Hypoxia inducible factor 2α promotes tolerogenic macrophage development during cardiac transplantation through transcriptional regulation of colony stimulating factor 1 receptor.

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.

Anti-intercellular adhesion molecule 1 monomaintenance therapy induced long-term liver allograft survival without chronic rejection.

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

Coordinated elimination of bacterial taxa optimally attenuates alloimmunity and prolongs allograft survival.

This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, Parabacteroides distasonis, as the most enriched following all Abx treatments. Oral administration of P.distasonis to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation.

The hepatocyte growth factor mimetic, ANG-3777, in kidney transplant recipients with delayed graft function: Results from a randomized phase 3 trial.

In kidney transplant recipients, delayed graft function increases the risk of graft failure and mortality. In a phase 3, randomized, double-blind, placebo-controlled trial, we investigated the hepatocyte growth factor mimetic, ANG-3777 (once daily for 3 consecutive days, starting ≤30 hours posttransplant), in 248 patients receiving a first kidney transplant from a deceased donor. At day 360, estimated glomerular filtration rate (primary endpoint) was not significantly different between the ANG-3777 and placebo groups. There were no significant between-group differences in the duration of dialysis through day 30 or in the percentage of patients with an estimated glomerular filtration rate of >30 mL/min/1.73 m2 at day 360. The incidence of both delayed graft function and acute rejection was similar between ANG-3777 and placebo groups (68.5% vs 69.4% and 8.1% vs 6.5%, respectively). ANG-3777 was well tolerated, and there was a numerically lower incidence of graft failure versus placebo (3.2% vs 8.1%). Although there is insufficient evidence to support an indication of ANG-3777 for patients at risk of renal dysfunction after deceased-donor kidney transplantation, these findings indicate potential biological activity that may warrant further investigation.

Differential induction of donor-reactive Foxp3+ regulatory T cell via blockade of CD154 vs CD40.

Recently published studies in both murine models and a meta-analysis of non-human primate renal transplant studies showed that anti-CD154 reagents conferred a significant survival advantage over CD40 blockers in both animal models and across multiple organs. Here we sought to compare the induction of donor-reactive forkhead box P3+-induced regulatory T cells (Foxp3+ iTreg) in mice treated with anti-CD154 versus anti-CD40 monoclonal antibodies (mAbs). Results indicated that while treatment with anti-CD154 mAb resulted in a significant increase in the frequency of donor-reactive CD4+ Foxp3+ iTreg following transplantation, treatment with anti-CD40 or Cd40 deficiency failed to recapitulate this result. Because we recently identified CD11b as an alternate receptor for CD154 during alloimmunity, we interrogated the role of CD154:CD11b interactions in the generation of Foxp3+ iTreg and found that blockade of CD11b in Cd40-/- recipients resulted in increased donor-reactive Foxp3+ iTreg as compared with CD40 deficiency alone. Mechanistically, CD154:CD11b inhibition decreased interleukin (IL)-1ß from CD11b+ and CD11c+ dendritic cells, and blockade of IL-1ß synergized with CD40 deficiency to promote Foxp3+ iTreg induction and prolong allograft survival. Taken together, these data provide a mechanistic basis for the observed inferiority of anti-CD40 blockers as compared with anti-CD154 mAb and illuminate an IL-1ß-dependent mechanism by which CD154:CD11b interactions prevent the generation of donor-reactive Foxp3+ iTreg during transplantation.

Obesity is associated with a higher incidence of rejection in patients on belatacept: A pooled analysis from the BENEFIT/BENEFIT-EXT clinical trials.

Though belatacept is administered with a weight-based dosing schema, there has been higher clearance reported in obese patients. Therefore, we evaluated the association between body mass index (BMI) and transplant outcomes in kidney transplant recipients who were randomized to cyclosporine- or belatacept-based immunosuppression in the BENEFIT and BENEFIT-EXT randomized clinical trials. A total of 666 and 543 patients underwent randomization and transplantation in BENEFIT and BENEFIT-EXT, respectively, of which 1056 had complete data and were included in this analysis. Patients were grouped categorically according to BMI: <25, 25 to <30, and ≥30 kg/m2. BMI did influence both the incidence and severity of acute rejection. Obese patients with BMI >30 kg/m2 in the low intensity belatacept group experienced significantly more rejection at 12 months than did patients with BMI <25 kg/m2 or BMI 25 to <30 kg/m2. In both the moderate intensity belatacept and low intensity belatacept groups, obese patients with BMI >30 kg/m2 experienced significantly more severe acute rejection than did patients with BMI < 25 kg/m2 or BMI 25 to <30 kg/m2. These results suggest that obese kidney transplant recipients are at an increased risk for acute rejection when under belatacept-based immunosuppression when compared to nonobese patients.

