Adjustment Of Immunosuppression Research Articles

Advanced Prediction of Glomerular Filtration Rate After Kidney Transplantation Using Gradient Boosting Techniques.

Clinicians often face uncertainty when interpreting whether a decline in estimated glomerular filtration rate is within the patient's expected range of fluctuation or if the decline signals a substantial deviation. Thus, accurate predictions of glomerular filtration rate can be an early warning system, prompting timely interventions, such as biopsies to preclude early graft rejection and adjustments in immunosuppression. Traditional models, encompassing linear and conventional methods, typically struggle with variabilities and complexities in posttransplant data. We evaluated the efficacy of a gradient boosting model in predicting posttransplant glomerular filtration rate, to potentially enhance accuracy over traditional prediction approaches. Our patient dataset included 68 pediatric patients aged 1 to 18 years who underwent kidney transplant between 2017 and 2023 at Baskent University Hospital (Ankara, Turkey). The dataset comprised 2285 glomerular filtration rate measurements, along with patient demographics and transplant-related data. For our model, we included "days to transplant" (glomerular filtration rate values pretransplant), "days from transplant" (glomerular filtration rate values up to 7 days posttransplant), patient age, sex, and donor types. We divided the dataset into a training set (70%) and a test set (30%). To evaluate model performance, we used mean absolute error and root mean squared error, with a focus on the accuracy of glomerular filtration rate predictions at various posttransplant stages. In the training set, the gradient boosting model demonstrated a significant improvement in prediction accuracy, achieving an mean absolute error of ~5.64 mL/min/1.73 m². Our model underscored the promise of advanced machine learning techniques in refining prediction of glomerular filtration rate after kidney transplant. With its augmented precision, the model can support clinicians in making informed decisions regarding early biopsies and interventions, thus highlighting the vital role of sophisticated analytical methods in medical prognosis and the monitoring of pediatric patient care.

Validation of the R3-AFP model for risk prediction of HCC recurrence after liver transplantation in the SiLVER randomized clinical trial.

Explant-based models for assessing HCC recurrence after liver transplantation serve as the gold standard, guiding post-liver transplantation screening and immunosuppression adjustment. Incorporating alpha-fetoprotein (AFP) levels into these models, such as the novel R3-AFP score, has notably enhanced risk stratification. However, validation of these models in high-evidence data is mandatory. Therefore, the aim of the present research was to validate the R3-AFP score in a randomized clinical trial. We analyzed the intention-to-treat population from the 2-arm SiLVER trial (NCT00355862), comparing calcineurin-based ([calcineurin inhibitors]-Group A) versus mammalian target of rapamycin inhibitors-based (sirolimus-Group B) immunosuppression for post-liver transplantation HCC recurrence. Competing risk analysis estimated sub-hazard ratios, with testing of discriminant function and calibration. Overall, 508 patients from the intention-to-treat analysis were included (Group A, n = 256; Group B, n = 252). The R3-AFP score distribution was as follows: 42.6% low-risk (n = 216), 35.7% intermediate-risk (n = 181), 19.5% high-risk (n = 99), and 2.2% very-high-risk (n = 11) groups. The R3-AFP score effectively stratified HCC recurrence risk, with increasing risk for each stratum. Calibration of the R3-AFP model significantly outperformed other explant-based models (Milan, Up-to-7, and RETREAT), whereas discrimination power (0.75 [95% CI: 0.69; 0.81]) surpassed these models, except for the RETREAT model ( p = 0.49). Subgroup analysis showed lower discrimination power in the mammalian target of rapamycin group versus the calcineurin inhibitors group ( p = 0.048). In conclusion, the R3-AFP score accurately predicted HCC recurrence using high-quality evidence-based data, exhibiting reduced performance under mammalian target of rapamycin immunosuppression. This highlights the need for further research to evaluate surveillance schedules and adjuvant regimens.

Association between COVID-19 infection and uveitis flare in patients with Behcet's disease, a retrospective multicenter cohort study.

