Interleukin-2 Receptor Blocker Research Articles

De novo design of mini-binder proteins against IL-2 receptor β chain

IL-2 regulates the immune response by interacting with different IL-2 receptor (IL-2R) subunits. High dose of IL-2 binds to IL-2Rβγc heterodimer, which induce various side effects while activating immune function. Disrupting IL-2 and IL-2R interactions can block IL-2 mediated immune response. Here, we used a computational approach to de novo design mini-binder proteins against IL-2R β chain (IL-2Rβ) to block IL-2 signaling. The hydrophobic region where IL-2 binds to IL-2Rβ was selected and the promising binding mode was broadly explored. Three mini-binders with amino acid numbers ranging from 55 to 65 were obtained and binder 1 showed the best effects in inhibiting CTLL-2 cells proliferation and STAT5 phosphorylation. Molecular dynamics simulation showed that the binding of binder 1 to IL-2Rβ was stable; the free energy of binder1/IL-2Rβ complex was lower, indicating that the affinity of binder 1 to IL-2Rβ was higher than that of IL-2. Free energy decomposition suggested that the ARG35 and ARG131 of IL-2Rβ might be the key to improve the affinity of binder. Our efforts provided new insights in developing of IL-2R blocker, offering a potential strategy for ameliorating the side effects of IL-2 treatment.

Combined Cytokine Blocking Therapy (CCBT) Using Basiliximab and Infliximab for Treatment of Steroid-Refractory Graft Versus Host Disease (SR-GvHD)

Background Despite improved advances in graft-vs-host disease (GvHD) prophylaxis regimens and post-allogeneic hematopoietic cell transplant (HCT) supportive care, clinically significant acute GvHD still develops in approximately 30-50% of HCT recipients (Lazaryan A et al. BMT 2016) and often results in increased transplanted-related morbidity and mortality and deterioration of quality of life (Choi J et al. Blood 2012). Standard first-line treatment is high-dose glucocorticoids have been limited including recently approved JAK2 inhibitor (ruxolitinib). The utilization of combined cytokine blockade therapy (CCBT) with the monoclonal antibodies infliximab (a TNF-α inhibitor, INF) and basiliximab (an IL-2 receptor blocker, BAS), has had limited discussion in the literature despite common utilization. The primary objective of this retrospective study was to determine overall response rate (ORR) at days 7, 14 and 28 for CCBT. Secondary outcomes included non-relapse mortality (NRM), and overall survival (OS). Methods 60 patients who met the inclusion criteria were analyzed. Patients included were ≥18 years old and had undergone HCT using any donor or graft source with any conditioning regimen between 2010-2021 at City of Hope Medical Center in Duarte, CA. Patients had steroid refractory aGvHD, according to Mount Sinai Consortium guidelines (Harris AC et al. BMT 2016) and received at least one dose of BAS and at least one dose of INF. Patients with >1 allogeneic transplant, chronic GVHD including overlap syndrome, relapse of primary disease, graft loss, and glucocorticoid treatment for indications other than GVHD were excluded. Treatment BAS was administered intravenously as 20mg doses given first as loading doses on days 1 and 4. Subsequent doses were given weekly starting 7 days after the final loading dose (day 4). INF was administered as 10 mg/kg doses infused weekly. Tacrolimus, sirolimus and cyclosporine dosing and monitoring were performed in accordance with institutional policies. All patients had clinical presentation of SR-GVHD defined as ≥1 of the following: GVHD increasing in stage in any organ or developing in a new organ after 3 days of ≥2 mg/kg methylprednisolone (MSPE) or equivalent, GVHD that has not improved in stage in ≥1 organ after 7 days of ≥2 mg/kg MSPE or equivalent, development of GVHD in a new organ after ≥1 mg/kg MSPE or equivalent for skin GVHD or patients who progress during tapering before a 50% decrease in glucocorticoids is achieved. Results The median age was 53 years (range, 5-78) at time of HCT. Of 60 patients, 65% were males and with 18.3% of male patients receiving grafts from female donor. HCT-CI at the time of HCT was 3 or more in 47% of the patients. Conditioning for those patients was ablative in 43.3% of patients with 76.7% of patients receiving PBSC grafts from mostly MSD/MUD in 75% of patients. Most patients had grade 3 or 4 overall acute GVHD (grade 3: n=35, 58.3%, grade 4: n=20, 33.3%). Median time to start of BAS after start of steroid was 7 days while time to start of INF after steroid was 11 days. Ruxolitinib was initiated in 33.3% (20/60) of patients prior to CCBT. ORR for CCBT therapy at day 7, 14, and 28 were 28.3% (17/60; CR 5.0%), 38.3% (23/60; CR 11.7%), and 38.3% (23/60; CR 23.3%), respectively. Patients who received ruxolitinib prior to CCBT had lower ORR (25%) compared to those who did not (47.5%). 37 patients died-20 of aGVHD, 4 of infection, 1 of sudden cardiac death and 1 of leukemia relapse. OS was 41.7% at 6 months and 36.5% at 12 months (Figure 1A). Cumulative incidence of NRM was 51.7% at 6 months and 55% at 12 months (Figure 1B). Cumulative incidence of any cGvHD was 33.6% at 12 months while it was 30% for extensive cGvHD at the same 12-month interval. In patients with and without ruxolitinib initiated prior to CCBT, OS at 12 months was 30% vs 40%, respectively (Figure 2A) while NRM at 12 months was 65% and 50%, respectively (Figure 2B). Conclusion CCBT has potential efficacy in steroid refractory aGVHD. The observed ORR is reflective of both advanced and highly refractory aGVHD with one-third of patients progressing on ruxolitinib. Given the favorable observed ORR in this difficult to treat population, CCBT is a potentially promising approach and suitable alternative in the second line or as salvage therapy in patients failing Ruxolitinib.

