxic crossmatches were performed. Significant reductions in anti-HLA class I and II DSA were seen intra-operatively shortly after reperfusion of the liver allograft. This effect was most pronounced for anti-HLA class I DSA (mean change, −85%, p < 0.05); changes to anti-HLA class II DSA were less robust (mean change, −47%, p = 0.15). Importantly, non-DSA anti-HLA antibodies remained unchanged throughout the perioperative period, suggesting the mechanism(s) by which the liver lowers DSA levels are specific to the DSA. These data demonstrate the immunologic benefit of performing SLK is lasting and occurs very shortly after liver reperfusion.

A Randomized Prospective Study Comparing Anti–T-Lymphocyte Igs to Basiliximab in Highly Sensitized Kidney Transplant Patients

BackgroundTwo prospective studies that were performed before the era of highly sensitive solid-phase assays have shown a lower incidence of acute rejection in highly sensitized kidney-transplant patients given polyclonal antibodies compared with those given anti-CD25 monoclonal antibodies.MethodsThis prospective pilot randomized French multicenter study aimed to compare anti–T-lymphocyte Ig (ATLG) (n = 32) and basiliximab (n = 27) in highly sensitized kidney-transplant patients without preformed donor-specific antibodies (pDSAs) as assessed by a Luminex Single-Antigen flow bead assay. Only patients with a calculated panel reactive antibody ≥50%, with at least 1 antibody with a mean fluorescence intensity ≥5000 and without a historical pDSA and without a pDSA on the day of transplantation were included.ResultsTreatment failure as defined by biopsy-proven acute rejection, patient lost to follow-up, graft loss, and death was observed in 18.8% (95% confidence interval [CI], 8.9%–37.1%) and 18.8% (95% CI, 8.9%–37.1%) in patients who received ATLG and 14.8% (95% CI, 5.8%–34.8%) and 28.2% (95% CI, 14.2%–51.2%) of patients who received basiliximab, respectively at 6 (P = 0.66) and 12 (P = 0.62) months post-transplantation. One T cell–mediated rejection was observed in ATLG-treated patients (3.1%). One antibody-mediated rejection due to a de novo donor-specific antibody (DSA) occurred in basiliximab-treated patients (3.7%). Patient survival, graft survival, kidney parameters, and infection rate were similar in the 2 groups.ConclusionThis pilot study indicates that in highly sensitized kidney-transplant patients without pDSAs, both ATLG and basiliximab can be used efficiently and safely. However, because of the lack of power, these results should be interpreted with caution.

Acute rejection after liver transplantation is less common, but predicts better prognosis in HBV-related hepatocellular carcinoma patients.

With a novel finding of significantly lower incidence of acute rejection (AR) in patients with hepatocellular carcinoma (HCC) after liver transplantation, compared with those with benign end-stage liver disease (BESLD), in a large national cohort, we analyzed the correlations among the perioperative immuno-inflammation status, postoperative AR, and prognosis in HCC and BESLD patients with same etiology of hepatitis B virus (HBV), who underwent liver transplantation. Patients who underwent liver transplantation due to HBV-related HCC or BESLD and experienced AR between September 2008 and April 2017 were analyzed retrospectively and followed up until April 2018. HCC patients with AR were matched with those without AR according to tumor stage and immunosuppressant concentration, at a 1:3 ratio. Preoperative immuno-inflammation status and prognosis of patients in both groups were compared. The overall incidences of AR in patients with HCC and BESLD were 8.60% and 10.61%, respectively. The postoperative 28-day incidence of AR was significantly lower in HCC compared with BESLD patients (3.23% vs 7.08%, p = 0.031). Compared with BESLD patients, the rejection activity index and perioperative CD4/CD8 ratio were significantly lower (p = 0.047 and p < 0.001, respectively), while platelet/lymphocyte ratio was significantly higher in HCC patients (p = 0.041). Later tumor stage in HCC patients was associated with higher systemic immuno-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio, aspartate aminotransferase/lymphocyte ratio, C-reactive protein/albumin ratio and fibrinogen level, and lower CD4/CD8 ratio before transplantation. In HCC patients with AR, the percentage of regulatory T cells (CD4+/CD25+) and the level of IL-10 significantly decreased (p = 0.0023, < 0.0001, respectively), while Th1/Th2 ratio, levels of IFN-γ and IL-2 markedly increased before transplantation (p = 0.0018, 0.0059, 0.0416, respectively). Preoperative monocyte/lymphocyte ratio was an independent risk factor for overall and recurrence-free survival after liver transplantation in HCC patients (p = 0.025, < 0.001, respectively). The 1-, 3-, and 5-year survival rates were 76%, 71% and 53% in the AR group, and 67%, 37% and 25% in the non-AR group (p = 0.042). Preoperative tumor-related immunosuppression may persist after liver transplantation in HCC patients, and reduce the incidence of AR. AR after liver transplantation may indicate a better prognosis in HCC patients.