Immunosuppression withdrawal in living-donor renal transplant recipients following induction with antithymocyte globulin and rituximab: Results of a prospective clinical trial.

Durable tolerance in kidney transplant recipients remains an important but elusive goal. We hypothesized that adding B cell depletion to T cell depletion would generate an immune milieu postreconstitution dominated by immature transitional B cells, favoring tolerance. The Immune Tolerance Network ITN039ST Research Study of ATG and Rituximab in Renal Transplantation was a prospective multicenter pilot study of live donor kidney transplant recipients who received induction with rabbit antithymocyte globulin and rituximab and initiated immunosuppression (IS) withdrawal (ISW) at 26 weeks. The primary endpoint was freedom from rejection at 52 weeks post-ISW. Six of the 10 subjects successfully completed ISW. Of these 6 subjects, 4 restarted immunosuppressive medications due to acute rejection or recurrent disease, 1 remains IS-free for over 9 years, and 1 was lost to follow-up after being IS-free for 42 weeks. There were no cases of patient or graft loss. CD19+ B cell frequencies returned to predepletion levels by 26 weeks posttransplant; immunoglobulin D+CD27--naïve B cells predominated. In contrast, memory cells dominated the repopulation of the T cell compartment. A regimen of combined B and T cell depletion did not generate the tolerogenic B cell profile observed in preclinical studies and did not lead to durable tolerance in the majority of kidney transplant recipients.

Rescue with obinutuzumab and daratumumab as combined B cell/plasma cell targeting approach in severe posttransplant focal segmental glomerulosclerosis recurrence.

The recurrence of primary focal segmental glomerulosclerosis (FSGS) after kidney transplantation is associated with a high graft loss rate with standard treatments based on plasmapheresis with/without rituximab. We present 2 consecutive cases of nongenetic early severe recurrent FSGS refractory to rituximab and anti-interleukin 1 treatment and with a partial response to plasmapheresis. Case 1 was a 22-year-old man who was rescue-treated for recurrence 36 weeks after transplantation with obinutuzumab (1000 mg/1.73 m2, 1 dose) and daratumumab (18 mg/kg each dose, 8 doses), resulting in plasmapheresis discontinuation and a drop of proteinuria from 29 to 2.3 g/d. Proteinuria increased with circulating CD38+ plasma cells and responded to an additional daratumumab dose. Currently, the proteinuria is 1.8 g/d, 14.5 months after discontinuing plasmapheresis and starting obinutuzumab and daratumumab therapy. Case 2 was a 15-year-old girl who was plasmapheresis dependent with 2 g/d proteinuria 82 weeks after transplantation, with a Tesio catheter in the right jugular vein as the only possible vascular access. After treatment with obinutuzumab and daratumumab (1 dose each), she achieved stable complete remission (0.3 g/d proteinuria) with persistent plasmapheresis discontinuation. These cases suggest the potential of combining obinutuzumab with daratumumab for the treatment of recurrent FSGS.

Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study.

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation.

BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Recombinant human IL-37 attenuates acute cardiac allograft rejection in mice.

BACKGROUND: Allograft rejection remains a major obstacle to long-term graft survival. Although previous studies have demonstrated that IL-37 exhibited significant immunomodulatory effects in various diseases, research on its role in solid organ transplantation has not been fully elucidated. In this study, the therapeutic effect of recombinant human IL-37 (rhIL-37) was evaluated in a mouse cardiac allotransplantation model. METHODS: The C57BL/6 recipients mouse receiving BALB/c donor hearts were treated with rhIL-37. Graft pathological and immunohistology changes, immune cell populations, and cytokine profiles were analyzed on postoperative day (POD) 7. The proliferative capacities of Th1, Th17, and Treg subpopulations were assessed in vitro. Furthermore, the role of the p-mTOR pathway in rhIL-37-induced CD4+ cell inhibition was also elucidated. RESULTS: Compared to untreated groups, treatment of rhIL-37 achieved long-term cardiac allograft survival and effectively alleviated allograft rejection indicated by markedly reduced infiltration of CD4+ and CD11c+ cells and ameliorated graft pathological changes. rhIL-37 displayed significantly less splenic populations of Th1 and Th17 cells, as well as matured dendritic cells. The percentages of Tregs in splenocytes were significantly increased in the therapy group. Furthermore, rhIL-37 markedly decreased the levels of TNF-α and IFN-γ, but increased the level of IL-10 in the recipients. In addition, rhIL-37 inhibited the expression of p-mTOR in CD4+ cells of splenocytes. In vitro, similar to the in vivo experiments, rhIL-37 caused a decrease in the proportion of Th1 and Th17, as well as an increase in the proportion of Treg and a reduction in p-mTOR expression in CD4+ cells. CONCLUSIONS: We demonstrated that rhIL-37 effectively suppress acute rejection and induce long-term allograft acceptance. The results highlight that IL-37 could be novel and promising candidate for prevention of allograft rejection.