Outcomes based on induction regimens in pediatric kidney transplantation: a NAPRTCS and PHIS collaborative study.

Induction agent used at the time of kidney transplant is often based upon center practice and recipient characteristics. We evaluated outcomes across induction therapies among children enrolled in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) transplant registry with data in the Pediatric Health Information System (PHIS). This is a retrospective study of merged data from NAPRTCS and PHIS. Participants were grouped by induction agent: interleukin-2 receptor blocker (IL-2 RB), anti-thymocyte/anti-lymphocyte globulin (ATG/ALG), and alemtuzumab. Outcomes assessed included 1-, 3-, and 5-year allograft function and survival, rejection, viral infections, malignancy, and death. A total of 830 children transplanted between 2010 and 2019. At 1year post-transplant, the alemtuzumab group had higher median eGFR (86ml/min/1.73m2) compared to IL-2 RB and ATG/ALG (79 and 75ml/min/1.73m2, respectively; P < 0.001); at 3 and 5years, there was no difference. Adjusted eGFR over time was similar across all induction agents. Rejection rates were lower among the alemtuzumab group vs. IL-2RBand ATG (13.9% vs. 27.3% and 24.6%, respectively; P = 0.006). Adjusted ATG/ALG and alemtuzumab had higher hazard ratio for time to graft failure compared to IL-2 RB (HR 2.48 and HR 2.11, respectively; P < 0.05). Incidence of malignancy, mortality, and time to first viral infection was similar. Although rejection and allograft loss rates were distinct, the incidences of viral infection and malignancy were comparable across induction agents. By 3years post-transplant, there was no difference in eGFR. A higher resolution version of the Graphical abstract is available as Supplementary information.

Induction with rATG versus No-induction in Deceased Donor Renal Transplantation - A Retrospective Observational Study.

Deceased donor renal transplantation (DDRT) poses special immunological challenges; particularly in resource-poor scenarios. There is substantial evidence that rabbit antithymocyte globulin (rATG) is superior to interleukin-2 receptor blocker and placebo among patients at high immunological risk. However, due to the lack of randomized controlled trials, this remains controversial in DDRT maintained on tacrolimus/mycophenolic acid/steroids. Here, in this study, we compared the clinical outcomes of induction with rATG therapy to no-induction therapy. The study was a single-center, retrospective cohort study. A total of 62 patients were divided into two groups, based on induction immunosuppression; induction with rATG (N = 25) and no-induction group (N = 37). Both groups received tacrolimus/mycophenolate mofetil sodium/prednisolone as maintenance immunosuppression. The main outcomes were incidence of acute rejection (AR) within the first year and graft survival at the end of 1 year. The AR at the end of 1-year was reported as 8% and 27% for the induction and no-induction groups (P = 0.07), respectively. A total of 15 patients died. Patient survival rates at 12 months were 83.8% (no-induction) and 64.0% (induction; P = 0.094). Death-censored graft survival rates, 12 months after transplantation, were similar in both treatment groups (83.7% vs. 83.5%, P = 0.972). The incidence of death with functioning graft was significantly high in the induction group (28% vs. 5.4%, P = 0.045). The incidence of AR was less in patients who received rATG induction compared with patients who did not receive any form of induction. An added advantage of induction with ATG in terms of reduced incidence of AR must be weighed against high incidence of infection, death with functioning graft, and death.

