ABSTRACT
High HLA sensitization (HS) limits access to compatible transplantation. New CD38-targeting agents have shown to reduce anti-HLA antibodies, although with important inter-patient variability thus, pre-treatment identification of responder and non-responder patients is needed for treatment decision-making. We analyzed 26 HS patients from two desensitization trials using anti-CD38 mAb. Hierarchical clustering identified three serological responder groups: high, low, and non-responders. Spectral flow-cytometry and functional HLA-specific memory B-cell (mBc) assessment was first conducted on PBMC and bone marrow samples from 16 patients treated with isatuximab (NCT04294459). Isatuximab effectively depleted bone marrow plasma cells, peripheral CD38-expressing plasmablasts, plasma cells, transitional B cells, and class-switch mBc, ultimately reducing frequencies of HLA-specific IgG-producing mBc. Multidimensional spectral flow cytometry with PLS-DA analysis revealed that pre-treatment abundance of specific circulating mBcs phenotypes, especially CD38neg class-switch mBc, accurately distinguished between high serological responders and low or non-responders (AUC 0.958, 0.860-1.000, p=0.009), who also displayed significantly lower frequencies of HLA-specific IgG-producing mBc (p<0.0001). This phenotypical mBc signature predicting response to therapy was validated in an external HS patient cohort (n=10) receiving daratumumab (NCT04204980). This study identifies critical circulating mBc subset phenotypes that distinguish HS patients with successful serological response to CD38-targeting desensitization therapies, potentially guiding treatment decision-making.
ABSTRACT
INTRODUCTION: It is unclear whether kidney/pancreas (KP) transplantation will prevent the progression of peripheral arterial disease (PAD) in patients with insulin dependent diabetes (IDDM) and end-stage renal disease. We sought to determine the pre- and posttransplant prevalence of symptomatic PAD and changes in carotid artery intima-media thickness (IMT) in KP recipients. METHODS: In this single center study, outcomes were compared between KP recipients with and without a history of PAD. A subset of recipients underwent pre- and posttransplant IMT measurements. RESULTS: Among the study group (N = 107), 18 (17%) recipients admitted to a pretransplant history of symptomatic PAD, comprised 11 foot infections and 7 amputations (5 minor and 2 major). Baseline characteristics of age, gender, race, years of diabetes, dialysis history, smoking history, years of hypertension, and history of coronary artery disease (CAD) were equivalent between PAD and non-PAD cohorts. At a median follow-up of 60 months (IQR: 28, 110), 16 (15%) KP recipients had suffered a PAD event. In multivariate analysis, a pretransplant history of PAD (hazard ratio [HR] 9.66, p < 0.001) and CAD (HR 3.33, p = 0.04) were independent predictors of posttransplant PAD events. Among a subset of 20 recipients (3 with PAD), mean IMT measurements pretransplant and at a median of 24 (range 18-24) months posttransplant, showed no evidence of disease progression. CONCLUSION: Based on IMT measurements and clinical results, KP transplantation stabilized PAD in most patients, but did not alter outcomes of symptomatic PAD recipients. A pretransplant history of PAD and CAD was an independent predictor of posttransplant PAD events.
Subject(s)
Carotid Intima-Media Thickness , Kidney Failure, Chronic , Kidney Transplantation , Pancreas Transplantation , Peripheral Arterial Disease , Humans , Female , Male , Pancreas Transplantation/adverse effects , Peripheral Arterial Disease/surgery , Peripheral Arterial Disease/etiology , Middle Aged , Follow-Up Studies , Kidney Transplantation/adverse effects , Kidney Failure, Chronic/surgery , Risk Factors , Prognosis , Diabetes Mellitus, Type 1/surgery , Diabetes Mellitus, Type 1/complications , Adult , Postoperative Complications/epidemiology , Retrospective Studies , Glomerular Filtration Rate , Kidney Function TestsABSTRACT
Background: The COVID-19 pandemic has led to an increase in SARS-CoV-2-test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19-positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19-positive donors at a single center are presented here. Methods: A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19-positive (nâ =â 29 total; 25 index, 4 redo) and COVID-19-negative (nâ =â 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results: COVID-19-positive donors were significantly younger (Pâ =â 0.04) and had lower kidney donor profile indices (Pâ =â 0.04) than COVID-19-negative donors. Recipients of COVID-19-positive donor grafts were older (Pâ =â 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; Pâ =â 0.89). There were 3 deaths among recipients of liver grafts from COVID-19-positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions: The utilization of liver grafts from COVID-19-positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19-positive donors may be used safely to expand the deceased donor pool.
