The influence of the antithymocyte globulin dose on clinical outcomes of patients undergoing kidney retransplantation

Optimizing antithymocyte globulin (rATG) dosage is critical for high immunological risk patients undergoing a repeat kidney transplant. This natural retrospective cohort study compared clinical outcomes of two successive cohorts of consecutive recipients of retransplants receiving 5 x 1 mg/kg (rATG-5, n = 100) or a single 3 mg/kg (rATG-3, n = 110) dose of rATG induction therapy. All patients had negative complement-dependent cytotoxicity crossmatch and no anti-HLA A, B, DR donor-specific antibodies (DSA). The primary endpoint was efficacy failure (first biopsy-proven acute rejection, graft loss, or death) at 12 months. There was no difference in the cumulative incidence of efficacy failure (18.0% vs. 21.8%, HR = 1.22, 95% CI 0.66–2.25), respectively. There were no differences in 3-years freedom from biopsy proven acute rejection, and patient, graft, and death-censored graft survivals. There were no differences in the incidence of surgical complications (25.0% vs. 18.2%; p 0.151), early hospital readmission (27.8% vs. 29.5%; p = 0.877) and CMV infections (49% vs. 40%; p = 0.190). There were also no differences in the incidence (59.6% vs. 58.7%, p = 0.897) and duration of delayed graft function but a stable difference in estimate glomerular filtration rate was observed from month 1 (54.7±28.8 vs. 44.1±25.3 ml/min/1.73 m2, p = 0.005) to month 36 (51.1±27.7 vs. 42.5±24.5, p = 0.019). Mean urinary protein concentration (month 36: 0.38±0.81 vs. 0.70±2.40 g/ml, p = 0.008) and mean chronic glomerular Banff score in for cause biopsies (months 4–36: 0.0±0.0 vs. 0.04±0.26, p = 0.044) were higher in the rATG-3 group. This cohort analysis did not detect differences in the incidence of efficacy failure and in safety outcomes at 12 months among recipients of kidney retransplants without A, B, and DR DSA, receiving induction therapy with a single 3 mg/kg rATG dose or the traditional 5 mg/kg rATG.

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Does Rabbit Antithymocyte Globulin (Thymoglobuline®) Have a Role in Avoiding Delayed Graft Function in the Modern Era of Kidney Transplantation?

Journal of Transplantation ◽

10.1155/2018/4524837 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Lluís Guirado

Keyword(s):

Lower Risk ◽

Antithymocyte Globulin ◽

Ischemia Reperfusion ◽

Graft Loss ◽

Graft Function ◽

Delayed Graft Function ◽

Kidney Graft ◽

Transplant Recipients ◽

Rabbit Antithymocyte Globulin ◽

Risk Patients

Delayed graft function (DGF) increases the risk of graft loss by up to 40%, and recent developments in kidney donation have increased the risk of its occurrence. Lowering the risk of DGF, however, is challenging due to a complicated etiology in which ischemia-reperfusion injury (IRI) leads to acute tubular necrosis. Among various strategies explored, the choice of induction therapy is one consideration. Rabbit antithymocyte globulin (rATG [Thymoglobuline]) has complex immunomodulatory effects that are relevant to DGF. In addition to a rapid and profound T-cell depletion, rATG inhibits leukocyte migration and adhesion. Experimental studies of rATG have demonstrated attenuated IRI-related tissue damage in reperfused tissues, consistent with histological evidence from transplant recipients. Starting rATG intraoperatively instead of postoperatively can improve kidney graft function and reduce the incidence of DGF. rATG is effective in preventing acute rejection in kidney transplant recipients at high immunological risk, supporting delayed calcineurin inhibitor (CNI) introduction which protects the graft from early insults. A reduced rate of DGF has been reported with rATG (started intraoperatively) and delayed CNI therapy compared to IL-2RA induction with immediate CNI in patients at high immunological risk, but not in lower-risk patients. Overall, induction with rATG induction is the preferred choice for supporting delayed introduction of CNI therapy to avoid DGF in high-risk patients but shows no benefit versus IL-2RA in lower-risk individuals. Evidence is growing that intraoperative rATG ameliorates IRI, and it seems reasonable to routinely start rATG before reperfusion.

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Modest dose anti-thymocyte globulin administered intraoperatively is safe and effective in kidney transplantations: a retrospective study

PeerJ ◽

10.7717/peerj.7274 ◽

2019 ◽

Vol 7 ◽

pp. e7274 ◽

Cited By ~ 1

Author(s):

Hui-Ying Liu ◽

Yuan-Tso Cheng ◽

Hao Lun Luo ◽

Chiang-Chi Huang ◽

Chien Hsu Chen ◽

...