Mechanisms and clinical applications of immunosuppressive medications

Immunosuppressive medications and regimens have evolved with significant advancements in the understanding of the immunologic process after solid organ transplantation. Medications can block the communication between antigen-presenting cells and T-cells, the activation and proliferation of T-cells, antibody production by plasma cells, and the activation of the complement system by antibodies. T-cell depleting antibodies and interleukin-2 receptor blockers are commonly used during induction therapy. Calcineurin inhibitors, antimetabolites, antiproliferative agents, and corticosteroids are commonly used in maintenance therapy regimens. These medications decrease the rates of rejection episodes and markedly increase the survival rates of short-term grafts. However, in terms of the survival rate of long-term grafts, there is still room for improvement. Opportunistic infections, development of cancer, metabolic diseases, and calcineurin inhibitor toxicity are hurdles in the improvement in survival rates of long-term grafts. Therefore, many efforts are being taken to overcome these hurdles, such as the development of new drugs, individualization of immunosuppression, and induction of immune tolerance.

Effect of Interleukin-2 Receptor Antibody Induction Therapy on Survival in Renal Transplant Patients Receiving Tacrolimus

Background: This study aims to assess outcomes of interleukin-2 (IL-2) receptor blocker induction therapy on allograft and patients’ outcomes in standard risk recipients in the tacrolimus era, analysing data form the British Renal Transplant Registry. Methods: The study population involved all standard-risk renal transplant patients from 2000 till 2015 who were registered in the UK transplant registry and followed up till May 2018. Standard risk transplants were defined as patients with <2DR mismatch, calculated reaction frequency <20%, live donors or donors after brain death and patients with no previous renal transplantation transplant. We used inverse probability weights to adjust different covariates between the groups. Cox regression analysis for adjusted data and treatment effects model were used to assess outcomes. Results: In all, 3,597 renal transplant patients were included in the study. Two groups were identified; induction group (n = 2,858) which included patients who received IL-2 receptor blocker induction therapy and the no-induction group (n = 739). There was no significant difference between both groups in terms of estimated glomerular filtration rate (eGFR) rate at 1-year post-transplant (correlation co-efficient = 1.224, 95% CI ranges from –0.347 to 2.796). Average eGFR was 59.922 mL/min/1.73 m² in the induction group (SD 29.171) and 64.557 mL/min/1.73 m² in the no-induction groups (SD 46.763). There was no significant difference between both groups regarding graft survival at 5 years post-transplant (hazard ratio [HR] 0.944, 95% CI ranges from 0.599 to 1.485, p = 0.804), patient survival at 5 years post-transplant (HR 0.809, 95% CI ranges from 0.477 to1.372, p = 0.433). Conclusion: In the standard risk renal transplant population, the IL2 receptor blocker induction regimen does not affect eGFR at 1 year or renal and graft outcomes at 5 years.

Induction Immunosuppression and Clinical Outcomes in Kidney Transplant Recipients Infected With Human Immunodeficiency Virus.

There is an increased risk of acute rejection (AR) in human immunodeficiency virus-positive (HIV+) kidney transplant (KT) recipients. Induction immunosuppression is standard of care for those at high risk of AR; however, use in HIV+ patients is controversial, given fears of increased infection rates. We sought to compare clinical outcomes between HIV+ KT recipients who were treated with (i) anti-thymocyte globulin (ATG), (ii) IL-2 receptor blocker, and (iii) no induction. We studied 830 HIV+ KT recipients between 2000 and 2014, as captured in the Scientific Registry of Transplant Recipients, and compared rates of delayed graft function (DGF), AR, graft loss and death. Infections and hospitalizations were ascertained by International Classification of Diseases, Ninth Revision codes in a subset of 308 patients with Medicare. Compared with no induction, neither induction agent was associated with an increased risk of infection (weighted hazard ratio [wHR] 0.80, 95% confidence interval [CI] 0.55-1.18). HIV+ recipients who received induction spent fewer days in the hospital (weighted relative risk [wRR] 0.70, 95% CI 0.52-0.95), had lower rates of DGF (wRR 0.66, 95% CI 0.51-0.84), less graft loss (wHR 0.47, 95% CI 0.24-0.89) and a trend toward lower mortality (wHR 0.60, 95% CI 0.24-1.28). Those who received induction with ATG had lower rates of AR (wRR 0.59, 95% CI 0.35-0.99). Induction in HIV+ KT recipients was not associated with increased infections; in fact, those receiving ATG, the most potent agent, had the lowest rates. In light of the high risk of AR in this population, induction therapy should be strongly considered.