To explore if COVID-19 infection and its subsequent immunosuppressant adjustment as well as previous vaccination status are associated with higher risks of uveitis flare in patients with Behcet's disease. This retrospective multicenter cohort study was conducted in January 2023 among patients with Behcet's uveitis, during the second wave of the COVID-19 pandemic in China, with an anticipated sample size of 250. The primary objective was to examine the association between COVID-19 infection and the occurrence of uveitis flare. The potential impact of other exposures, including the patient's vaccination status and treatment adjustments to the risk of uveitis flare and the course of COVID-19 infection were also analyzed. 207 patients with COVID-19 infection and 47 patients without COVID-19 infection were included. A total of 127 uveitis flares occurred in the observational period (14.29 events per 100 person-month). COVID-19 infection was found to be significantly associated with a higher rate of uveitis flare (adjusted rate ratio = 4.8, 95% CI 3.7 to 6.3, P < 0.001). However, neither systemic immunosuppressive adjustment nor COVID-19 vaccination status showed a significant association with uveitis flare or the course of COVID-19 infection. This study provides evidence of an association between COVID-19 infection and an increased risk of uveitis flare in patients with Behcet's disease. However, there was no significant evidence to support that baseline immunosuppressive therapy regimens, treatment adjustment after COVID-19 infection, or vaccination status were associated with higher risks of uveitis flare or prolonged COVID-19 course.

Impact of COVID-19 on anti-HLA antibodies in kidney transplantation

The effects of COVID-19 on the immune profile of kidney transplant recipients are unknown. Immunosuppression adjustment during the illness can increase the risk for de novo donor-specific anti-HLA antibodies (DSA) and acute rejection episodes. This single-center retrospective study includes adult kidney transplant recipients diagnosed with COVID-19 between March 2020 and December 2022, screened for anti-HLA antibodies (AbHLA) pre-transplant and after COVID-19. Analyzed data comprised demographics, immunosuppressive therapy before and during the illness, hospitalization rate, and AbHLA specificity. Two hundred sixty-seven transplant recipients were included and divided according to the pre-transplant AbHLA profile: absent [PRA- (n = 206, 77%)], non-DSA (N = 46, 17%), and DSA+ (n = 15, 6%). The DSA+ group was younger (40.5 ± 16.5; PRA- 50.3 ± 13.4; non-DSA 49.3 ± 11.7 years; p = 0.02). The hospitalization rate was higher in groups with preformed AbHLA (DSA+ n = 8, 53%; non-DSA = 24, 52%; PRA- n = 54, 26%; p < 0.01). Immunosuppression was maintained in 222 (83%), withdrawn in 33 (12%), and reduced in 11 (4%) cases without difference among groups. Twenty-two (8%) cases of de novo DSA were observed after COVID-19 [PRA-, n = 16 (73%) and non-DSA, n = 6 (27%)]. In the DSA+ group, the AbHLA profile remained stable. There were 6 (2%) cases of post-COVID-19 antibody-mediated rejection (DSA+ n = 4, 66%; non-DSA n = 1, 17%, PRA- n = 1, 17%) without T cell-mediated rejection cases. Post-COVID-19 de novo DSA was more frequent in groups without pre-transplant AbHLA, not having association with changes in immunosuppressive therapy.

#2082 Effectiveness of a surveillance protocol and early mTORi conversion according to Urine BK viral load in Thai kidney transplant recipients

Abstract Background and Aims BK viral nephropathy (BKVN) is a crucial cause of early kidney allograft failure. Early detection and prompt treatment in the case of a high urine viral load might be more advantageous than waiting until BK viremia occurs. Data regarding outcome of BK infection based on adjustments of immunosuppression according to urine viral load is limited. Method A prospective cohort study of kidney transplant (KT) recipients at Siriraj Hospital, conducted between January 2015 and June 2020, involved monitoring urine BK viral load (RT-PCR) at 1, 2, 3, 6, 12, 18, and 24 months after KT. Determination of BK viremia and adjustments to immunosuppression were performed in patients with urine BK viral loads exceeding 1,000,000 copies/ml or demonstrating progressive increments in BK viruria. Initially, mycophenolate (MPA) dosage was reduced, and subsequently, conversion to mTOR inhibitors was considered for non-responsive cases. Data on the overall incidence and risk factors of BK viremia and/or BKVN were collected. Results Out of a total of 339 enrolled patients, 234 (69%) underwent deceased KT, and 49 (14.5%) received induction therapy with anti-thymocyte globulin. The incidence of BK viruria, viremia, and BKVN were 38.6% (131 patients), 9.7% (33 patients), and 4.1% (14 patients), respectively. The median time of occurrence for BK viruria and BKVN was 3 (IQR 1-12) and 4.5 (IQR 3–18) months after KT, respectively. Most BKVN cases (71.4%) developed within the first six months post KT. We did not find any significant risk factors associated with the occurrence of BK viremia or BKVN. Regarding the adjustment of immunosuppression, the initial reduction of MPA dosage was effective in 48 out of 92 patients (52.17%). In cases with an extremely high urine BK viral load or no response to MPA reduction, 46 patients received a change from MPA to everolimus, which was successful in 38 patients (82.6%). No graft loss due to BKVN was observed throughout the study. Conclusion The incidence of BK infection after KT in Thai recipients is high, comparable to western population. A surveillance protocol with urine BK viral load and early mTORi conversion is effective for prevention of allograft loss from BKVN.