Keyword(s):

Acute Rejection ◽

Induction Therapy ◽

Dose Regimen ◽

Low Dose ◽

Graft Loss ◽

Graft Function ◽

Calcineurin Inhibitors ◽

Kidney Transplant Recipients ◽

Significant Difference ◽

Kidney Transplantations

Background Anti-thymocyte globulin (ATG) as induction therapy in renal transplantation is facing the dilemma of reducing the incidence of acute rejection (AR) and delayed graft function (DGF) or increasing risks of infection and malignancy. The purpose of this study was to delineate the safety and efficiency of the optimal ATG dosage. Methods We retrospectively evaluated 91 deceased donor kidney transplant recipients (KTRs) in our institution between March 2011 and January 2019. The patients were classified into three groups based on induction therapy: (1) Group 1: modest-dose ATG (three mg/kg) intraoperatively (N = 21); (2) Group 2: low-dose ATG (1–1.5 mg/kg) intraoperatively (N = 23); (3) Group 3: basiliximab 20 mg both on day 0 and 4 (N = 47). In Groups 1 and 2, all patients received a daily low-dose program (1–1.5 mg/kg each day) with target dosage of six mg/kg. Induction therapy was combined with standard immunosuppressive regimen consisting of calcineurin inhibitors, mycophenolate/the mammalian target of rapamycin inhibitors and corticosteroids. Results There was no significant difference in patient characteristics among groups. The outcomes of infection rate, biopsy-proven acute rejection, post-transplant diabetes mellitus, graft survival, and patient survival were similar among groups. Compared to the daily low-dose ATG regimen, the intraoperative modest-dose regimen did not cause more dose interruption and hence was more likely to reach the target ATG dosage. The intraoperative modest-dose regimen also seemed to reduce the rate of DGF. Discussion In recent years, a trend of using a “lower” dose of ATG has seemed to emerge. Our results suggest intraoperative modest-dose ATG followed by daily low-dose ATG regimen was safe and effective in cadaveric renal transplantations for preventing DGF, AR, and graft loss.

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Increased Immunogenicity and Cause of Graft Loss of Old Donor Kidneys

Journal of the American Society of Nephrology ◽

10.1681/asn.v1271538 ◽

2001 ◽

Vol 12 (7) ◽

pp. 1538-1546

Author(s):

JOHAN W. DE FIJTER ◽

MARKO J. K. MALLAT ◽

ILIAS I. N. DOXIADIS ◽

JAN RINGERS ◽

FRITS R. ROSENDAAL ◽

...

Keyword(s):

Acute Rejection ◽

Graft Survival ◽

Negative Impact ◽

Graft Loss ◽

Graft Function ◽

Significant Risk ◽

Donor Age ◽

Independent Predictive Factor ◽

Long Term Outcome ◽

Old Donor

Abstract. Donor age was identified recently as a major factor that determines long-term outcome after transplantation, but the mechanism that is responsible for increased graft loss of old donor kidneys is unknown. The influence of donor age on graft survival was assessed retrospectively in 514 consecutive first cadaveric transplants that were treated with cyclosporine maintenance immunosuppression. Donor age ≥50 yr (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.2 to 2.6), acute rejection (RR = 2.0; 95% CI, 1.3 to 3.0), and type of rejection (RR = 3.3; 95% CI, 2.0 to 5.3) had a significant impact on graft survival. However, when subsets of patients who entered subsequent intervals after transplantation were analyzed, donor age was not an independent predictive factor of graft loss. Donor age (RR = 1.53; 95% CI, 1.19 to 1.98), human leukocyte antigen-DR mismatch (RR = 2.28; 95% CI, 1.78 to 2.92), and recipient age (RR = 1.34; 95% CI, 1.05 to 1.72) were associated significantly with acute rejection episodes. Delayed graft function alone was not associated independently with the occurrence of early acute rejection (RR = 1.24; 95% CI, 0.96 to 1.61). The timing of the rejection episodes of old donor kidneys was not different, and the excess rejection prevalence was attributable entirely to interstitial (grade I) types of rejection. Interstitial rejection episodes in kidneys from old donors had a significant (P< 0.05) negative impact on graft survival. Beyond the first year, poor renal function and proteinuria were significant risk factors for graft loss, regardless of rejection. Our data fit best the hypothesis that increased graft loss of older donor kidneys results from an increased incidence of acute interstitial rejection episodes in the early posttransplantation months. It is proposed that kidneys from older donors are more immunogenic than kidneys from young donors and that acute rejection episodes result in functional deterioration. Contrary to interstitial rejection in kidneys from younger donors, kidneys from old donors seem to have an impaired ability to restore tissue.