Polyclonal and monoclonal antibodies in renal transplant: an update.

There are several monoclonal and polyclonal antibodies used in renal transplantation today, this article will discuss several agents, their updates and newer agents. Antithymocyte globulin and interleukin-2 (IL-2) receptor blocker continue to be used as induction agents. The risk of acute rejection was higher in IL-2 receptor blockers mainly in the first year, but graft survivals were similar in both groups long term. Belatacept is the only approved intravenous maintenance immunosuppressive therapy which provides the benefit of glomerular filtration rate preservation, but it was associated with a higher risk of acute rejection and post-transplant lymphoproliferative disorder. Bortezomib may help decrease donor-specific antibody levels, but there are limited data to support its use for desensitization or rejection. Eculizumab may help in antibody-mediated rejection in some cases but has not shown promising long-term effects in high-risk individuals. Newer agents have been continuously tested for improved efficacy and safety. Transplantation is the standard of care for end-stage renal disease patients, but we still have a long way to go, as we need to improve long-term outcomes. The manipulation of the immune system is a delicate undertaking, with risks of adverse events; therefore, risk versus benefit needs to be carefully evaluated and treatment needs to be individualized.

Pharmacologic targeting of regulatory T cells for solid organ transplantation: current and future prospects.

The last three decades have witnessed significant advances in the development of immunosuppressive medications used in kidney transplantation leading to a remarkable gain in short-term graft function and outcomes. Despite these major breakthroughs, improvements in long-term outcomes lag behind due to a stalemate between drug-related nephrotoxicity and chronic rejection typically due to donor-specific antibodies. Regulatory T cells (Tregs) have been shown to modulate the alloimmune response and can exert suppressive activity preventing allograft rejection in kidney transplantation. Currently available immunosuppressive agents impact Tregs in the alloimmune milieu with some of these interactions being deleterious to the allograft while others may be beneficial. Variable effects are seen with common antibody induction agents such that basiliximab, an IL-2 receptor blocker, decreases Tregs while lymphocyte depleting agents such as antithymocyte globulin increase Tregs. Calcineurin inhibitors, a mainstay of maintenance immunosuppression since the mid-1980s, seem to suppress Tregs while mammalian targets of rapamycin (less commonly used in maintenance regimens) expand Tregs. The purpose of this review is to provide an overview of Treg biology in transplantation, identify in more detail the interactions between commonly used immunosuppressive agents and Tregs in kidney transplantation and lastly describe future directions in the use of Tregs themselves as therapy for tolerance induction.

Clinical outcomes associated with induction regimens among retransplant kidney recipients in the United States.

Numerous studies have evaluated outcomes and risk factors associated with induction protocols among kidney transplant recipients. However, few studies have evaluated outcomes in the subset of retransplant recipients who often have unique immunologic condition and risk profile and represent an increasing proportion of transplant patients in the United States. We evaluated the association of common induction treatments (alemtuzumab, thymoglobulin, interleukin-2 receptor blockers, and no induction) given at transplantation with clinical outcomes among adult recipients retransplant between 2003 and 2011 using national Scientific Registry of Transplant Recipients data (n = 14,336). We used a propensity score analysis to minimize potential selection biases for allocation of treatment. In adjusted models, there were no significant differences between induction groups for outcomes of delayed graft function, 1-year acute rejection, 1-year BK virus or patient death. Acute rejection before hospital discharge was lowest among patients treated with thymoglobulin and alemtuzumab. The no induction group had the highest average 1-year estimated glomerular filtration rate (62 mL/min/1.73 kg/m(2)) and lowest incidence of any malignancies within 1 year (1.0%). Hospitalizations after transplantation were highest among patients treated with thymoglobulin (42% at 1 year). Recipients with alemtuzumab had the highest relative risk for graft loss (adjusted hazard ratio, 1.19; 95% confidence interval, 1.01-1.40, relative to patients treated with thymoglobulin). There is moderate variation in clinical outcomes associated with induction treatment among retransplant kidney recipients in the United States, including higher graft loss rates among recipients treated with alemtuzumab but similar patient survival between all regimens.

Infection and rejection risk after cardiac transplantation with induction vs. no induction: a multi-institutional study.