Long-term outcomes of pediatric kidney transplantation: A single-center experience over the past 34years in Japan.

To evaluate long-term outcomes and risk factors for graft loss in pediatric kidney transplantation over a 30-year period. We retrospectively assessed 400 consecutive kidney transplants carried out in 377 children during 1975-2009. Patients were stratified according to the immunosuppressive regimen (era1: methylprednisolone and azathioprine; era2: calcineurin inhibitor-based therapy, including methylprednisolone and azathioprine or mizoribine; era3: basiliximab induction therapy, including calcineurin inhibitors, methylprednisolone and mycophenolate mofetil). The median age and bodyweight at transplantation were 9.7years and 20.6kg, respectively. In total, 364 (91.0%) children received a living related donor transplantation. The acute rejection rate within 1year post-transplant decreased significantly from 61.0% in era1 to 14.5% in era3 (P<0.001). For transplant eras1-3, 1-year graft survival was 81%, 93% and 95%; 5-year graft survival was 66%, 86% and 93%; and 10-year graft survival was 47%, 79% and 89%, respectively. The overall 5-, 10- and 20-year patient survival rates were 96%, 93% and 88%, respectively. A Cox multivariate analysis identified cold ischemia time (hazard ratio 1.385, 95% confidence interval 1.251-1.603), acute rejection (hazard ratio 1.682, 95% confidence interval 1.547-3.842), re-transplant (hazard ratio 2.680, 95% confidence interval 1.759-3.982) and donor type (hazard ratio 2.957, 95% confidence interval 1.754-4.691) as independent risk factors for graft loss at 10years post-transplant. The progress of immunosuppressive therapy has led to a low incidence of acute rejection and a high graft survival rate across 30years of pediatric transplantation.

End-Stage Renal Disease-Associated Gut Bacterial Translocation: Evolution and Impact on Chronic Inflammation and Acute Rejection After Renal Transplantation.

Chronic inflammation in end-stage renal disease (ESRD) is partly attributed to gut bacterial translocation (GBT) due to loss of intestinal epithelium integrity. Increased levels of circulating lipopolysaccharide (LPS) –a surrogate marker of GBT– contribute to maintain a chronic inflammatory state. However, circulating LPS can be neutralized by lipoproteins and transported to the liver for elimination. While ESRD-associated GBT has been widely described, less is known about its changes and impact on clinical outcome after kidney transplantation (KT). One hundred and forty-six renal transplant recipients with serum samples obtained immediately before and 1 year after transplantation (1-Year post KT) were included. Intestinal epithelium integrity (iFABP), total LPS (by measuring 3-hydroxymyristate), LPS activity (biologically active LPS measured by the LAL assay), inflammatory biomarkers (sCD14 and cytokines), lipoproteins and LPS-binding proteins (LBP and phospholipid transfer protein [PLTP] activity) were simultaneously measured. At 1-Year post KT, iFABP decreased but remained higher than in normal volunteers. Total LPS concentration remained stable while LPS activity decreased. Inflammation biomarkers decreased 1-Year post KT. We concomitantly observed an increase in lipoproteins. Higher sCD14 levels before transplantation was associated with lower incidence of acute rejection. Although GBT remained stable after KT, the contemporary increase in lipoproteins could bind circulating LPS and contribute concomitantly to neutralization of LPS activity, as well as improvement in ESRD-associated chronic inflammation. Chronic exposure to LPS in ESRD could promote endotoxin tolerance and explain why patients with higher pre-transplant sCD14 are less prompt to develop acute rejection after transplantation.