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Identifying 4 Novel lncRNAs as Potential Biomarkers for Acute Rejection and Graft Loss of Renal Allograft

Journal of Immunology Research ◽

10.1155/2020/2415374 ◽

2020 ◽

Vol 2020 ◽

pp. 1-22

Author(s):

Zedan Zhang ◽

Yanlin Tang ◽

Hongkai Zhuang ◽

Enyu Lin ◽

Lu Xie ◽

...

Keyword(s):

Acute Rejection ◽

Graft Survival ◽

Risk Score ◽

Renal Allograft ◽

Graft Loss ◽

Gene Set Enrichment Analysis ◽

Operating Characteristics ◽

Risk Patients ◽

Score Model ◽

Potential Biomarkers

Acute rejection (AR) after kidney transplant is one of the major obstacles to obtain ideal graft survival. Reliable molecular biomarkers for AR and renal allograft loss are lacking. This study was performed to identify novel long noncoding RNAs (lncRNAs) for diagnosing AR and predicting the risk of graft loss. The several microarray datasets with AR and nonrejection specimens of renal allograft downloaded from Gene Expression Omnibus database were analyzed to screen differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). Univariate and multivariate Cox regression analyses were used to identify optimal prognosis-related DElncRNAs for constructing a risk score model. 39 common DElncRNAs and 185 common DEmRNAs were identified to construct a lncRNA-mRNA regulatory relationship network. DElncRNAs were revealed to regulate immune cell activation and proliferation. Then, 4 optimal DElncRNAs, ATP1A1-AS1, CTD-3080P12.3, EMX2OS, and LINC00645, were selected from 17 prognostic DElncRNAs to establish the 4-lncRNA risk score model. In the training set, the high-risk patients were more inclined to graft loss than the low-risk patients. Time-dependent receiver operating characteristics analysis revealed the model had good sensitivity and specificity in prediction of 1-, 2-, and 3-year graft survival after biopsy ( AUC = 0.891 , 0.836 , and 0.733 , respectively). The internal testing set verified the result well. Gene set enrichment analysis which expounded NOD-like receptor, the Toll-like receptor signaling pathways, and other else playing important role in immune response was enriched by the 4 lncRNAs. Allograft-infiltrating immune cells analysis elucidated the expression of 4 lncRNAs correlated with gamma delta T cells and eosinophils, etc. Our study identified 4 novel lncRNAs as potential biomarkers for AR of renal allograft and constructed a lncRNA-based model for predicting the risk of graft loss, which would provide new insights into mechanisms of AR.

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Exploratory Analysis of the Impact of an mHealth Medication Adherence Intervention on Tacrolimus Trough Concentration Variability: Post Hoc Results of a Randomized Controlled Trial

Annals of Pharmacotherapy ◽

10.1177/1060028020931806 ◽

2020 ◽

Vol 54 (12) ◽

pp. 1185-1193 ◽

Cited By ~ 1

Author(s):

John W. McGillicuddy ◽

Jessica L. Chandler ◽

Luke R. Sox ◽

David J. Taber

Keyword(s):

Medication Adherence ◽

Acute Rejection ◽

Coefficient Of Variation ◽

Graft Loss ◽

Graft Function ◽

Innovative Technology ◽

Controlled Clinical Trial ◽

Mhealth Intervention ◽

Randomized Controlled ◽

The Impact

Background: Medication nonadherence is a leading cause of late allograft loss in kidney transplantation (KT). Tacrolimus trough coefficient of variation (CV), measured using the coefficient of variation, is strongly correlated with acute rejection, graft function, and graft loss. Objective: The objective of this study was to determine if this mobile health (mHealth) intervention aimed at improving medication adherence in a nonadherent KT population would affect high intrapatient tacrolimus variability. Methods: A 6-month, prospective, parallel-arm, randomized controlled clinical trial was conducted to determine the effects of an mHealth intervention on tacrolimus CV. Intervention arm participants utilized an electronic medication tray and an mHealth app to monitor home-based adherence. Tailored motivational reinforcement messages were delivered to promote competence for adherence. Tacrolimus CV was measured using a 12-month rolling average, assessed at monthly intervals (6-month intervention period and 6 months after completion of the study); 80 were included, 40 in each arm. Results: At baseline, tacrolimus CV was similar between arms (37% ± 15% intervention, 37% ± 13% control, P = 0.894). Patients randomized to the intervention had a significant reduction in mean 12-month tacrolimus CVs ( P = 0.046) and a significant improvement in the proportion achieving low tacrolimus CV (tacrolimus CV < 40%; P = 0.001), as compared with the control arm. Conclusion and Relevance: High tacrolimus CV is a risk factor for acute rejection and graft loss; these results offer the potential promise of improved medication adherence and clinical outcomes through the use of innovative technology.