Two novel assays demonstrate persistent daratumumab exposure in a pediatric patient with delayed engraftment following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism. METHODS: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment. RESULTS: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted. CONCLUSIONS: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.

Iscalimab Combined With Transient Tesidolumab Prolongs Survival in Pig-to-Rhesus Monkey Renal Xenografts.

OBJECTIVE: To evaluate the clinically relevant anti-CD40 antibody iscalimab for baseline immunosuppression in a preclinical pig-to-rhesus renal xenograft model. SUMMARY BACKGROUND DATA: CD40/CD40L co-stimulation blockade-based immunosuppression has been more successful than calcineurin-based protocols in prolonging xenograft survival in preclinical models. METHODS: GGTA1 knockout/CD55 transgenic pig kidneys were transplanted into rhesus monkeys (n = 6) receiving an iscalimab-based immunosuppressive regimen. RESULTS: Two grafts were lost early (22 and 26 days) because of ectatic donor ureters with otherwise normal histology. The other recipients survived 171, 315, 422, and 439 days with good renal function throughout the posttransplant course. None of the recipients experienced serious infectious morbidity. CONCLUSIONS: It may be reasonable to evaluate an iscalimab-based immunosuppressive regimen in clinical renal xenotransplantation.

Cell-Based Therapies Induce Tolerance of Vascularized Composite Allotransplants: A Systematic Review.

INTRODUCTION: Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging functional outcomes of VCA, the consequences of long-term immunosuppression remain the main obstacle in its application. In this review, we provide researchers and surgeons with a summary of the latest advances in the field of cell-based therapies for VCA tolerance. METHODS: Four electronic databases were searched: PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature , and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis as the basis of our organization. RESULTS: Hematopoietic stem cells prolonged VCA survival. A combination of immature dendritic cells and tacrolimus was superior to tacrolimus alone. T cell Ig domain and mucin domain modified mature dendritic cells increased VCA tolerance. Bone marrow-derived mesenchymal stem cells prolonged survival of VCAs. A combination of adipose-derived mesenchymal stem cells, cytotoxic T-lymphocyte antigen 4 immunoglobulin, and antilymphocyte serum significantly improved VCA tolerance. Ex-vivo allotransplant perfusion with recipient's bone marrow-derived mesenchymal stem cells increased VCA survival. Recipient's adipose-derived mesenchymal stem cells and systemic immunosuppression prolonged VCA survival more than any of those agents alone. Additionally, a combination of peripheral blood mononuclear cells shortly incubated in mitomycin and cyclosporine significantly improved VCA survival. Finally, a combination of donor recipient chimeric cells, anti-αß-T cell receptor (TCR), and cyclosporine significantly prolonged VCA tolerance. CONCLUSIONS: Evidence from animal studies shows that cell-based therapies can prolong survival of VCAs. However, there remain many obstacles for these therapies, and they require rigorous clinical research given the rarity of the subjects and the complexity of the therapies. The major limitations of cell-based therapies include the need for conditioning with immunosuppressive drugs and radiation, causing significant toxicity. Safety concerns also persist as most research is on animal models. While completely replacing traditional immunosuppression with cell-based methods is unlikely soon, these therapies could reduce the need for high doses of immunosuppressants and improve VCA tolerance.

Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

Early Tapering of Cyclosporine Is Feasible in Haploidentical Stem Cell Transplantation: A Single Center Experience.