Trasplante renal de donante vivo ABO incompatible. Estudio de 48 pacientes tras desensibilización

BackgroundABO-incompatible living-donor kidney transplantation was regarded as an absolute contraindication. However, it has been carried out for years with good outcomes. ObjectiveOur aim was to show the results obtained with this technique in our hospital. MethodsForty-eight patients with a mean age of 50.9±10.9 years were included. Follow-up was 44.6±30.9 months. Conditioning: rituximab 375mg/m2, tacrolimus, mycophenolate mofetil or mycophenolate sodium, prednisone, plasmapheresis/immunoadsorption and intravenous immunoglobulin. Accepted IgG and IgM titres for transplantation:<1:8. ResultsPre-process IgG titre 1:124±1:140, IgM titre 1:77±1:55. After 6±3 sessions, IgG decreased to<1:8 in 47 patients and to<1:16 in one. IgM was<1:8 in all cases. Twenty-four patients (50%) had haematoma, 7 re-intervention (14.6%), 29 (60%) required transfusion. At 5 years, acute rejection had occurred in 5 cases (8.7%), CMV infection in 9 (19.7%), BK viraemia in 5 (12.4%), post-transplant diabetes in 10 (23.4%) and lymphocele in 3 (6.4%). Patient survival was 97.1% at 5 years and graft survival 95.7% at one year and 93% at 5 years. Causes of graft loss: thrombosis (n=1); mixed rejection (n=1); and death (n=2). Serum creatinine levels were 1.4±0.4mg/dl at one and 3 years and 1.3±0.3mg/dl at 5 years. Proteinuria was 0.2±0.2g/24h at one, 3 and 5 years. ConclusionsABO-incompatible living-donor kidney transplantation after conditioning with rituximab, plasmapheresis/immunoadsorption and immunoglobulins is a valid option offering excellent outcomes. There is a low incidence of acute rejection and no increase in infectious complications. An increased tendency for postoperative bleeding was found.

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function.

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.

Incisional hernias after liver transplantation: risk factors, treatment and outcomes

Introduction: Incisional hernias (IH) develop in upto 20% of liver transplant(LT) recipients and can cause significant morbidity. Methods: Single-center retrospective review of patients developing IH after LT from 2003-2015 with aim of identifying risk factors and assessing outcomes. Results: 1051 patients underwent 1099 LT's during study period. 32 died within 30-days of LT and were excluded. 166/1019(16%) LT-recipients developed IH at a median of 20 mos post-LT. 73 (44%) underwent surgical repair (85% open vs. 15% lap; mesh in 90%), while 93 (56%) were managed non-operatively. Repair group had shorter median interval from LT to hernia compared to non-repair group (8 mos vs 27 mos; p<0.05). 3% (4/166) patients presented with acute incarceration requiring urgent repair. There was no difference in IH and no-IH groups in age, BMI, MELD, DM history, smoking, radiation, in-hospital stay before LT, operative time, level of assisting fellow and number of re-explorations after LT. IH group had significantly higher proportion of males (82% vs 64%; p<0.0001) and re-transplants (p=0.029) and lower incidence of acute-rejection (14% vs 24%; p=0.0060). Overall survival was significantly better in patients who developed IH compared to those who did not (91% vs. 77% at 5-years; p=0.0062). Recurrence rate after repair was 14% (10% with mesh vs 43% without mesh; 15% with open vs 9% with lap repair; p< 0.05). Conclusions: IH is a late complication after LT with male gender and re-transplantation as risk factors. Patient presenting earlier are more likely to be repaired surgically. Acute presentation is uncommon and elective repair can be undertaken in most. Mesh repair has advantage of significantly lower recurrence risk.