ABSTRACT
Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic ß-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr-/-) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to ß-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on ß-cell identity and function. LDLr-/- mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin-glucagon colocalization, islet size and %ß-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %ß and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin-glucagon colocalization, and reduction in ß-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to ß-cell identity in LDLr-/- mice and offers intriguing clinical implications for countering metabolic syndrome.
Subject(s)
Diabetes Mellitus, Type 2 , Hyperinsulinism , Insulin-Secreting Cells , Islets of Langerhans , Metabolic Syndrome , Animals , Mice , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Glucagon/metabolism , Hyperinsulinism/metabolism , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Islets of Langerhans/metabolism , Lipoproteins, LDL , Metabolic Syndrome/genetics , Mice, Inbred C57BL , Mice, Knockout , Osteocalcin/metabolism , Proinsulin/metabolism , Weight GainABSTRACT
SIGNIFICANCE STATEMENT: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. BACKGROUND: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. RESULTS: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. CONCLUSIONS: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT04294459 .
Subject(s)
Kidney Transplantation , Humans , Antibodies, Monoclonal, Humanized , Kidney , Isoantibodies , Antilymphocyte SerumABSTRACT
Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients' survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.
ABSTRACT
Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.
Subject(s)
Kidney Transplantation , Humans , Aged , Middle Aged , Adolescent , Young Adult , Adult , Kidney Transplantation/adverse effects , Living Donors , Graft Survival , Graft Rejection/etiology , HLA Antigens , Risk FactorsABSTRACT
Combined liver-lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung-liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods: A single-center, retrospective review of the medical records of 19 adult lung-liver transplant recipients was conducted, comparing early recipients (2009-2014) with a recent cohort (2015-2021). Patients were also compared with the center's single lung or liver transplant recipients. Results: Recent lung-liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung-liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung-liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions: The severity of illness in lung-liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.
ABSTRACT
In July 2022, the Scientific Registry of Transplant Recipients (SRTR) hosted an innovative, multistakeholder consensus conference to identify information and metrics desired by stakeholders in the transplantation system, including patients, living donors, caregivers, deceased donor family members, transplant professionals, organ procurement organization professionals, payers, and regulators. Crucially, patients, caregivers, living donors, and deceased donor family members were included in all aspects of this conference, including serving on the planning committee, participating in preconference focus groups and learning sessions, speaking at the conference, moderating conference sessions and breakout groups, and shaping the conclusions. Patients constituted 24% of the meeting participants. In this report, we document the proceedings and enumerate 160 recommendations, 10 of which have been highly prioritized. SRTR will use the recommendations to develop new presentations of information and metrics requested by stakeholders to support informed decision-making.
Subject(s)
Tissue and Organ Procurement , Transplants , Humans , Transplant Recipients , Benchmarking , Registries , Tissue Donors , Living DonorsABSTRACT
INTRODUCTION: In an effort to maximize living donor kidney utilization, we describe the use of deceased donor vein extension grafts for right-sided living donor kidneys and report our single-center experience using this technique. METHODS: A retrospective review of kidney transplant recipients (KTR) who received a right living donor kidney with deceased donor vein extension graft. Recipient demographics, postoperative graft function, and surgical complications were reviewed. Living donor nephrectomies were performed laparoscopically. Vein grafts were obtained from recent deceased donor procurements. End-to-end anastomosis of the graft to the renal vein was performed prior to implantation. RESULTS: Thirty-eight KTR received a right kidney transplant with deceased donor extension grafts. The median recipient age and BMI were 53.0 years and 29.3 kg/m2 . Total 71% were male. Ninety-five percent of grafts displayed immediate graft function, with two recipients requiring temporary dialysis due to anaphylaxis from induction therapy. Median serum creatinine at two weeks was 1.6 mg/dL and at three months was 1.5 mg/dL. There were no graft thromboses. CONCLUSION: Utilization of deceased donor extension grafts for short right renal veins is a simple technique that expands the donor pool for living donor renal transplantation. Our experience resulted in no technical complications and excellent early graft function.