#3045 Understanding BK polyomavirus: surveillance and clearance in kidney transplant recipients

Abstract Background and Aims BK virus allograft nephropathy (BKVN) can develop graft loss. The aim of this study was to describe BK viraemia and BKVN related factors, our experience in treatment and the impact in graft survival. Method We introduce a retrospective cohort of 78 kidney transplant recipients (KTRs) with BKV viraemia between January 2013 from January 2020 and with follow-up until December 31, 2022 in our center. Results Thirty-four (43%) were living donor KTRs, 30 (38.5%) DBD, 11 (14.1%) DCD III, and 2 (4.3%) DCD II. Twenty-seven (34.6%) of recipients were sensitized. Immunosuppressive induction was based on Anti-CD25 in 33 (42.3%), and antilymphocytes antibodies in 44 (56.4%). Basal treatment was TAC+MPA+PDN in 44 (56.4%) and TAC+iMTOR+PDN in 31 (39.7%). Median FK levels were 7.9 (ng/ml) in the first replication. Median BK load at first replication was 3636 [1030-97151]cp/ml. Median time to replication from transplant was 6 months, and from highest load 9 months. Immunosuppression adjustment after replication was switch to imTOR+FK 25 (32.1%), low FK 17 (21.8%), imTOR 4 (5.1%). Only surveillance was chosen in 27 (35.9%). Others therapies were Leflunomide 4 (5.1%), IVIG 6 (7.7%) or both 3 (3.8%). Photopheresis was used in 2 cases. Viraemia was cleared in 17/24 (70.8%) of the cases in which conversion to mTOR was performed as an immunosuppression adjustment strategy, versus 9 (56.3%) in which it was decided to lower FK and in 3 (75%) with low MMF. Ten cases in which surveillance was carried out became negative for viremia, possibly because they were patients with a lower replicative load. BKN occurred in 28/78 (36%) cases, interstitial fibrosis (ci&amp;gt;2) was found in 14/28 (48.27%). Graft rejection after BKN was developed in 11/28 (37.9%). Graft loss occurred in 26/78 (33.3%) of cohort and in 19 (65%)of patients with BKN, reaching a significant value. Viraemia clearance was reached in 41 (60.3%) in mean time of 10 months [4-27]. Mean time since BKVN until graft loss was 22.3 months [10.2-34.2]. Exitus occurred in 7/78 (9%) of replication cases and in 3/28 (10.7%)of BKN patients. Maximum BK load Exp β; [1-1], p 0.033, first replication load &amp;gt;10.000 (cp/ml) and deceased donor status (Exp β; 6,9 [2.43-19.57] and 2.98 [1.10-8.07] p 0.031, were related to BKVN in bivariate analysis. No significant differences were found between therapy in BKVN and graft loss, maybe due to low BKVN cases. Conclusion In our cohort, maximum BK load, first replication load &amp;gt;10,000 (cp/ml), and deceased donor status appear to be related to nephropathy. No significant differences were found between induction, basal or adjuvant therapy and graft loss. The current challenge is to stop replication before fibrosis, without increasing the risk of rejection.

Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients. Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

AbstractThe absence of a standardized definition for graft-versus-host disease (GVHD) flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22%, and flares were associated with a higher risk of nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P < .001). Flares were more severe (grades 3/4, 41% vs 16%; P < .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P < .001) than the initial GVHD. At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs AA1: aHR, 1.81 [95% CI, 1.32-2.48; P = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P < .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.

Worldwide variations in COVID-19 vaccination policies and practices in liver transplant settings: results of a multi-society global survey.