Data from Cardiac Transplant Research Database (CTRD) were analyzed from 1999 to 2006 to examine the effects of different induction strategies at the time of cardiac transplantation. A total of 2090 primary heart transplants were categorized by induction with interleukin-2 receptor blocker (IL-2RB), antithymocyte globulin (ATG), or no induction (NI). Probabilities for rejection and infection were estimated with parametric time-related models. Using these models, hazard was calculated for two theoretical patient profiles, one at lower risk for rejection and higher risk of infection (Profile 1) and higher risk for rejection and lower risk of infection (Profile 2). Of the 2090 transplants, 49.8% (1095) did not receive induction, 27.3% (599) received IL-2RB, and 18.0% (396) received ATG. Profile 1 patients had lower hazard for rejection with IL-2RB compared to ATG and NI (p<0.01), but at the cost of increased risk of infection (5.0 vs. 1.8 vs. 1.6, respectively, at four wk, p<0.01). Profile 2 patients experienced a fivefold decreased hazard for rejection when treated with IL-2RB compared with ATG and NI (p<0.01). In patients at high risk of infection, IL-2RB reduced risk of rejection but at the expense of increased hazard for infection.

C4d Negative Antibody Mediated Rejection(AMR) Has a Similar Prognosis as C4d Positive AMR in Desensitized Live Donor Kidney Transplant Recipients.

INTRO:AMR is characterized by graft dysfunction, donor specific antibodies(DSA), microcirculatory inflammation, and evidence of complement activation in peritubular capillaries(C4d). Many of our positive crossmatch patients have histologic features of AMR but are C4d neg. We reviewed our live donor +XM cohort to identify whether AMR outcomes differed by C4d pos and C4d neg status. METHODS/RESULTS: We performed 58 +XM kidney transplants from 9/2004 to 12/2013. All received a minimum of two pre- and post- txp plasmapheresis with IVIG replacement (100mg/kg) and maintenance immunosuppression with tacrolimus, mycophenolate, and steroids. Induction therapy varied, and included either an IL-2 receptor blocker or Thymoglobulin® with or without intra-op rituximab, and IV methylpred with taper to pred 20 mg by post-op day 4. AMR was defined as graft dysfunction, PTCitis and +DSA testing by solid phase assay or XM. 30 +XM patients met these criteria for AMR as their first rejection episode -- 15 were C4d neg and 15 were C4d pos.(see table) Both groups were similar in terms of age, gender, sensitization history, and CDC vs flow +XM. Time to rejection was shorter in the C4d neg cohort (6 vs. 10 days, p=0.01), however, response to treatment, cellular rejections, recurrent rejections, and renal function were similar between groups. More C4d neg AMR grafts failed, but this difference was not statistically significant.Table: No Caption available.CONCLUSION: Our data suggest that desensitized patients with AMR have similar outcomes regardless of C4d staining. Patients with features of AMR and negative C4d stain should be considered for DSA testing. Diagnostic criteria of AMR may need modified to include patients with negative C4d testing.

Steroid maintenance in repeat kidney transplantation: influence of induction agents on outcomes.

The influence of steroid maintenance on the outcomes of repeat kidney transplant (RKT) recipients with respect to induction type is unclear. Using the Organ Procurement and Transplant Network/United Network of Organ Sharing (OPTN/UNOS) database, we identified patients (≥ 18 years) who underwent deceased donor RKT from January 2000 to December 2008 after receiving induction with rabbit-antithymocyte globulin (r-ATG), alemtuzumab or an IL-2 receptor blocker (IL-2B) and were discharged on a calcineurin inhibitor/mycophenolate mofetil regimen with or without steroids. Of 5634 patients, 3643 received r-ATG (steroid = 3157, no-steroid = 486), 448 alemtuzumab (steroid = 196, no-steroid = 252) and 1543 an IL-2B (steroid = 1465, no-steroid = 78). Unadjusted graft survivals were similar for the no-steroid versus steroid groups for induction with r-ATG [hazard ratio (HR) 0.85 and 95% confidence interval (95% CI) 0.70-1.03, P = 0.10], alemtuzumab (HR 0.76, 95% CI 0.51-1.14, P = 0.18) and IL-2B (HR 0.77, 95% CI 0.56-1.70, P = 0.23). In the adjusted model, steroid use improved graft survival in alemtuzumab (HR 0.44, 95% CI 0.25-0.76, P = 0.003) but not in the r-ATG (HR 0.86, 95% CI 0.68-1.09, P = 0.21) or IL-2B (HR 0.98, 95% CI 0.56-1.70, P = 0.94) groups. Steroid use was associated with inferior patient survival in unadjusted (HR 1.30, 95% CI 1.17-1.44, P <0.001) and adjusted (HR 1.29, 95% CI 1.14-1.45, P <0.001) models for r-ATG induction, whereas this was not observed with alemtuzumab (unadjusted HR 1.11, 95% CI 0.89-1.37, P = 0.36; adjusted HR 0.90, 95% CI 0.68-1.20, P = 0.49) or IL-2B (unadjusted HR 1.01, 95% CI 0.87-1.18, P = 0.87; adjusted HR 1.15, 95% CI 0.97-1.38, P = 0.12) inductions. Our study showed a graft survival benefit in the alemtuzumab- and patient death risk in the r-ATG-induced RKT recipients discharged on steroids.