Kidney transplantation of 32 patients from HLA-incompatible live donors: Efficacy and outcome after desensitization

Desensitization is a procedure undergone by the recipient of a kidney transplant from a donor who is cross-match positive. The aim of this study was to present the outcomes from our hospital of kidney transplant recipients from HLA-incompatible live donors after desensitization.We studied 32 patients aged 46±14 years with a mean fluorescence intensity (MFI) versus class I HLA of 7979±4089 and 6825±4182 MFI versus class II and relative intensity scale (RIS) of 8.9±7.6. The complement-dependent cytotoxicity (CDC) cross-matching test was positive in 18 patients, flow cytometry was positive in 7 patients and donor-specific antibodies (DEA) were detected in 7. The protocol used was rituximab, plasmapheresis/immunoadsorption, immunoglobulins, tacrolimus, mycophenolic acid derivatives and prednisone.After 8±3 sessions of plasmapheresis/immunoadsorption, 23 patients were transplanted (71.9%) and desensitization was ineffective in 9. There were baseline differences in MFI class I (p<0.001), RIS (p=0.008), and CDC cross-matching, DSA and flow cytometry (p=0.05). MFI class I and RIS were predictors of inefficiency in ROC curves. After follow-up of 43±30 months, 13 patients (56%) presented postoperative bleeding, 3 (13%) delayed graft function, 4 (17.4%) acute rejection, 6 (26%) CMV viremia and 1 (4%) BK viremia. Five-year patient survival was 90%, with 86% allograft survival. Five-year creatinine was 1.5±0.4 and proteinuria was 0.5±0.7. ConclusionsKidney transplantation from HLA-incompatible live donors after desensitization was possible in 71.9% of patients. MFI class I and RIS predict the inefficiency of desensitization. Five-year allograft survival (86%) was acceptable with a low incidence of acute rejection (17.4%), although with a greater trend toward postoperative bleeding.

Trasplante renal procedente de donante vivo HLA incompatible: Eficacia y pronóstico en 32 pacientes tras desensibilización

Desensitisation is a procedure undergone by the recipient of a kidney transplant from a donor who is cross-match positive. The aim of this study was to present the outcomes from our hospital of kidney transplant recipients from HLA-incompatible live donors after desensitisation.We studied 32 patients aged 46±14 years with a mean fluorescence intensity (MFI) versus class I HLA of 7979±4089 and 6825±4182 MFI versus class II and relative intensity scale (RIS) of 8.9±7.6. The complement-dependent cytotoxicity (CDC) cross-matching test was positive in 18 patients, flow cytometry was positive in 7 patients and donor-specific antibodies (DEA) were detected in 7. The protocol used was rituximab, plasmapheresis/immunoadsorption, immunoglobulins, tacrolimus, mycophenolic acid derivatives and prednisone.After 8±3 sessions of plasmapheresis/immunoadsorption, 23 patients were trasplanted (71.9%) and desensitisation was ineffective in 9. There were baseline differences in MFI class I (P<.001), RIS (P=.008), and CDC cross-matching, DSA and flow cytometry (P=.05). MFI class I and RIS were predictors of inefficiency in ROC curves. After follow-up of 43±30 months, 13 patients (56%) presented postoperative bleeding, 3 (13%) delayed graft function, 4 (17.4%) acute rejection, 6 (26%) CMV viraemia and 1 (4%) BK viraemia. Five-year patient survival was 90%, with 86% allograft survival. Five-year creatinine was 1.5±0.4 and proteinuria was 0.5±0.7. ConclusionsKidney transplantation from HLA-incompatible live donors after desensitisation was possible in 71.9% of patients. MFI class I and RIS predict the inefficiency of desensitisation. Five-year allograft survival (86%) was acceptable with a low incidence of acute rejection (17.4%), although with a greater trend towards postoperative bleeding.

