Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

OBJECTIVES: Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. MATERIALS AND METHODS: We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. RESULTS: We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. CONCLUSIONS: In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Feasibility of steroid-free tacrolimus-basiliximab immunosuppression in pediatric liver transplantation and predictors for steroid requirement.

Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14 d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9-58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6-12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4 ng/mL vs. < 6.4 ng/mL: HR 0.4, 95% CI, 0.2-0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4 ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.

Could thymoglobulin increase hemorrhagic risk in the perioperative transplantation period of sensitized kidney recipients?

OBJECTIVE: It has been described that thymoglobulin could increase the risk of infections and malignancies, in comparison to basiliximab. Leukopenia and thrombocytopenia are also more common within the first days after transplantation among thymoglobulin patients. Our objective was to analyze bleeding complications in this subset of patients. MATERIAL AND METHODS: Bleeding complications were evaluated among 515 renal transplants carried out at our institution between 2012 and 2018. We compared patients treated with thymoglobulin (Group 1, N=91) with those treated with basiliximab (Group 2, N=424). RESULTS: We found differences in platelet decrease: 95,142.2 (55,339.6) in Group 1 and 52,364.3 (69,116.6) in Group 2 (P=0.001), number of patients with severe thrombocytopenia (<75,000/mm3) (20.8% vs. 3.7%, P=0.001), number of blood units transfused (3.25 (0.572) vs. 2.2 (0.191, P=0.028) and percentage of patients that required surgery due to bleeding (18.2% vs. 7.7%, P=0.046). In a multiple lineal regression multivariable analysis (dependent variable was number of blood units transfused), only age [OR 0.037, 95% CI (0.003-0.070)] and type of immunosuppression [OR 1.592, 95% CI (1.38-2.84)] showed statistical significance. CONCLUSIONS: The use of thymoglobulin in the perioperative transplantation period could increase bleeding complications. In our series, in the group of patients with thymoglobulin, severe thrombocytopenia was 6 times more frequent, and active bleeding that required surgery was also 2.5 times more frequent. One way to continue with the use of this immunosuppression agent, might be to adjust the dose instead of discontinuing it. The use of thymoglobulin should be a factor to consider in the postoperative period of these patients.

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation.

CD25, the alpha chain of the IL-2 receptor, is expressed on activated effector T cells that mediate immune graft damage. Induction immunosuppression is commonly used in solid organ transplantation and can include antibodies blocking CD25. However, regulatory T cells (Tregs) also rely on CD25 for their proliferation, survival, and regulatory function. Therefore, CD25-blockade may compromise Treg protective role against rejection. We analysed in vitro the effect of basiliximab (BXM) on the viability, phenotype, proliferation and cytokine production of Treg cells. We also evaluated in vivo the effect of BXM on Treg in thymectomized heart transplant children receiving BXM in comparison to patients not receiving induction therapy. Our results show that BXM reduces Treg counts and function in vitro by affecting their proliferation, Foxp3 expression, and IL-10 secretion capacity. In pediatric heart-transplant patients, we observed decreased Treg counts and a diminished Treg/Teff ratio in BXM-treated patients up to 6-month after treatment, recovering baseline values at the end of the 12-month follow up period. These results reveal that the use of BXM could produce detrimental effects on Tregs, and support the evidence suggesting that BXM induction could impair the protective role of Tregs in the period of highest incidence of acute graft rejection.

Opportunistic Infections After Induction With Alemtuzumab or Basiliximab: A 3-Year Kidney Transplantation Experience.