Impact of steroid maintenance on the outcomes in first-time deceased donor kidney transplant recipients: Analysis by induction type.

To analyze the impact of steroid maintenance on the outcomes in kidney transplant recipients stratified by induction agent received. Patients who underwent first-time deceased donor kidney transplantation between 2000 and 2008 after receiving induction therapy with rabbit-antithymocyte globulin (r-ATG), alemtuzumab or an interleukin-2 receptor blocker (IL-2B) and discharged on a calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)-regimen along with or without steroids were identified from the Organ Procurement and Transplant Network/United Network of Organ Sharing database. For each induction type, adjusted overall and death-censored graft as well as patient survivals were compared between patients discharged on steroid vs no steroid. Among r-ATG induced patients, analysis was repeated after splitting the group into low and high immune risk groups. Among the 37217 patients included in the analysis, 17863 received r-ATG (steroid = 13001, no-steroid = 4862), 3028 alemtuzumab (steroid = 852, no-steroid = 2176) and 16326 IL-2B (steroid = 15008, no-steroid = 1318). Adjusted overall graft survival was inferior (HR = 1.16, 95%CI: 1.06-1.27, P = 0.002) with similar death-censored graft survival (HR = 0.99, 95%CI: 0.86-1.14, P = 0.86) for steroid vs no-steroid groups in r-ATG induced patients. Both adjusted overall and death-censored graft survivals for steroid vs no-steroid groups were similar in alemtuzumab (HR = 0.92, 95%CI: 0.73-1.15, P = 0.47 and HR = 0.87, 95%CI: 0.62-1.22, P = 0.43 respectively) and IL-2B (HR = 1.05, 95%CI: 0.91-1.21, P = 0.48 and HR = 0.94, 95%CI: 0.75-1.18, P = 0.60 respectively) induced groups. Adjusted patient survivals were inferior for steroid vs no-steroid groups in r-ATG induced (HR = 1.31, 95%CI: 1.15-1.49, P < 0.001) but similar in alemtuzumab (HR = 1.02, 95%CI: 0.75-1.38, P = 0.92) and IL-2B (HR = 1.17, 95%CI: 0.97-1.40, P = 0.10) induced patients. Among the r-ATG induced group there were 4346 patients in the low immune risk and 13517 patients in the high immune risk group. Adjusted overall graft survivals were inferior for steroid vs no steroid groups in both low immune (HR = 1.34, 95%CI: 1.09-1.64, P = 0.001) and high immune (HR = 1.18, 95%CI: 1.07-1.30, P = 0.005) risk groups. Adjusted death-censored graft survivals for steroid vs no steroid groups were similar in both low (HR = 1.06, 95%CI: 0.78-1.45, P = 0.70) and high (HR = 1.04, 95%CI: 0.98-1.20, P = 0.60) immune risk groups. Adjusted patient survivals were inferior for steroid vs no steroid groups in both low immune (HR = 1.54, 95%CI: 1.18-2.02, P < 0.001) and high immune (HR = 1.32, 95%CI: 1.16-1.51, P = 0.002) risk groups. Overall, there were significantly higher deaths from infections and cardiovascular causes in patients maintained on steroids. Our study showed an association between steroid addition to a CNI/MMF-maintenance regimen and increased death with functioning graft in patients receiving r-ATG induction for first-time deceased donor kidney transplantation.