Outcome of Pretransplantation Therapeutic Plasma Exchange in Highly Sensitized Deceased-donor Kidney Transplant Recipients

BackgroundSensitization is associated with a high rate of post-transplantation rejection. A desensitization protocol using therapeutic plasma exchange (TPE) was proposed to reduce anti-HLA antibody before transplantation, but there has been limited data regarding the efficacy of pretransplantation TPE in highly sensitized deceased-donor kidney transplantation (DDKT). MethodsA retrospective cohort study of 142 patients who received DDKT was conducted and divided into two groups: a high–panel-reactive antibody (PRA) >50% group and a low-PRA ≤50% group. The high-PRA group was sub-divided into those who received and did not receive pretransplantation TPE. Donor-specific anti-HLA antibodies (DSA) were also collected pretransplantation in the high-PRA group. ResultsThe probability of acute rejection was 26, 4, and 9 cases/1000/person month in the high-PRA group with no TPE, the high-PRA group receiving TPE, and the low-PRA group, respectively (P = .0208). In the multivariable logistic regression analysis, the hazard ratio for graft rejection was 2.37 (95% confidence interval: 0.89 to 6.35) and 2.22 (95% confidence interval: 0.54 to 9.13) in the group of high-PRA who received TPE and high-PRA with no TPE, compared with the low-PRA group, respectively (P value not significant). The incidence of antibody-mediated rejection in 6 months in the DSA-positive subgroup was not different between those who received TPE or no TPE. ConclusionDesensitization with TPE is a reasonable alternative for highly sensitized DDKT. Patients who received pretransplantation TPE had a lower incidence of acute rejection compared to the group that did not receive TPE. However, pretransplantation TPE alone was not effective in the prevention of acute rejection in recipients with DSA.

Immunosuppression with prolonged-release tacrolimus in kidney or liver transplantation in India

Aim: Tacrolimus has proven efficacy as an immunosuppressive therapy to prevent transplant rejection and is widely used as an immediate-release formulation in a twice-daily regimen. Once-daily prolonged-release tacrolimus aims to improve the outcomes by reducing variability in exposure and improving adherence. However, there are limited published data available on prolonged-release tacrolimus in routine clinical practice in India. Methods: This was a Phase IV, multicenter, prospective study of prolonged-release tacrolimus conducted over 12 weeks in adult patients eligible for de novo kidney or liver transplantation in India. Primary efficacy end-point was the event rate of biopsy-confirmed acute rejections (BCARs). Secondary end-points included corticosteroid-resistant rejection incidence, time to first BCAR, graft loss, and death. Safety end-points included renal function, lipid profile, incidence of new-onset diabetes mellitus after transplantation (NODAT), and infection. Results: The study enrolled 92 patients undergoing kidney (81 [88.0%]) or liver transplantation (11 [12.0%]); a total of 76 patients (82.6%) completed the study. Ten kidney transplant patients (overall 10.9%) experienced BCAR. There were seven corticosteroid-sensitive and three corticosteroid-resistant rejections. Median (range) time to kidney transplant rejection was 6.5 (1.0–76.0) days. Renal function was stable or improved. Lipid levels showed a significant increase. Eleven instances of NODAT and seven infections occurred and there were eight deaths (8.7%; six kidney and two liver transplant patients). Conclusions: In de novo kidney and liver transplant recipients in India, prolonged-release tacrolimus was well-tolerated and efficacious with a low incidence of acute rejection. Safety profile was similar to immediate-release tacrolimus from published data.

The pharmacokinetics and pharmacodynamics of mycophenolate mofetil in younger and elderly renal transplant recipients.

Elderly transplant recipients have a lower incidence of acute rejection, and a higher risk to die from infectious complications. A potential cause may be differences in the pharmacokinetics (PK) or pharmacodynamics (PD) of the immunosuppressive drugs they are taking. This study was designed to comprehensively evaluate the influence of age on the PK and PD of mycophenolic acid (MPA). In this study the PK and PD of MPA was studied in 26 elderly and 54 younger renal transplant recipients treated with mycophenolate mofetil and tacrolimus. Patients were sampled repetitively, both before and during the first 6 months after kidney transplantation. Age-related variability in MPA PK, baseline IMPDH activity, as well as MPA-induced IMPDH inhibition were studied. The IMPDH activity pre-transplantation did not differ between elderly and younger patients. Neither IMPDH activity pre-transplantation nor maximum IMPDH inhibition was significantly correlated with the patients' age. The area under the MPA plasma concentration-time curve (AUC0-12h ) and the area under the effect (IMPDH activity)-time curve (AEC0-12h ) from 0 to 12h were also not significantly different between the two groups. We found no significant differences in EC50 and Emax between elderly and younger patients. Age did not significantly affect the PK or PD of MPA. It is unlikely that the lower incidence of acute rejection in elderly patients, or the higher risk to die from a severe infection in elderly patients is due to different handling of MPA in the elderly.