Despite the WHO's report of 24 available SARS-CoV-2 vaccines, limited data exist regarding vaccination policies for liver transplant (LT) patients. To address this, we conducted a global multi-society survey (EASL-ESOT-ELITA-ILTS) in LT centers. A digital questionnaire assessing vaccine policies, safety, efficacy, and center data was administered online to LT centers. Out of 168 responding centers, 46.4%, 28%, 13.1%, 10.7%, and 1.8% were from European, American, Western Pacific, Southeast Asian, and Eastern Mediterranean Regions. Most LT centers prioritized COVID-19 vaccine access for LT patients (76%) and healthcare workers (86%), while other categories had lower priority (30%). One-third of responders recommended mRNA vaccine exclusively, while booster doses were widely recommended (81%). One-third conducted post-vaccine liver function tests post COVID-19 vaccine. Only 16% of centers modified immunosuppression, and mycophenolate discontinuation or modification was the main approach. Side effects were seen in 1 in 1,000 vaccinated patients, with thromboembolism, acute rejection, and allergic reaction being the most severe. mRNA showed fewer side effects (-3.1, p = 0.002). COVID-19 vaccines and booster doses were widely used among LT recipients and healthcare workers, without a specific vaccine preference. Preventative immunosuppression adjustment post-vaccination was uncommon. mRNA vaccines demonstrated a favorable safety profile in this population.

631. Using a commercially available assay that measures cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity to predict protection against CMV: Results from a prospective, blinded clinical trial

Abstract Background Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality among kidney transplant recipients (KTR). Given toxicities and costs of antivirals, there is growing interest in assays that measure CMV-specific T-cell immunity (TCI), which may predict protection against clinical infection. The Viracor® CMV TCI Panel (TCIP) uses flow cytometry and intracellular cytokine staining to measure %CMV-specific CD4+ and CD8+ T-cells; it is the only commercially available TCI assay in the US. In this investigator-initiated study, we evaluated the performance of the TCIP in predicting clinically significant CMV events. To our knowledge, this is the first prospective blinded clinical study of the TCIP. Methods We enrolled consecutive donor (D) or recipient (R) CMV seropositive KTR, who had TCIP testing monthly until either discontinuation of valganciclovir prophylaxis or the primary outcome. We also enrolled KTR with low-level untreated DNAemia, or after completion of valganciclovir treatment, to evaluate assay predictive values for progression or relapse of CMV infection, respectively. The primary outcome was CMV DNAemia (tested at the discretion of the treating provider for symptoms or laboratory findings), prompting treatment initiation. Secondary outcomes were any DNAemia and DNAemia &amp;gt;1000 IU/mL. Treating providers were unaware of TCIP results. Results We included 46 KTR. Median age was 50.5 (range 18-74) years. 73.6% identified as men, 10.8% Black, 8.7% Hispanic; 41.3% had CMV D+/R- status. KTR with CMV events had significantly lower %CMV-specific CD8+ T-cells (Fig. 1A, p=0.024), and the CMV protection ROC AUC was significant (Fig. 1B: AUC 0.78, 95%CI 0.55-0.99, p=0.026). The positive predictive values of both CD4+ and CD8+ T-cell positivity &amp;gt;0.2% for CMV protection were 96.3% (95%CI 81-99.9%) for the primary outcome, 92.6% (95%CI 75.7-99.1%) for any DNAemia, and 100% (one-sided 95%CI 87.2%) for DNAemia &amp;gt;1000 IU/mL.Figure 1.A. Comparison of CMV-specific %CD8+ T-cells between patients with or without (protected) CMV events. B Receiver Operating Characteristic (ROC) curve for CMV protection. Conclusion The TCIP exhibited good performance in predicting protection from CMV events and could be a useful adjunct tool in clinical decision-making, regarding initiation or extension of CMV prophylaxis or treatment, as well as adjustments in immunosuppression. Disclosures Panos Arvanitis, MS, NIH: Grant/Research Support|NIH: Brown University Summer Assistantship program and from the Brown Emerging Infectious Disease Scholars (EIDS) (5R25AI140490) Dimitrios Farmakiotis, M.D., Astellas: Grant/Research Support|Merck: Grant/Research Support|Viracor: Advisor/Consultant|Viracor: Grant/Research Support