BACKGROUND: Antibody induction immunosuppression is commonly used in kidney transplantation to decrease the risk of early acute rejection. However, infectious complications may arise in patients treated with higher intensity induction immunosuppression. In this study, we compared the rate of opportunistic infections during the 3 years after kidney transplantation in recipients who received either alemtuzumab or basiliximab for induction therapy. METHODS: All renal transplant recipients from our center who received induction with alemtuzumab between 2011 and 2016 were included and matched 1:2 (by age and date of transplant) to renal transplant recipients who received basiliximab. The primary outcome was the rate of opportunistic infections. RESULTS: Twenty-seven patients received alemtuzumab (mean age = 50.8 years; SD ±12), and 54 received basiliximab (mean age = 50.8 years; SD ±11.8). Infections within 3 years posttransplant were not different between groups: BK viremia (P = .99), BK nephritis (P = .48), cytomegalovirus infection (P = .13), varicella zoster virus (P = .22), and all infections (P = .87). Time to infection (P = .67), patient survival (P = .21), and time to rejection (P = .098) were similar in both groups. There were also no group differences in delayed graft function (P = .76), graft loss (P = .97), or rejection (P = .2). CONCLUSION: The rate of infection was not significantly increased in recipients receiving lymphocyte-depleting alemtuzumab compared to recipients receiving basiliximab induction therapy, despite receiving similar maintenance immunosuppression. Although the immunologic risks differed between the 2 groups, there was no observable difference in clinical outcomes.

Efficacy and safety of basiliximab as initial immunosuppression in liver transplantation: A single center study.

INTRODUCTION AND AIM: The interleukin-2 receptor antagonist; basiliximab is used to allow delayed introduction of Calcineurin inhibitors (CNI) after liver transplantation and thus delay their renal insult. However, there is only little evidence for the safety and the efficacy of this regimen. This study aimed to evaluate the effectiveness and safety of basiliximab induction in liver transplantation. MATERIALS AND METHODS: This study included 89 patients who were classified into two groups: standard triple immunosuppression (IS) regimen of steroid, tacrolimus (TAC) and mycophenolate mofetil (MMF) (n = 47) and induction IS regimen of basiliximab, low dose steroids and MMF with delayed introduction of CNI (n = 42). All patients were followed after liver transplantation for at least six months or until death. RESULTS: There were no significant differences in patient survival, graft dysfunction, infection rate or type, or wound healing between both groups. The acute rejection rate was equivalent in both groups. Renal dysfunction in the first six months post-transplant was less in the basiliximab group in comparison to the other group (7.1% and 19.1% respectively). CONCLUSION: Basiliximab-induced IS protocol is a safe regimen that reduces medium-term renal dysfunction and achieves similar survival without increasing the acute rejection or infection rate in liver transplantation recipients.

Incidence of and Risk Factors for Multiple Readmissions after Kidney Transplantation.

Unplanned readmission is often used as a surgical quality metric. A subset of kidney transplant recipients undergos multiple readmissions (MRs), although the incidence and risk factors are not well described. The aim of this study was to evaluate risk factors for MR after deceased donor kidney transplantation. All patients undergoing deceased donor kidney transplantation at a single center over a three-year period were analyzed via retrospective chart review for factors associated with MR. P values <0.05 were considered significant. Of 141 patients, the 30-day readmission rate was 26.2 per cent. MR occurred in 43 (30.5%) patients. Age, race, gender, initial organ function, and dialysis vintage were not associated with MR. Diabetic recipients, those who received basiliximab induction, those with acute rejection, and those with unplanned reoperations were at increased risk for MR. Infection was the most common reason for initial readmission in patients with MR (23.3%). One-year patient survival and death-censored graft survival were reduced for patients with MR. MRs are required for 30 per cent of kidney transplant recipients, primarily because of infection and immunologic causes. Recipients with diabetes and those who have acute rejection are at greatest risk.

Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients.

BACKGROUND: The efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear. METHODS: This retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010-June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone. High-risk patients not undergoing 3-month protocol biopsy were continued on triple immunosuppression. RESULTS: Steroid withdrawal could be safely achieved in low immunological risk recipients with IL2 receptor antibody induction. The incidence of biopsy-proven acute rejection was 15.1% in the low-risk and 13.9% in the high-risk group (including sub-clinical rejection detected at protocol biopsy). One- year graft survival was 93.3% and patient survival 98.5% in the low-risk group, and 97.3 and 100% respectively in the high-risk group. Graft function was similar in each group at 1 year (mean eGFR 61.2 ± 23.4 mL/min low-risk and 64.6 ± 19.2 mL/min high-risk). CONCLUSIONS: Immunosuppression regimen comprising basiliximab induction, tacrolimus, MMF and prednisolone with early steroid withdrawal in low risk patients and MMF withdrawal in high risk patients following a normal 3-month protocol biopsy is effective in limiting acute rejection episodes and produces excellent rates of patient survival, graft function and complications.