Cytomegalovirus prophylaxis in pediatric kidney transplantation: The Dutch experience

Many children receiving a kidney transplant are seronegative for CMV and therefore, highly susceptible to a primary CMV infection. This study aims at evaluating incidence, time of occurrence, and severity of CMV infection in the first year post-transplantation in relation to different types of CMV prophylaxis. Transplantations in three centers in the Netherlands between 1999 and 2010 were included. Retrospective, observational, multicenter study. Clinical data and PCR measurements of CMV were collected. Prophylaxis in high-risk patients (CMV serostatus D+R-) consisted of (val)ganciclovir during threemonths, or acyclovir plus CMV immunoglobulin at a former stage. Intermediate-risk patients (R+) received (val)acyclovir, or acyclovir plus CMV immunoglobulin at a former stage. Low-risk patients (D-R-) did not receive prophylaxis. Infection was defined as CMV PCR above 50geq/mL plasma or whole blood, a clinically relevant infection above 1000geq/mL. One hundred and fifty-nine transplantations were included. CMV infection was documented for 41% of high-risk, 24% of intermediate-risk, and 13% of low-risk patients, in the latter two groups typically during the first threemonths. The infection rate was highest in the high-risk group after cessation of valganciclovir prophylaxis. Valganciclovir provided better protection than did acyclovir+CMV immunoglobulin. Adding an IL2-receptor blocker to the immunosuppressive regimen did not affect the infection rate. Acute graft rejection was not related with CMV infection. Valganciclovir prophylaxis effectively prevents CMV infection in high-risk pediatric kidney recipients, but only during prophylaxis. Valacyclovir prophylaxis in intermediate-risk patients is less effective.

Influence of Maintenance Steroids on the Outcomes in Deceased-Donor Kidney Transplant Recipients Exposed to Prolonged Pretransplantation Dialysis

BackgroundPre-transplant dialysis duration exerts a graded negative influence on outcomes after kidney transplantation. Higher immune reactivity associated with prolonged dialysis with consequent increased acute rejection could be contributory. MethodsUsing the Organ Procurement and Transplant Network/United Network of Organ Sharing database, we identified patients ≥18 years of age who received deceased-donor kidney (DDK) transplants from 2000 to 2008 after being on maintenance dialysis for ≥4 years. Patients received induction therapy with rabbit antithymocyte globulin (r-ATG), alemtuzumab, or an interleukin-2 receptor blocker (IL-2B) and were discharged on calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)–based immunosuppression with or without steroid. Unadjusted and adjusted graft/patient survivals were compared in steroid versus no-steroid groups by induction type. ResultsA total of 14,459 patients were identified, of which 7,684 received r-ATG (steroid, 6,098; no-steroid, 1,586), 1,292 alemtuzumab (steroid, 362; no-steroid, 930), and 5,483 an IL-2B agent (steroid, 5,107; no-steroid, 376). Adjusted graft survivals were similar for steroid versus no-steroid groups in r-ATG (hazard ratio [HR] 1.10, 95% confidence interval (CI) 0.96–1.26, P = .16), alemtuzumab (HR 0.88, 95% CI 0.65–1.19; P = .40), and IL-2B (HR 0.91, 95% CI 0.73–1.13; P = .38) groups. Adjusted patient survival for steroid versus no-steroid groups was inferior in r-ATG (HR 1.41, 95% CI 1.17–1.71; P < .001) but similar in alemtuzumab (HR 1.05, 95% CI 0.70–1.59; P = .80) and IL-2B (HR 1.17, 95% CI 0.86–1.58; P = .32) groups. ConclusionsOur analysis failed to show a graft survival benefit for the addition of steroid to a CNI/MMF-based immunosuppression after induction with r-ATG, alemtuzumab, or an IL-2B agent in DDK recipients exposed to prolonged pretransplantation dialysis.

Effect of Induction Agent on Posttransplant Outcomes in Deceased Donor Kidney Transplant Recipients: Influence of Race

BackgroundThe effect of induction agents on kidney transplant outcomes with respect to race is not well studied. We aimed to compare the outcomes of deceased donor kidney (DDK) transplants in African American (AA) and non-African American (non-AA) recipients who underwent induction therapy with rabbit-antithymoglobulin (rATG), alemtuzumab (ALE), or interleukin (IL)-2 receptor blocker (IL-2B) and were maintained on a calcineurin inhibitor, (CNI)/mycophenolate mofetil (MMF)–based regimen with/without steroid. MethodsUsing OPTN/UNOS database, we identified patients (≥18 years) who underwent DDK transplants from January 2000 to December 2008 and received rATG (n = 21,506), ALE (n = 3476), or IL- 2B (n = 17,869) and were maintained on a CNI/MMF–based regimen with/without steroids. Multivariate analysis was performed adjusting for steroid use and factors known to adversely impact graft outcome. ResultsThe median follow up was 29.6 months (range, 10.7–60.1). ALE induction as compared to rATG had inferior adjusted graft (P < .001) and patient (P = .003) survivals in non-AA recipients but similar in AA recipients. In non-AA recipients, IL-2 induction as compared with rATG had similar adjusted graft but inferior patient survival (P = .04), and in AA recipients had inferior graft (P = .002) but similar patient survival. ConclusionOur study shows racial differences in renal transplant outcomes with regard to induction modality.