Management of incisional hernias in renal transplant patients

BackgroundIncisional hernia (IH) remains one of the most common complications following abdominal organ transplantation with no consensus on the optimal management. This study is a narrative review of the incidence, risk factors, diagnosis, and management of IH post-transplantation. MethodsA literature search using the EMBASE and MEDLINE from 1.1.2016 to 15.8.2002 was conducted. Included studies reported on IH after open abdominal organ transplantation. The outcomes included in our analysis were the incidence of IH, significant patient risk factors, the diagnostic approach used to detect IH, and proposed strategies for the management of IH. 54 publications that involved 9336 transplant patients who developed IH were included. ResultsThe incidence of IH ranged from 1.7 % to 43 % in liver transplant patients and was lower following kidney transplantation (1.1 %-7.0 %). Patient risk factors predisposing to IH were body mass index>30, age (>50), smoking history, previous open abdominal surgery, open surgical repair, a Mercedes or inverse T incision and surgical site infections. The most common diagnostic approach for IH is clinical examination, followed by US or CT imaging in cases of complex IH. Following IH repair, recurrence rates ranged from 0 to 76.9 %, and complication rates from 12 % - 52.9 %, the most common of which were surgical site occurrences (11.0–79.2 %) including infection (0 - 65.4 %) and seroma formation (0–8 %). Management of IH should include preoperative optimisation of patients through weight reduction, smoking cessation and adjustment of immunosuppression using a multidisciplinary (MDT) approach. Mesh repair, either open or laparoscopic, is the gold standard for the treatment of IH, resulting in a significantly lower recurrence rate than primary closure. There is no consensus on the type and positioning of mesh, and very limited studies have reported on other perioperative factors such as wound closure. ConclusionsPrehabilitation and MDT approach are important in ensuring good outcomes following IH repair. Further prospective studies and the establishment of a relevant registry are required to propose a consensus pathway for IH repair in the transplanted population.

COVID-19 Vaccine in Renal Transplant Recipients: A Bibliometric-Based Analysis of Trends

The global community has been affected by COVID-19, which emerged in December 2019. Since then, many studies have been conducted on kidney transplant recipients (KTRs) and COVID-19. This study aimed to perform a bibliometric and visual analysis of the published relationship between KTRs and COVID-19. To discuss the current status, hot spots, and development trend of research on KTRs vaccination with the COVID-19 vaccine and to provide a reference for researchers in related fields. Visual analysis of countries/regions, institutions, authors, references cited, and keywords for 2020 to 2023 via Microsoft Office Excel 2019 and CiteSpace (6.1.R6) based on the Web of Science core database. A total of 366 publications were included after screening, with a rapid increase in the global literature studying the COVID-19 vaccine of KTRs. The US has the highest number of publications, indicating that it is the leading country in this field of research. Charite University of Medicine Berlin and Schrezenmeier E are the most published institutions and authors, respectively. "Antibody Response After a Third Dose of the messenger RNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses" is the most central co-cited reference; The keywords "kidney transplant recipient," "covid 19 vaccine," and "mortality" have become hot topics of research. The keywords "humoral response" and "bnt162b2" are the latest research frontiers for detecting bursts. This paper analyzed the current status and trends of vaccination studies in KTRs through bibliometric analysis. Several studies support the vaccination of KTRs with the COVID-19 vaccine. However, the evidence for improving vaccine efficacy by adjustment of immunosuppression is still limited, and future studies on vaccination will remain a hot topic in this field.

Isolated arterial mucoid intimal thickening lesion in early post-transplant kidney allograft biopsies.

Thrombotic microangiopathy (TMA) on kidney biopsy shows a variable combination of features: arterial mucoid intimal thickening, acellular closure of glomerular capillary loops, fragmented red blood cells, fibrin thrombi, and arterial fibrinoid necrosis. However, some early post-transplant kidney biopsies show only arterial mucoid intimal thickening. We aimed to elucidate the importance of this finding. We identified 19 biopsies showing isolated arterial mucoid intimal thickening and compared them with 22 bona fide TMA biopsies identified based on the pathological findings (excluding rejection) (2011-2020). Additionally, delayed graft function (DGF) (n=237), and no DGF (control, n=1314) groups were included for survival analysis. Seven of 19 cases with isolated arterial mucoid intimal thickening showed peripheral blood schistocytes but no other systemic features of TMA. Eight patients underwent adjustments in maintenance immunosuppression (mainly calcineurin inhibitors). None of the cases progressed to full-blown TMA on consecutive biopsies. The overall and death-censored graft survival rates in this group were comparable to the DGF group, but significantly better than the TMA group (P=.005 and .04, respectively). Isolated arterial mucoid intimal thickening in early post-transplant biopsies may be an early/mild form of TMA, probably requiring adjustment in immunosuppressive regimen. Careful exclusion of known causes of TMA, and donor-derived arterial injury are important.