Assessment of infectious complications in elderly kidney transplant recipients receiving induction with anti-thymocyte globulin vs basiliximab.

BACKGROUND: Elderly transplant recipients experience lower rates of acute rejection with higher rates of infectious complications compared to their younger counterparts. While less intensive immunosuppression may be preferable, there are no recommendations for depleting versus non-depleting induction strategies. We sought to compare infectious complications between anti-thymocyte globulin (ATG) and basiliximab (IL2RA) induction in elderly kidney transplant recipients (KTRs). METHODS: We reviewed 146 KTRs ≥65 years receiving ATG or IL2RA induction. Per institution protocol, ATG was administered to patients with the following characteristics, irrespective of age: African American (AA), PRA ≥20%, and/or re-transplantation. Infectious complications (bacterial, viral, and invasive fungal) at 1 year were compared. RESULTS: There were significantly more AA, deceased donors, and sensitized KTRs in the ATG group, reflecting criteria for induction agent. ATG KTRs experienced higher rates of overall infectious complications (77% vs 56%, P = .01), driven by increased bacterial (54% vs 39%, P = .08) and viral infections (51% vs 35%, P = .05). Urinary tract infections (UTIs) and CMV in particular occurred at high rates among ATG patients (46% and 32%, respectively). In multivariate analysis, the only independent risk factor associated with increased risk for infection was induction with ATG (adjusted HR 1.71 [95% CI 1.04-2.83], P = .04). Overall rates of immunologic outcomes were low. CONCLUSION: Elderly KTRs receiving ATG are at an increased risk for infectious complications, largely attributed to high rates of UTIs and CMV. Additional strategies aimed at mitigating these complications in elderly patients requiring ATG may be beneficial.

Induction Therapy in Elderly Kidney Transplant Recipients With Low Immunological Risk.

BACKGROUND: In nonimmunized patients, similar rejection rates are observed for patients who have undergone thymoglobulin (antithymocyte globulins [ATG]) or basiliximab (BSX) therapy. While ATG may improve delayed graft function, it may also be associated with higher infection rates and malignancy risk. We compared survival and clinical outcomes in elderly recipients with low immunological risk according to their induction therapy. METHODS: We conducted a multicentric study on nonimmunized patients ≥65 years of age receiving a first kidney transplant between 2010 and 2017. The principal outcome was patient and graft survival. Secondary outcomes were cumulative probabilities of infection, first acute rejection episode, malignancy, de novo donor specific antibody, posttransplant diabetes (PTD), cardiac complications, estimated glomerular filtration rate, and occurrence of delayed graft function. Cox, logistic, or linear statistical models were used depending on the outcome studied, and models were weighted on the propensity scores. RESULTS: Two hundred and four patients were included in the BSX group and 179 in the ATG group with the average age of 71.0 and 70.5 years, respectively. Patient and graft survival at 3 years posttransplantation were 74% (95% CI, 65%-84%) and 68% (95% CI, 60%-78%) in ATG and BSX group, respectively, without significant difference. Occurrence of PTD was significatively higher in BSX group (23% versus 15%, P = 0.04) due to higher trough levels of Tacrolimus on month 3 (9.48 versus 7.30 ng/mL, P = 0.023). There was no difference in other evaluated outcomes. CONCLUSIONS: In elderly recipients, ATG does not lead to poorer outcomes compared with BSX and could permit lower trough levels of Tacrolimus, thus reducing occurrence of PTD.

Usefulness of Delayed Introduction of Tacrolimus in Kidney Transplants Using Type-III Donors After Circulatory Death.