Subject(s)
Kidney Transplantation , Male , Humans , Female , Kidney Transplantation/methods , Living Donors , Graft Survival , Kidney , Renal Veins/surgery , Retrospective Studies , Treatment OutcomeABSTRACT
SUMMARY: This report provides a 5-year follow-up on the first reported simultaneous scalp, calvarium, kidney, and pancreas transplant. The previously published case report represented both the first composite calvarial-scalp transplant and combination of a vascularized composite allotransplantation with double organ transplantation. Over the ensuing 5 years, the patient underwent a single episode of acute scalp rejection successfully managed with intravenous Solu-Medrol, one resection of a basal cell carcinoma on the native scalp, hardware removal, and bony contouring. In addition, the patient developed seizures secondary to delayed, postirradiation cerebral necrosis requiring craniotomy and resection. His seizures were ultimately controlled. Currently, more than 5 years after his multiorgan transplant, the patient continues to have excellent allograft function and a very satisfactory aesthetic outcome, demonstrating that in certain cases, combined vascularized composite allotransplantation with solid organ transplantation can be performed safely without compromising the solid organ transplantation.
Subject(s)
Pancreas Transplantation , Scalp , Humans , Scalp/surgery , Follow-Up Studies , Skull , Kidney , Graft Rejection/pathologyABSTRACT
BACKGROUND: The need for liver retransplantation (reLT) has increased proportionally with greater numbers of liver transplants (LTs) performed, use of marginal donors, degree of recipient preoperative liver dysfunction, and longer survival after LT. However, outcomes following reLT have been historically regarded as poor. METHODS: To evaluate reLT in modern recipients, we retrospectively examined our single-center experience. Analysis included 1268 patients undergoing single LT and 68 patients undergoing reLT from January 2008 to December 2021. RESULTS: Pre-LT mechanical ventilation, body mass index at LT, donor-recipient ABO incompatibility, early acute rejection, and length of hospitalization were associated with increased risk of needing reLT following index transplant. Overall and graft survival outcomes in the reLT cohort were equivalent to those after single LT. Mortality after reLT was associated with Kidney Donor Profile Index, national organ sharing at reLT, and LT donor death by anoxia and blood urea nitrogen levels. Survival after reLT was independent of the interval between initial LT and reLT, intraoperative packed red blood cell use, cold ischemia time, and preoperative mechanical ventilation, all previously linked to worse outcomes. CONCLUSIONS: These data suggest that reLT is currently a safer option for patients with liver graft failure, with comparable outcomes to primary LT.
Subject(s)
Liver Diseases , Liver Transplantation , Humans , Reoperation/adverse effects , Retrospective Studies , Risk Factors , Liver Transplantation/adverse effects , Graft SurvivalABSTRACT
Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.
Subject(s)
Diabetes Mellitus, Type 1 , Islets of Langerhans Transplantation , Islets of Langerhans , Rats , Animals , Male , Diabetes Mellitus, Type 1/therapy , Immunosuppression Therapy , Immune Tolerance , Immunosuppressive Agents/pharmacology , Graft SurvivalABSTRACT
BACKGROUND: Solid organ transplant (SOT) recipients are predicted to have worse COVID-19 outcomes due to their compromised immunity. However, this association remains uncertain because published studies have had small sample sizes and variability in chronic comorbidity adjustment. METHODS: In this retrospective cohort study conducted at a multihospital health system, we compared COVID-19 outcomes and survival up to 60 days following hospital admission in SOT recipients taking baseline immunosuppressants versus hospitalized control patients. RESULTS: The study included 4,562 patients who were hospitalized with COVID-19 (108 SOT recipients and 4,454 controls) from 03/2020 to 08/2020. Mortality at 60 days was higher for SOT recipients (17% SOT vs 10% control; unadjusted odds ratio (OR) = 1.74, 95% confidence interval (CI) 1.04-2.91, P = 0.04). We then conducted a 1:5 propensity matched cohort analysis (100 SOT recipients; 500 controls) using age, sex, race, body mass index, hypertension, diabetes, chronic kidney disease, liver disease, admission month, and area deprivation index. Within 28 days of admission, SOT recipients had fewer hospital-free days (median; 17 SOT vs 21 control; OR = 0.64, 95%CI 0.46-0.90, P = 0.01) but had similar ICU-free days (OR = 1.20, 95%CI 0.72-2.00, P = 0.49) and ventilator-free days (OR = 0.91, 95%CI 0.53-1.57, P = 0.75). There was no statistically significant difference in 28-day mortality (9% SOT vs 12% control; OR = 0.76, 95%CI 0.36-1.57, P = 0.46) or 60-day mortality (16% SOT vs 14% control; OR = 1.15, 95%CI 0.64-2.08, P = 0.64). CONCLUSIONS: Hospitalized SOT recipients appear to need additional days of hospital care but can achieve short-term mortality outcomes from COVID-19 that are similar to non-SOT recipients in a propensity matched cohort study.