Application of prophylactic or pre-emptive therapy after allogeneic transplantation for high-risk patients with t(8;21) acute myeloid leukemia

ABSTRACTObjectivesTo determine the impact of pretransplant measurable residual disease (pre-MRD) and the efficacy of maintenance therapy in t(8;21) acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (allo-HCT).MethodsWe retrospectively analyzed 100 t(8;21) AML patients who underwent allo-HCT between 2013 and 2022. 40 patients received pre-emptive therapy including immunosuppressant adjustment, azacitidine, and donor lymphocyte infusion (DLI) combined with chemotherapy. 23 patients received prophylactic therapy, including azacitidine or chidamide.ResultsPatients with a positive pre-MRD (pre-MRDpos) had a higher 3-year cumulative incidence of relapse (CIR) (25.90% [95% CI, 13.87%–39.70%] vs 5.00% [95% CI, 0.88%–15.01%]; P = 0.008). Pre-MRDpos patients were less likely to have a superior 3-year disease-free survival (DFS) (40.83% [95% CI, 20.80%–80.16%]) if their MRD was still positive at 28 days after transplantation (post-MRD28pos). The 3-year DFS and CIR were 53.17% (95% CI, 38.31% – 73.80%) and 34.87% (95% CI, 18.84% – 51.44%), respectively, for patients receiving pre-emptive interventions after molecular relapse. The 3-year DFS and CIR were 90.00% (95%CI, 77.77% – 100%) and 5.00% (95%CI, 0.31% – 21.10%), respectively, for high-risk patients receiving prophylactic therapy. In most patients, epigenetic-drug-induced adverse events were reversible with dose adjustment or temporary discontinuation.ConclusionPatients with pre-MRDpos and post-MRD28pos were more likely to have higher rates of relapse and inferior DFS, even after receiving pre-emptive interventions. Prophylactic therapy may be a better option for high-risk t(8;21) AML patients; however, this warrants further investigation.

Pretransplant C-peptide Levels and Pancreas Transplant Outcomes: Risk and Reward.

We read with interest the report by Parajuli et al1, chronicling the University of Wisconsin experience in simultaneous pancreas-kidney transplantation (SPKT) according to the pretransplant fasting serum C-peptide levels. The authors demonstrated that higher pretransplant C-peptide levels predicted the risk of a composite outcome (combination of pancreas graft failure according to the United Network for Organ Sharing definition and pancreas graft dysfunction defined as initiation of any antidiabetic agent) posttransplant in patients with a type 2 diabetes phenotype.1,2 Recipients were categorized into 3 groups based on pretransplant fasting serum C-peptide levels: low (≤2 ng/mL, n = 14), medium (>2–8 ng/mL, n = 47), and high (>8 ng/mL, n = 15). The uncensored composite outcome of pancreas graft failure or dysfunction occurred in 0% in the low, 23% in the medium, and 33% of patients in the high C-peptide groups, respectively, suggesting that higher levels of pretransplant C-peptide are associated with inferior posttransplant outcomes. These findings confirm our recent report based on a case-controlled, single-center, retrospective study of 46 SPKT patients with pretransplant fasting serum C-peptide levels ≥2.0 ng/mL compared with 46 control patients (C-peptide level <0.5 ng/mL) matched for recipient age, gender, race, and transplant date.3 In our study, we likewise reported inferior mid-term outcomes in the group with higher pretransplant C-peptide levels. In our overall SPKT experience, we have 205 patients with a minimum of 5-y follow-up. Using the above C-peptide categories as per the Wisconsin study, we identified 166 patients in the low, 32 patients in the medium, and 7 patients in the high C-peptide groups. Five-y actual (uncensored) patient and graft survival rates were as follows: patient (91% low versus 93.8% medium versus 85.7% high) and kidney (80.7% versus 71.9% versus 71.4%), respectively. Using the composite end point of pancreas graft failure or dysfunction, pancreas outcomes were 25.3% low versus 34.4% medium versus 71.4% high C-peptide (P = 0.10). Similar to the Wisconsin study, we are limited by the small sample size in the high pretransplant C-peptide group but the findings indicate a trend toward a greater need for supplemental antidiabetic therapy in patients with higher pretransplant C-peptide levels. Unfortunately, what is missing from these studies is a better characterization of patients with partial pancreas allograft function (dysfunction) who continue to be free from wide glycemic excursions and do not experience hypoglycemia (despite the need for antidiabetic therapy) because of preserved counterregulatory function of the pancreas allograft.4 In our experience, we identified posttransplant weight gain, insulin resistance, and rejection as potential mitigating factors to explain these inferior outcomes. Consequently, we recommend greater emphasis on weight management strategies, behavioral modification, nutritional counseling, structured physical training programs, timely adjustments in (and use of less diabetogenic) immunosuppression, more intense long-term monitoring by the transplant center, and increased use of novel antidiabetic agents such as Glucagon-like peptide 1 receptor agonists and Sodium-glucose cotransporter-2 inhibitors when indicated in this unique population. We congratulate the authors on this excellent study and agree that these findings should not be an impetus to limit access to pancreas transplantation but rather help guide clinical decision-making and optimize posttransplant management.