INTRODUCTION: Our study compares 2 immunosuppressive strategies to reduce tacrolimus nephrotoxicity and its risk of acute tubular necrosis: delayed introduction of tacrolimus plus thymoglobulin vs initial tacrolimus plus basiliximab on the results of kidney transplant (KT) using type-III donation after circulatory death (III-DCD). MATERIAL AND METHODS: We analyzed all the transplants performed using type-III DCD in our hospital (42 cases). They were distributed in a first stage with delayed tacrolimus (3°-4° day) + thymoglobulin and a second one with initial tacrolimus + basiliximab, with a follow-up of 6 months. The rate of delayed graft function, the evolution of renal function, and the incidence of rejection were compared. RESULTS: 28 patients received thymoglobulin with delayed tacrolimus, and 13 patients received basiliximab and tacrolimus from day 0 (1 excluded). There were no significant differences in delayed graft function (27% group 1 and 23% group 2) or in rejection (10.7% and 15.4%), respectively. Serum creatinine at day 3, 7, 14, 30, and 180 showed no statistically significant differences. The levels of tacrolimus measured at 10, 30, 90, and 180 days after transplantation were similar, except for the first month: 10.10 ± 2.3 in group 1 and 12 ± 1.7 ng/mL in group 2 (P = .007). CONCLUSIONS: Delayed introduction of tacrolimus does not seem to suppose a benefit in KT using type-III DCD; therefore, the use of thymoglobulin, with its higher profile of adverse effects, seems unjustified in patients with normal immunological risk.

Clinical-economic impact of the change of protocol for use of basiliximab in liver transplant.

OBJECTIVE: Evaluation of the clinical and economic impact after the protocol  change of basiliximab use in orthohepatic transplant. METHOD: Retrospective study in which all liver transplant patients were included  during the years 2013, 2014 and until February 15, 2015. The study was divided into two stages according to the protocol used: 1) administration of basiliximab  only if factors of previous risk, and 2) administration of the first dose of  basiliximab to all transplant patients and the second dose if it had risk factors. RESULTS: 83 patients were included, 34 according to protocol 1 and 49 according  to protocol 2. No significant differences were found in the clinical  variables evaluated or in the variables related to health outcomes. Considering  that the percentage of patients without risk factors who received basiliximab was 43% and without differences in the stays, we could estimate an additional cost  for the universal use of basiliximab in orthohepatic transplant of € 21,400.00. CONCLUSIONS: In our population, the protocol change making universal the first  dose of basiliximab has not shown the expected benefits, but an increase in  costs, so the suitability of the new protocol in consensus with the medical team  must be reconsidered. The evidence regarding the use of basiliximab in  orthohepatic transplant remains limited and although its benefit seems clear in  patients with risk factors, especially renal failure, recommendations about its use universally remains controversial.

Objetivo: Evaluación del impacto clínico y económico tras el cambio de protocolo de uso de basiliximab en el trasplante ortohepático. Método: Estudio retrospectivo en el que se incluyó a todos los pacientes trasplantados de hígado durante los años 2013, 2014 y hasta el 15 de  febrero de 2015. El estudio se dividió en dos etapas según el protocolo  empleado: 1) administración de basiliximab solo si existían factores de riesgo  previos, y 2) administración de la primera dosis de basiliximab a todos los  pacientes trasplantados y de una segunda dosis si existían factores de riesgo. Resultados: Se incluyeron 83 pacientes, 34 según el protocolo 1 y 49 según el  protocolo 2. No se encontraron diferencias significativas en las variables clínicas  evaluadas ni en las variables relacionadas con los resultados en salud.  Considerando que el porcentaje de pacientes sin factores de riesgo que recibieron basiliximab fue del 43% y sin diferencias en las estancias,  podríamos estimar un coste adicional por el empleo universal de basiliximab en  el trasplante ortohepático de 21.400 €.Conclusiones: En nuestra población, el cambio de protocolo haciendo universal  la primera dosis de basiliximab no ha mostrado los beneficios esperados, pero sí  un aumento de los costes, por lo que debe replantearse la idoneidad del nuevo  protocolo en consenso con el equipo médico. La evidencia en relación con el  empleo de basiliximab en el trasplante ortohepático sigue siendo limitada y  aunque parece claro su beneficio en pacientes con factores de riesgo,  especialmente fallo renal, las recomendaciones acerca de su uso de forma  universal sigue siendo controvertido.