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Incidence, Risk Factors, and Outcomes of Kidney Transplant Recipients Treated With Both Basiliximab and Antithymocyte Globulin

Canadian Journal of Kidney Health and Disease ◽

10.1177/2054358120964061 ◽

2020 ◽

Vol 7 ◽

pp. 205435812096406

Author(s):

Rachel Jeong ◽

Robert R. Quinn ◽

Krista L. Lentine ◽

Pietro Ravani ◽

Feng Ye ◽

...

Keyword(s):

Risk Factors ◽

Cohort Study ◽

Kidney Transplant ◽

Induction Therapy ◽

Graft Failure ◽

Antithymocyte Globulin ◽

Graft Function ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Incidence Risk

Background: Kidney transplant recipients are given induction therapy to rapidly reduce the immune response and prevent rejection. Guidelines recommend that an interleukin-2 receptor antibody (basiliximab) be the first-line agent and that a lymphocyte-depleting agent (antithymocyte globulin [ATG]) be reserved for those at high immunologic risk. Objective: To determine the incidence, risk factors, and outcomes for patients who receive both basiliximab and ATG for induction compared to either agent alone. Design: Retrospective cohort study. Setting: We used the transplant electronic medical record at the University of Alberta Hospital in Edmonton, Canada. Patients/samples/participants: We included incident adult kidney transplant recipients from 2013 to 2018. Measurements: We measured baseline characteristics, type, and dose of induction therapy used, estimated glomerular filtration rate (eGFR) at 1-year posttransplant, and outcomes of all-cause graft failure, death-censored graft failure, all-cause mortality, and death with a functioning graft. Methods: Differences between induction groups were compared using chi-square test for categorical variables and Kruskal-Wallis tests for continuous variables. We performed multivariable logistic regression modeling with type of induction therapy as the dependent variable and the case-level factors as the predictors (adjusted odds ratio). We estimated the Kaplan-Meier failure functions and used log-rank tests to assess statistical significance of differences in unadjusted incidence across induction therapy types. We compared cumulative incidence functions using a Fine and Gray competing risk regression model. Results: In all, 430 kidney transplant recipients were followed for a mean of 3.9 years (standard deviation 1.5). Of these, 71% (n = 305) received basiliximab alone, 22% (n = 93) received ATG alone, and 7% (n = 32) received both basiliximab and ATG. After adjusting for age and sex, compared to the basiliximab alone group, patients were more likely to receive dual-induction therapy if they were sensitized (calculated panel reactive antibody ≥80%), had diabetes mellitus or peripheral vascular disease, or experienced delayed graft function. Compared to the ATG alone group, the dual-induction therapy group had worse graft function at 1 year (mean eGFR 42 vs. 59 mL/min/1.73 m2, P = .0008) and an increased risk of all-cause graft failure (31% vs. 13%, P = .02) and death-censored graft failure (16% vs. 4%, P = .03). Limitations: There is a risk of confounding by indication, as patients who received dual-induction therapy likely had worse outcomes due to the indication for dual-induction therapy (such as delayed graft function). Conclusions: In our study, 1 out of 10 recipients who were treated with basiliximab also received ATG for induction therapy. These patients experienced worse outcomes than those treated with ATG alone. Trial registration: Not applicable (cohort study).

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The Pre-Transplant Drop in Panel-Reactive Antibodies Titer Evaluated Using Complement-Dependent Cytotoxicity (PRA-CDC) and the Risk of Early Acute Rejection in Sensitized Kidney Transplant Recipients

Medicina ◽

10.3390/medicina54050066 ◽

2018 ◽

Vol 54 (5) ◽

pp. 66

Author(s):

Aureliusz Kolonko ◽

Beata Bzoma ◽

Piotr Giza ◽

Beata Styrc ◽

Michał Sobolewski ◽

...