Optimizing the use of nirmatrelvir/ritonavir in solid organ transplant recipients with COVID-19: A review of immunosuppressant adjustment strategies.

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant burden of morbidity and mortality worldwide, with solid organ transplant recipients (SOTRs) being particularly vulnerable. Nirmatrelvir and ritonavir have demonstrated the potential for reducing the risk of hospitalization and death in patients with mild-to-moderate COVID-19. However, ritonavir has a strong drug-drug interaction with CYP3A-dependent drugs such as calcineurin inhibitors, potentially leading to rapid increases in blood concentration. As SOTRs are commonly prescribed immunosuppressants, co-administration with nirmatrelvir/ritonavir requires careful consideration. To address this issue, we conducted a literature review to evaluate the use and adverse effects of nirmatrelvir/ritonavir in SOTRs and explore feasible immunosuppressant adjustment regimens. Our findings suggest that nirmatrelvir/ritonavir could be a feasible treatment option for COVID-19 in SOTRs, provided that appropriate immunosuppressive drug management is in place during co-administration. Although prescribing the novel anti-SARS-CoV-2 drug to transplant recipients poses challenges, potential strategies to overcome these issues are discussed. Further studies are needed to determine the optimal dosing strategies of nirmatrelvir/ritonavir, immunosuppressant adjustment, and monitoring in this patient population.

Adjustment of Immunosuppressants to Facilitate Anti-COVID-19 Antibody Production after mRNA Vaccination in Liver Transplant Recipients.

Liver transplant recipients are immunocompromised and have low immunogenicity to produce antibodies in anti-COVID-19 vaccination. Whether immunosuppressant adjustment could facilitate anti-COVID-19 antibody production in anti-COVID-19 mRNA vaccination is undetermined. Our patients were informed to temporarily suspend mycophenolate mofetil (MMF) or everolimus (EVR) for 2 weeks during both the 1st and 2nd doses of Moderna mRNA-1273 vaccine. A total of 183 recipients receiving two doses of Moderna mRNA-1273 vaccine were enrolled and grouped into tacrolimus monotherapy (MT, n = 41), and dual therapy with non-adjustment (NA, n = 23), single suspension (SS, n = 19) and double suspension (DS, n = 100) of MMF/EVR in two-dose mRNA vaccination. A total of 155 (84.7%) patients had a humoral response to vaccines in this study. The humoral response rates were 60.9%, 89.5%, 91.0% and 80.5% in NA, SS, DS, and MT group patients, respectively (p = 0.003). Multivariate analysis showed that favorable factors for humoral response were temporary suspension of MMF/EVR and monotherapy, and unfavorable factors were deceased donor liver transplantation, WBC count < 4000/uL, lymphocyte < 20% and tacrolimus trough level ≥ 6.8 ng/mL. In conclusion, temporary two-week suspension of anti-proliferation immunosuppressants could create a window to facilitate antibody production during anti-COVID-19 mRNA vaccination. This concept may be applied to other vaccinations in liver transplant recipients.

Protocol Biopsies in Pediatric Liver Transplantation Recipients Improve Graft Histology and Personalize Immunosuppression.