Subject(s)
COVID-19 , Organ Transplantation , Humans , Cohort Studies , Retrospective Studies , Hospitalization , Transplant RecipientsABSTRACT
BACKGROUND: Solid organ transplant (SOT) recipients are at increased risk for morbidity and mortality from COVID-19 due to their immunosuppressed state and reduced immunogenicity from COVID-19 mRNA vaccines. This investigation examined the association between COVID-19 mRNA vaccination status and mortality among SOT recipients diagnosed with COVID-19. METHODS & FINDINGS: A retrospective, registry-based chart review was conducted investigating COVID-19 mortality among immunosuppressed solid organ transplant (SOT) recipients in a large metropolitan healthcare system in Houston, Texas, USA. Electronic health record data was collected from consecutive SOT recipients who received a diagnostic SARS-CoV-2 test between March 1, 2020, and October 1, 2021. The primary exposure was COVID-19 vaccination status at time of COVID-19 diagnosis. Patients were considered 'fully vaccinated' at fourteen days after completing their vaccine course. COVID-19 mortality within 60 days and intensive care unit admission within 30 days were primary and secondary endpoints, respectively. Among 646 SOT recipients who were diagnosed with COVID-19 at Houston Methodist Hospital between March 2020, and October 2021, 70 (10.8%) expired from COVID-19 within 60 days. Transplanted organs included 63 (9.8%) heart, 355 (55.0%) kidney, 108 (16.7%) liver, 70 (10.8%) lung, and 50 (7.7%) multi-organ. Increasing age was a risk factor for COVID-19 mortality, while vaccination within 180 days of COVID-19 diagnosis was protective in Cox proportional hazard models with hazard ratio 1.04 (95% CI: 1.01-1.06) and 0.31 (0.11-0.90), respectively). These findings were confirmed in the propensity score matched cohort between vaccinated and unvaccinated patients. CONCLUSIONS: This investigation found COVID-19 mortality may be significantly reduced among immunosuppressed SOT recipients within 6 months following vaccination. These findings can inform vaccination policies targeting immunosuppressed populations worldwide.
Subject(s)
COVID-19 , Organ Transplantation , Humans , Infant, Newborn , COVID-19/mortality , COVID-19 Testing , COVID-19 Vaccines/administration & dosage , Organ Transplantation/adverse effects , Retrospective Studies , SARS-CoV-2 , Transplant RecipientsABSTRACT
Islet and ß-cell function is intrinsic to glucose homeostasis. Pancreatectomy and islet autotransplantation (PIAT) for chronic pancreatitis (CP) treatment is a useful model for assessing islet function in the absence of immune-suppression and to perform extensive presurgical metabolic evaluations not possible from deceased donors. We recently showed that in CP-PIAT patients, preoperative islet identity loss presented with postoperative glycemic loss. Here, we examine presurgical islet function using Homeostatic Model Assessment-Beta Cell Function (%) (HOMA-ß) and glycemic variables and compared them with postsurgical insulin independence and their predicted alignment with Secretory Unit of Islet Transplant Objects (SUITO) and beta cell score after transplantation (BETA-2) scores. Methods: Seven CP-PIAT patients were assessed for ß-cell function metrics, including pretransplant and 6-mo posttransplant HOMA-ß using insulin and C-peptide and evaluations of proposed insulin independence by SUITO and BETA-2 graft function equations. These were compared with oral glucose tolerance tests and pancreas histological samples taken at the time of transplant, examined for ß-cell maturity markers. Results: Pre-PIAT, HOMA-ß (60%-100%) associated with post-PIAT insulin independence. This association was only moderately supported by post-PIAT SUITO threshold scores (≥26) but robustly by BETA-2 scores (≥16.2). Appropriate posttransplant oral glucose tolerance test curves were found in those patients with normal pretransplant HOMA-ß values. Preoperative low serological ß-cell function was displayed by concurrent evidence of ß-cell identity alterations including colocalization of insulin and glucagon, loss of urocortin-3, and increased intra-islet vimentin in patients who were insulin-dependent post-PIAT. Conclusions: These data encourage HOMA-ß assessment before PIAT for estimating posttransplant insulin independence.