Keyword(s):

Acute Rejection ◽

Kidney Transplant ◽

Multiple Logistic Regression Analysis ◽

Graft Function ◽

Study Groups ◽

Cytotoxicity Test ◽

Kidney Transplant Recipients ◽

Complement Dependent Cytotoxicity ◽

Transplant Candidates ◽

The Relationship

Background: The panel-reactive antibodies that use the complement-dependent cytotoxicity test (PRA-CDC) are still a standard method for monitoring the degree of immunization in kidney transplant candidates on active waiting lists in some countries, including Poland. The aim of this study was to analyze the relationship between the maximum and the last pre-transplant PRA titer on the percentage of positive cross-matches and rate of early acute rejection episodes. Material and methods: The retrospective analysis included 528 patients from two transplant centers. All patients were divided into three groups, depending on their peak and last pre-transplant PRA titers. There were 437 (82.8%) patients with peak PRA <20% (non-sensitized group, non-ST) and 91 (17.2%) patients with peak PRA >20%. Among the latter group, 38 had maintained PRA level >20% at the time of transplantation (sensitized patients, ST), whereas 53 had pre-transplant PRA ≤20% (previously sensitized patients, prev-ST). Results: The percentages of positive crossmatches were 76.9% in ST and 53.7% in prev-ST groups versus 18.4 in non-ST group (both p < 0.001). The acute rejection rates were 18.9, 17.6 and 6.8%, respectively (p < 0.001 for ST or prev-ST versus non-ST). The pre-transplant PRA titer drop did not decrease the risk of early acute rejection [OR = 1.09 (95% CI: 0.31–3.85)] in a multiple logistic regression analysis. The occurrences of primary graft non-function and delayed graft function were similar in all study groups. Conclusions: Previously immunized kidney transplant candidates even with substantial decrease in pre-transplant PRA-CDC levels are still at high immunological risk when compared with non-immunized patients, and they should receive lymphocyte-depleting induction therapy.

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Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis

Journal of the American Society of Nephrology ◽

10.1681/asn.2018111101 ◽

2019 ◽

Vol 30 (9) ◽

pp. 1697-1707 ◽

Cited By ~ 11

Author(s):

Philip A. Clayton ◽

Stephen P. McDonald ◽

Graeme R. Russ ◽

Steven J. Chadban

Keyword(s):

Cardiovascular Disease ◽

Acute Rejection ◽

Kidney Transplant ◽

Graft Loss ◽

Graft Function ◽

High Rate ◽

Sensitivity Analyses ◽

Transplant Recipients ◽

Kidney Transplant Recipients

BackgroundDeclining rates of acute rejection (AR) and the high rate of 1-year graft survival among patients with AR have prompted re-examination of AR as an outcome in the clinic and in trials. Yet AR and its treatment may directly or indirectly affect longer-term outcomes for kidney transplant recipients.MethodsTo understand the long-term effect of AR on outcomes, we analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics.ResultsAR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results.ConclusionsAR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials.

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Immunosuppressive Management of Pediatric Kidney Transplant Recipients

Current Pharmaceutical Design ◽

10.2174/1381612826666200708133429 ◽

2020 ◽

Vol 26 (28) ◽

pp. 3451-3459

Author(s):

Tomáš Seeman

Keyword(s):

Immunosuppressive Therapy ◽

Kidney Transplant ◽

Induction Therapy ◽

Graft Loss ◽

Calcineurin Inhibitors ◽

Mtor Inhibitors ◽

Therapeutic Drug ◽

High Dose ◽

Transplant Recipients ◽

Kidney Transplant Recipients

: Kidney transplantation is a preferable treatment of children with end-stage kidney disease. All kidney transplant recipients, including pediatric need immunosuppressive medications to prevent rejection episodes and graft loss. : Induction therapy is used temporarily only immediately following transplantation while maintenance immunosuppressive drugs are started and given long-term. There is currently no consensus regarding the use of induction therapy in children; its use should be decided based on the immunological risk of the child. : The recent progress shows that the recommended strategy is to use as maintenance immunosuppressive therapy a combination of a calcineurin inhibitor (preferably tacrolimus) with an antiproliferative drug (preferably mycophenolate mofetil) with steroids that can be withdrawn early or late in low-risk children. The mTOR-inhibitors (sirolimus, everolimus) are used rarely in pediatrics because of common side effects and no evidence of a benefit over calcineurin inhibitors. The use of calcineurin inhibitors, mycophenolate, and mTOR-inhibitors should be followed by therapeutic drug monitoring. : Immunosuppressive therapy of acute rejection consists of high-dose steroids and/or anti-lymphocyte antibodies (T-cell mediated rejection) or plasma exchange, intravenous immunoglobulines and/or rituximab (antibodymediated rejection). : The future strategies for research are mainly precise characterisation of children needing induction therapy, more specific indications for mTOR-inhibitors and for the far future, the possibility to reach the immuno tolerance.

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