INTRODUCTION: Cyclosporine-A (CsA) and post transplantation cyclophosphamide (PTCy) are common agents used for graft versus host disease (GVHD) prophylaxis in Haploidentical hematopoietic cell transplantation (haplo-HCT). However, the impact of CsA cessation timing in the posttransplant setting on clinical outcomes is uncertain. We aimed to investigate the impact of a novel approach that integrated early CsA cessation with PTCy utilization. PATIENTS AND METHODS: This study was a single arm retrospective study carried out at a tertiary referral hospital hematology and bone marrow transplantation center between 2009 and 2022. The patients who received haplo-HCT with ATG, PTCy and CsA as GVHD prophylaxis were included. CsA was planned for cessation starting at day 45 to day 60. Acute and chronic GVHD were evaluated and graded. CsA blood concentrations and its impact on acute and chronic GVHD was evaluated. RESULTS: Thirty-one patients composed of 19 (61.3%) male and 12 (38.7%) female patients with a median age of 31 years (20-58). Busulfan and TBI based conditioning regimens were the most utilized regimens. The majority of donors were first degree relatives. Stem cell origin was peripheral blood for all patients. GVHD prophylaxis consisted of ATG, CsA and PTCy. Acute GVHD was observed in 9 (29%) cases, whereas chronic GVHD was seen in 3 (9.7%) cases, with 2 of them having overlapping GVHD. Age, gender, number of chemotherapy lines, transplant characteristics, infused CD34 cell count, and engraftment durations were similar among patients with and without GVHD. Patients with GVHD had similar 1st, 2nd, 3rd and 4th week CsA concentrations compared to patients without GVHD (p > 0.05). The presence of GVHD was not associated with worse progression free survival and overall survival (p = 0.6, p = 0.5, respectively). CMV reactivation was more common in the GVHD group. CONCLUSION: In the current study, we did not find an impact of CsA concentration on GVHD and post-transplant outcomes in Haplo-HCT setting. Therefore, together with the use of PTCy, early CsA cessation can be an option; further studies are needed to understand all aspects of this approach.

Significant Long-Term Prevention of High Sensitization After Kidney Allograft Failure by Maintaining Calcineurin Inhibitor-Based Immunosuppression.

INTRODUCTION: Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). METHODS: Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). RESULTS: Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0% vs. 85.5%, p < 0.001) and 24 months (61.0% vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4% vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6% vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9% vs. 18.6%, p = 0.003, OR = 0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406 vs. 813 days, p = 0.001) without an increased risk of complications. CONCLUSIONS: CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications.

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

INTRODUCTION: Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. METHODS: A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. RESULTS: Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. CONCLUSION: Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Eculizumab as Salvage Treatment for Thrombotic Microangiopathy After Lung Transplantation.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare complication after lung transplantation (LT) that has seldom been characterized in detail. Recent evidence has linked TMA other than primary atypical hemolytic uremic syndrome (aHUS) with hyperactivation of the complement alternative pathway. The focus of this investigation was to analyze the treatment response with eculizumab in TMA after LT. METHODS: Case series where we have studied 11 patients with TMA after LT from 2 Spanish tertiary healthcare centers. Clinical data and response rates to eculizumab are provided. RESULTS: The main indication for lung transplant was chronic obstructive pulmonary disease (COPD) (36%) and most cases (82%) received bilateral LT. The median time to TMA diagnosis was 11.6 months (4.7-28.9) and the TMA trigger in the majority of cases (73%) was immunosuppressive drugs. Platelet and hemoglobin nadir were 58 × 103/µL (24-108) and 7.7 g/dL (7.1-7.9), respectively. All cases presented acute kidney injury (AKI) with a median creatinine of 4 mg/dL (3.2-4.8) and 54.5% required acute dialysis. Eculizumab was started after a median time of 8 days (6-14) with a median duration of 3 weeks (2-8). Complete TMA response was observed in 7 (63.6%) cases and hematologic response in 10 (90.9%). The time to hematologic and renal response was 23 days (13-29) and 28 days (14-46), respectively. CONCLUSIONS: TMA after LT is infrequent but potentially devastating. Our findings suggest that short cycles of eculizumab may be effective for severe TMA after LT.

The Number of Episodes of Subtherapeutic Tacrolimus Blood Level Is Independently Associated With Reduced Kidney Graft Survival.

BACKGROUND: Tacrolimus blood level variability is associated with reduced graft survival among kidney transplant recipients. To date, no practical approach for reducing variability has been validated. We defined specific tacrolimus blood level patterns correlated with variability and evaluated their independent association with reduced graft survival. METHODS: In this single-center retrospective study, we predefined 12 patterns that exhibited correlation with high tacrolimus blood level variability. Subsequently, we utilized a multivariate Cox proportional hazard model, in conjunction with the Akaike information criteria, to evaluate the association between the predefined patterns and decreased graft survival. RESULTS: Our cohort included 1305 kidney transplant recipients. The primary outcome of this trial was graft loss, defined as the initiation of chronic dialysis or the need for retransplantation. The secondary outcome was the combination of death-censored graft loss and death with a functioning graft. During the study's follow-up period, there were 131 events of graft loss. The number of episodes of subtherapeutic tacrolimus level during the first-year posttransplantation was significantly associated with graft loss (HR 1.208 per episode, 95% CI 1.075-1.356, p = 0.001) and significantly improved the relative likelihood of the model compared to the multivariate model as demonstrated by the delta AIC value (8.256, p = 0.016). CONCLUSION: In addition to increased tacrolimus blood level variability, the number of episodes of subtherapeutic tacrolimus levels is independently associated with decreased graft survival among kidney transplant recipients.