Outpatient Management of Delayed Graft Function Is Associated With Reduced Length of Stay Without an Increase in Adverse Events.

Delayed graft function (DGF) is a common and costly complication of kidney transplantation. In July 2011, we established a multidisciplinary DGF clinic managed by nurse practitioners to facilitate early discharge and intensive management of DGF in the outpatient setting. We compared length of stay, 30-day readmission, acute rejection, and patient/graft survival in 697 consecutive deceased donor kidney transplantations performed between July 2009 and July 2014. Patients were divided into three groups: no DGF (n=487), DGF before implementation of the DGF clinic (n=118), and DGF clinic (n=92). Baseline characteristics including age, gender, panel reactive antibody, retransplantation rates, HLA mismatches, induction, and maintenance immunosuppression were not significantly different between pre- and post-DGF clinic groups. Length of stay was significantly longer in pre-DGF clinic (10.9±6.2 vs. 6.1±2.1days, p<0.001). Thirty-day readmission (21% vs. 16%), graft loss (7% vs. 20%), and patient death (2% vs. 11%) did not differ significantly between pre- and post-DGF clinic. Patients in the DGF clinic were less likely to develop acute rejection (21% vs. 40%, p=0.006). Outpatient management of DGF in a specialized clinic is associated with substantially shorter hospitalization and lower incidence of acute rejection without significant difference in 30-day readmission or patient and graft survival.

Low incidence of acute rejection in hepatitis B virus positive liver transplant recipients and the impact of hepatitis B immunoglobulin

Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects.We compared the incidence, risk factors and outcomes of ACR among 40,593 primary LT recipients with HBV, hepatitis C, steatohepatitis, and immune liver disease (OPTN 2000-2011). We also assessed the in vitro effect of HBIG on alloimmune lymphoproliferation and regulatory T cell generation using mixed lymphocyte reactions.In multivariate analysis, HBV status remained a strong independent predictor of freedom from ACR (OR 0.58, 95% CI: 1.5–2.1). Patient (67.7% vs 72.3%) and graft (60.8% vs 69.1%) survival were significantly lower in patients with ACR versus no ACR for all causes except HBV. HBIG use had no statistical association with ACR. In vitro, HBIG at concentrations equivalent to clinical dosing did not inhibit lymphoproliferation or promote regulatory T cell development.In summary, the incidence and impact of ACR is lower now for HBV LT and does not appear to be secondary to HBIG by our in vitro and in vivo analyses. Rather, it may be due to the innate immunosuppressive properties of chronic HBV infection.

Early and Sustained Reduction in Donor-Specific Antibodies in Desensitized Living Donor Kidney Transplant Recipients: A 3-Year Prospective Study.

BackgroundDesensitization with IVIG and rituximab allows acceptable graft survival in sensitized kidney transplant recipients with preexisting donor-specific antibodies (DSAs) and a positive crossmatch. There is little published data reporting the durability of DSA removal in kidney transplant recipients treated with IVIG and rituximab.MethodsWe conducted a 3-year prospective DSA monitoring study in living donor kidney recipients with preexisting DSA to assess the durability of DSA removal after a perioperative protocol of IVIG and rituximab. All recipients had flow crossmatch titers less than 1:32. Data were analyzed using linear mixed effects models and Kaplan-Meier survival methods.ResultsThe longitudinal database comprised 210 mean fluorescence intensity (MFI) determinations. Forty-two DSAs were identified in 29 patients. Pretreatment MFI averaged 4715 ± 3962 (range, 947-20 129). At 1 month posttransplant, 18 patients (62%) had a complete response (MFI < 1000) and an additional 9 patients (31%) had a partial response (MFI reduced but >1000). There was a 46% reduction (P < 0.001) in DSA MFI at 1 month posttransplant that was sustained throughout the 3-year follow-up period and was observed for both class I and II DSAs regardless of pretreatment MFI levels. With a mean posttransplant follow-up of 1048 ± 574 days, 3-year patient and graft survivals were 95% and 90%. Four patients (14%) had acute rejection between days 125 and 560.ConclusionsDesensitization with IVIG and rituximab results in early and sustained DSA removal over a 3-year posttransplant period in living donor kidney transplant recipients with pretransplant DSA and a positive crossmatch, excellent patient and graft survivals and a low incidence of acute rejection.