ABSTRACT
Introduction: Donation after circulatory death (DCD) is rapidly increasing in the United States. Detailed data outlining the process from referral to organ transplantation is lacking. Project Aims: We sought to quantify differences at each stage along the referral to donation pathway by donor type. Additionally, we examined factors associated with successful DCD organ utilization. Design: This program evaluation analyzed data from a single organ procurement organization in 2018 to assess demographic and clinical predictors of progression through the donation process, including the role of first-person authorization in DCD. Descriptive statistics were examined by donation stage for demographic characteristics using chi-square; univariate and multivariate logistic regression was used to model predictors of utilization and authorization by organ type, respectively. Results: There were 2466 organ donation referrals during 2018, including 575 donations after brainstem death (DBD), 1890 controlled DCD referrals, and 1 uncontrolled DCD referral. Univariate and multivariate logistic regression models highlighted differences in authorization rates by donor type (DCD vs DBD) and by age, race, and ethnicity. Next-of-kin authorization was declined in 23% of first-person authorized potential DCD, highlighting issues related to the role of donor registration in DCD. Pre-mortem heparin administration was predictive of DCD organ utilization; donor age and warm ischemia time of less than 30 min was statistically significantly associated with DCD extra-renal organ utilization. Conclusion: These results provided insight into strategies for increasing authorization and transplantation of organs from DCD donors and identified areas of improvement for process standardization and policy development.
Subject(s)
Organ Transplantation , Tissue and Organ Procurement , Humans , Brain Death , Tissue Donors , Warm Ischemia , Death , Retrospective Studies , Graft SurvivalABSTRACT
A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n = 1037). MMF was associated with significantly lower odds of positive antibody response (aOR = 0.09 0.130.18 ). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = 1.00 1.452.13 ); however, importantly, this seemingly protective tendency disappeared (aOR = 0.47 0.731.12 ) after adjusting for MMF. We repeated this comparison by combinations of immunosuppression agents. Compared to MMF + tacrolimus, MMF-free regimens were associated with higher odds of positive antibody response (aOR = 2.39 4.267.92 for mTORi+tacrolimus; 2.34 5.5415.32 for mTORi-only; and 6.78 10.2515.93 for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = 0.81 1.542.98 for MMF + mTORi; and 0.81 1.512.87 for MMF-only). We repeated these analyses in an independent cohort (n = 512) and found similar results. Our study demonstrates that the recently reported findings were confounded by MMF, and that mTORi is not independently associated with improved vaccine responses.
Subject(s)
COVID-19 , Kidney Transplantation , Humans , Tacrolimus , Mycophenolic Acid/therapeutic use , Antibody Formation , MTOR Inhibitors , COVID-19 Vaccines , SARS-CoV-2 , Graft Rejection/prevention & control , COVID-19/prevention & control , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Transplant Recipients , TOR Serine-Threonine Kinases , mRNA VaccinesABSTRACT
Response to two doses of a nucleoside-modified messenger ribonucleic acid (mRNA) vaccine was evaluated in a large solid-organ transplant program. mRNA COVID-19 vaccine was administered to transplant candidates and recipients who met study inclusion criteria. Qualitative anti-SARS-CoV-2 Spike Total Immunoglobulin (Ig) and IgG-specific assays, and a semi-quantitative test for anti-SARS-CoV-2 Spike protein IgG were measured in 241 (17.2%) transplant candidates and 1163 (82.8%) transplant recipients; 55.2% of whom were non-Hispanic White and 44.8% identified as another race. Transplant recipients were a median (IQR) of 3.2 (1.1, 6.8) years from transplantation. Response differed by transplant status: 96.0% versus 43.2% by the anti-SARS-CoV-2 Total Ig (candidates vs. recipients, respectively), 93.5% versus 11.6% by the anti-SARS-CoV-2 IgG assay, and 91.9% versus 30.1% by anti-spike titers after two doses of vaccine. Multivariable analysis revealed candidates had higher likelihood of response versus recipients (odds ratio [OR], 14.6; 95 %CI 2.19, 98.11; P = .02). A slightly lower response was demonstrated in older patients (OR .96; 95 %CI .94, .99; P = .002), patients taking antimetabolites (OR, .21; 95% CI .08, .51; P = .001). Vaccination prior to transplantation should be encouraged.
Subject(s)
COVID-19 , Organ Transplantation , Aged , Antibodies, Viral , BNT162 Vaccine , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity, Humoral , Immunoglobulin G , RNA, Messenger , SARS-CoV-2 , Transplant RecipientsABSTRACT
Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.