Does Induction Type Influence Outcomes in Kidney Transplant Recipients at Different Phases of Hepatitis B Infection?

OBJECTIVES: Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression. Here, we compared outcomes of depleting (antithymocyte globulin/alemtuzumab) versus nondepleting (basiliximab/daclizumab) antibody induction in kidney transplant recipients at different serologic phases of hepatitis B virus infection. MATERIALS AND METHODS: We used the Organ Procurement and Transplantation Network/United Network for Organ Sharing database to identify adult kidney transplant recipients at different serologic phases of hepatitis B virus infection (transplants received from 2001-2011 after patients received perioperative induction with discharge on calcineurin inhibitors/mycophenolate mofetil with/without steroids). We used a Cox model to compare outcomes among patient groups. RESULTS: Median follow-up was 50.7 months (range, 28.6 to 82.6 mo). Serologic phase for the 7681 study patients were as follows: 1098 at HBsAg+/anti-HBc- (depleting = 652, nondepleting = 446), 446 at HBsAg+/anti-HBc+ (depleting = 250, nondepleting = 216), and 6117 at HBsAg-/anti-HBc+ (depleting = 3562, nondepleting = 2555) (where anti-HBc denotes hepatitis B core antibody, HBsAg denotes hepatitis B surface antigen, and +/- denote positive/negative). When we compared those with depleting versus nondepleting agents, hazard ratios (95% confidence intervals) for adjusted overall graft, death-censored graft, and patient survival were 0.97 (0.78-1.26; P = .86), 1.20 (0.83-1.60; P = .44), and 0.92 (0.66-1.30; P = .51) in the HBsAg+/anti-HBc-; 0.81 (0.55-1.18; P = .27), 0.59 (0.32-1.12; P = .11), and 0.95 (0.60-1.49; P = .83) in the HBsAg+/anti-HBc+; and 0.96 (0.86-1.05; P = .37), 0.95 (0.60-1.49; P = .97), and 0.92 (0.80-1.05; P = 0.22) in the HBsAg-/anti-HBc+ groups. CONCLUSIONS: Our study did not show adverse graft and patient outcomes associated with depleting versus nondepleting antibody induction in kidney transplant recipients at different phases of hepatitis B virus infection. This supports the selection and use of induction agents based on immunologic risk in such patients.

High-dose mizoribine combined with calcineurin inhibitor (cyclosporine or tacrolimus), basiliximab and corticosteroids for renal transplantation: A Japanese multicenter study.

OBJECTIVE: To evaluate the utility and safety of high-dose mizoribine combination therapy using cyclosporine and tacrolimus as calcineurin inhibitors in patients undergoing kidney transplant. METHODS: The present study enrolled 156 patients who received kidney transplants in 18 institutions between 2009 and 2013. ABO-incompatible and/or pre-sensitized recipients were excluded. Immunosuppression used cyclosporine (88) or tacrolimus (68) as a calcineurin inhibitor, and the dosage was adjusted based on blood concentrations. Mizoribine was started at 6 mg/kg/day, and the target trough level was 1-2 ng/mL. Primary efficacy end-points of this study were 2-year patient survival, 2-year graft survival and the acute rejection rate within 2 years after transplantation. RESULTS: The 2-year patient and graft survival rates in the cyclosporine group were 98.9% and 94.3%, respectively, whereas those in the tacrolimus group were 100% and 98.5%, respectively, with no significant difference between groups. Rates of onset of rejection during the observation period were also equivalent, at 22.7% in the cyclosporine group and 17.6% in the tacrolimus group. Furthermore, groups showed no significant differences in transplanted renal function. No notable differences in adverse events were observed between groups. CONCLUSIONS: A regimen of high-dose mizoribine in combination with calcineurin inhibitors basiliximab, and corticosteroids can provide effective immunosuppression while lowering the rate of cytomegalovirus infection in kidney transplant patients.