Effect of induction therapy in kidney transplantation in sensitive patients: analysis of risks and benefits.

Sensitization is associated with worse clinical outcomes after kidney transplantation (KT), including increased incidence of delayed graft function, acute rejection (AR) and graft loss. To evaluate 1-year efficacy and safety outcomes in sensitized KT recipients receiving antithymocyte globulin (ATG) induction and compare them to non-sensitized patients. Deceased donors KT recipients transplanted between January 1998 and December 2009 were divided into 5 groups: control group 1 -n = 89, PRA negative, without induction therapy; control group 2 - n = 94, PRA negative, basiliximab induction; control group 3 - n = 81, PRA negative, ATG induction; test group 4 - n = 64, PRA 1-49%, ATG induction; test group 5 -n = 118, PRA ≥ 50%, ATG induction. There was no difference in the incidence of AR among patients sensitized and non-sensitized, except for group 1, with highest incidence of AR (20.2%,p = 0.006 vs. Group 4 and p = 0.001 vs. group 5). Sensitized patients induced with ATG had higher incidence of citomegalovirus infection when compared with group 2 (26.6% and 14.4% vs. 2.1%). There were no differences in graft and patient survivals. In multivariable analysis, PRA > 50% and ATG induction were not associated with graft loss, death or death-censored graft loss. Sensitized patients induced with ATG presented similar or lower incidence of AR when compared with non-sensitized patients not induced. Besides, these patients had similar safety profile and graft and patient survivals at 1 year.

Abstract 18653: Outcomes After Induction Immunosuppression in Heart Transplant Patients

Introduction: Outcomes after induction immunosuppression in heart transplant patients have not been investigated since the heart allocation policy was changed in 2006. The optimal induction therapy continues to be controversial with many centers continuing to use none at all. We evaluated the outcomes after modern induction immunosuppression agents with the primary end points being survival and rejection. Methods: The United Network for Organ Sharing (UNOS) database was examined for all heart transplants from January 2006 to December 2012. Patients receiving induction therapy were compared to those receiving no induction agent. Additional subgroup analysis was performed on the induction group including those patients receiving either basiliximab (Simulect), thymoglobulin, or alemtuzumab (Campath). Kaplan Meier survival curves and multivariate cox regression analysis were utilized to evaluate outcomes. Results: Of the 14,210 heart transplants performed during this time period, 5905 (41%) received no induction while 8605 (59%) received induction therapy. Interestingly, the no induction group had a lower incidence of acute rejection (15.5% vs. 36.8%, p = 0.005). However, Kaplan Meier analysis revealed no difference in survival between the two cohorts (6.36 vs. 6.23 years; p = 0.59). On multivariate analysis, induction was not associated with a survival advantage (HR: 0.95; 0.88 - 1.03, p = 0.23). Subgroup analysis revealed that patients receiving Campath had the highest incidence of acute rejection (29.5% vs. 19.3% vs. 9.6%, p &lt; 0.0001) and highest panel reactive antibody (7.6 vs 4.3 vs. 4.9, p = 0.002) while those receiving thymoglobulin had the lowest. However, Simulect (HR: 1.08; 0.97 - 1.19, p = 0.16), Campath (HR: 0.87; 0.69 - 1.09, p = 0.22), and Thymoglobulin (HR: 0.94; 0.77 - 1.14, p = 0.50) did not provide a survival benefit on multivariate or Kaplan Meier analysis (6.26 vs. 5.59 vs. 6.26 years; p = 0.21). Conclusions: This analysis of induction agents on outcomes after heart transplantation since the change in allocation policy in 2006 shows that induction does not affect survival when compared to no induction. Furthermore, there is no difference in survival when comparing the three most commonly used agents: Simulect, Campath, and thymoglobulin.