Protocol liver biopsies (PLBs) are part of the follow-up program at many pediatric liver transplant centers, but the impact on clinical decision-making and allograft histology following adjustments of immunosuppression (IS) after PLB has not been thoroughly analyzed. Following our previous single-center cohort study, we have now evaluated histological findings of 178 PLBs of 118 pediatric patients transplanted at our center between 1998 and 2017. In particular, we focused on the changes in allograft histology in the follow-up biopsy of a subgroup of 22 patients, in which the histologic findings led to an adjustment of immunosuppressive therapy. All biopsies of this sub-study group were reevaluated by an experienced pathologist. The overall frequency and severity of fibrosis increased over time after orthotopic liver transplantation. Patients with donor-specific antibodies (DSAs) had a higher prevalence of fibrosis than DSA-negative patients. Graft inflammation decreased significantly after intensifying IS, but renal function needs to be monitored. A significant increase in fibrosis was detected in children with reduced IS. The adjustment of IS following PLBs has a significant impact on allograft histology. Since chronic inflammatory changes may lead to graft failure, adjustment of IS seems to be of major importance for the long-term outcome.

Determinants of Antibody Response to SARS-CoV-2 Vaccines in Liver Transplant Recipients: The Role of Immunosuppression Reduction.

Liver transplant recipients on chronic immunosuppression show an attenuated antibody response after SARS-CoV-2 vaccination. Adjusting immunosuppressants during vaccination remains debated. We enrolled 380 liver transplant recipients receiving 2 doses of a protein subunit, mRNA, or a vector vaccine. The patients were informed to temporarily suspend immunosuppression for 2 weeks for both vaccination doses. We measured anti-live-SARS-CoV-2 spike neutralizing antibody levels at 1-2 months after the second vaccination; 83.9% of patients had humoral responses (SARS-CoV-2 NT50 ≥ 9.62 IU/mL) to 2 doses of vaccines. The mRNA (86.7%) and protein subunit vaccines (85%) yielded higher response rates than the vector vaccines (40.9%). Immunosuppression suspension during the two vaccinations yielded a higher response rate (91.5% vs. 57.7%). Only eight patients (2.1%) experienced transaminase level elevation of thrice the normal value (&gt;110 IU/L) after the second vaccination. Most recovered spontaneously after resuming immunosuppression. Multivariate analysis revealed ABO incompatibility, white blood cell count &lt;4000, lymphocyte count &lt;20%, tacrolimus trough level &gt;6.5 ng/mL, and no immunosuppression adjustment as independent risk factors to nonresponse. The mRNA and protein subunit vaccines yielded a higher response rate. Immunosuppression suspension for 2 weeks enhanced the antibody response. ABO incompatibility, leukopenia, lymphopenia, a high tacrolimus trough level, and no immunosuppression adjustment are associated with nonresponse.

Pre-transplant immune cell function assay as a predictor of early cardiac allograft rejection.

ImmuKnow, an immune cell function assay that quantifies overall immune system activity can assist in post-transplant immunosuppression adjustment. However, the utility of pre-transplant ImmuKnow results representing a patient's baseline immune system activity is unknown. This study sought to assess if pre-transplant ImmuKnow results are predictive of rejection at the time of first biopsy in our cardiac transplant population. This is a single center, retrospective observational study of consecutive patients from January 1, 2018 to October 1, 2020 who underwent orthotopic cardiac transplantation at NYU Langone Health. Patients were excluded if a pre-transplant ImmuKnow assay was not performed. ImmuKnow results were categorized according to clinical interpretation ranges (low, moderate, and high activity), and patients were divided into two groups: a low activity group versus a combined moderate-high activity group. Pre-transplant clinical characteristics, induction immunosuppression use, early postoperative tacrolimus levels, and first endomyocardial biopsy results were collected for all patients. Rates of clinically significant early rejection (defined as rejection≥1R/1B) were compared between pre-transplant ImmuKnow groups. Of 110 patients who underwent cardiac transplant, 81 had pre-transplant ImmuKnow results. The low ImmuKnow activity group was comprised of 15 patients, and 66 patients were in the combined moderate-high group. Baseline characteristics were similar between groups. Early rejection occurred in 0 (0%) patients with low pre-transplant ImmuKnow levels. Among the moderate- high pre-transplant ImmuKnow group, 16 (24.2%) patients experienced early rejection (P=.033). The mean ImmuKnow level in the non-rejection group was the 364.9ng/ml of ATP compared to 499.3ng/ml of ATP for those with rejection (P=.020). Patients with low pre-transplant ImmuKnow levels had lower risk of early rejection when compared with patients with moderate or high levels. Our study suggests a possible utility in performing pre-transplant ImmuKnow to identify patients at-risk for early rejection who may benefit from intensified upfront immunosuppression as well as to recognize those where slower calcineurin inhibitor initiation may be appropriate.