Forma aguda da doença enxerto contra o hospedeiro após transplante de fígado. Existe opção terapêutica para as formas refratárias ao tratamento com esteróides?

Background: Acute graft-versus-host disease (GVHD) usually occurs by 8 weeks after liver transplantation (LT) usually is an uncommon complication but has both high mortality and major diagnostic challenge in addition most of them are associated with resistance to steroid therapy. Objective: Discuss the pathogenesis, treatment and long-term results of Acute Graft versus Host Diseaseafter Liver Transplantation. Methods: A PubMed search was performed to identify all reported cases of GVHD following LT. The medical subject heading GVHD disease was used in combination with LT, including adults (19 + years) and children. The bibliographiesof the articles found though PubMed were then searched for further reports of GVHD. Results: We reviewed 102 cases of acute GVHD, 96 (94.1%) adults and 6 (5.8%) children. After treatment24 (25%) adults and 3 (50%) children were alive only. As far as the treatment of GVHD is concern the therapy used in adults and in children patients was respectively : anti-thymocyte globulin + prednisolone – 19 (19.5%); interleukin-2 receptor blocker – 17 (17.5%); OKT3 – 12 (12.3%); cyclosporine – 9 (9,2% ); others – 39 (40.2%) and in children anti-thymocyte globulin – 1 (20%); anti-thymocyte globulin + prednisolone – 1 (20%); prednisolone – 1 (20%); anti-thymocyte globulin + prednisolone + interleukin-2 receptor blocker-1 (20%); not mentioned – 1.There was no standard treatment of acute GVHD for both children and adults. Conclusion: Although acute GVHD following LT is rare complication and mortalityis still very high, there is no consensus for the treatment of steroid-refractory forms. Further researches are needed to provide new approach for treating effectively such condition.

Influence of Induction Modality on the Outcome of Deceased Donor Kidney Transplant Recipients Discharged on Steroid-Free Maintenance Immunosuppression

Over last several years, alemtuzumab induction has been increasingly used in kidney transplantation especially in patients maintained on steroid-free immunosuppression. It is unclear which induction agent is associated with better graft and patient outcomes in these patients. Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, graft and patient survivals were compared with multivariate analysis for deceased donor kidney transplant recipients from January 2000 to December 2008 who received induction with rabbit-antithymocyte globulin (r-ATG), alemtuzumab, or an interleukin-2 (IL-2) receptor blocker and were discharged on a calcineurin inhibitor/mycophenolate mofetil/steroid-free immunosuppression. When compared with r-ATG (n=5348), adjusted graft survival was inferior with alemtuzumab (n=2428, hazards ratio [HR] 1.26, 95% confidence interval [CI] 1.10-1.43, P=0.001) and IL-2 receptor blocker (n=1396, HR 1.19, 95% CI 1.01-1.39, P=0.04) inductions and patient survival was inferior with alemtuzumab (HR 1.29, 95% CI 1.08-1.55, P=0.006). Alemtuzumab induction was associated with higher adjusted graft failure risks in patients with panel reactive antibody more than 20% (HR 1.30, 95% CI 1.01-1.68, P=0.04), recipients of expanded criteria donor kidneys (HR 1.58, 95% CI 1.23-2.02, P<0.001), and kidneys with cold ischemia time more than 24 hr (HR 1.31, 95% CI 1.04-1.65, P=0.02) and higher patient death risks in recipients of expanded criteria donor kidney (HR 1.66, 95% CI 1.20-1.30, P=0.002) and kidneys with cold ischemia time more than 24 hr (HR 1.44, 95% CI 1.04-2.00, P=0.03). Adjusted graft survival rates were similar for different induction agents in the low-immune risk group. When compared with alemtuzumab and IL-2 receptor blocker, r-ATG induction seems to be associated with superior outcomes in deceased donor kidney transplant recipients maintained on calcineurin inhibitor/mycophenolate mofetil/steroid-free regimen.

Immunosuppression and HCV recurrence after liver transplantation

HCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens. From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency. There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6 months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed.