scholarly journals Current Approaches to Desensitization in Solid Organ Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Carrie Schinstock ◽  
Anat Tambur ◽  
Mark Stegall

Major advancements in the development of HLA antibody detection techniques and our understanding of the outcomes of solid organ transplant in the context of HLA antibody have occurred since the relevance of sensitization was first recognized nearly 50 years ago. Additionally, kidney paired donation programs (KPD) have become widespread, deceased donor allocation policies have changed, and several new therapeutic options have become available with promise to reduce HLA antibody. In this overview we aim to provide thoughtful guidance about when desensitization in kidney transplantation should be considered taking into account the outcomes of HLA incompatible transplantation. Novel therapeutics, desensitization endpoints, and strategies for future study will also be discussed. While most of our understanding about desensitization comes from studying kidney transplant candidates and recipients, many of the concepts discussed can be easily applied to desensitization in all of solid organ transplantation.

2020 ◽  
Vol 26 (28) ◽  
pp. 3497-3506
Author(s):  
Raymund R. Razonable

Cytomegalovirus is the classic opportunistic infection after solid organ transplantation. This review will discuss updates and future directions in the diagnosis, prevention and treatment of CMV infection in solid organ transplant recipients. Antiviral prophylaxis and pre-emptive therapy are the mainstays of CMV prevention, but they should not be mutually exclusive and each strategy should be considered depending on a specific situation. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is emphasized as a major factor that should pave the way for an individualized approach to prevention. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management, and strategies for managing drug-resistant CMV infection are enumerated. There is increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, and their potential role in optimizing CMV prevention and treatment efforts is discussed.


BMJ Open ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. e043731
Author(s):  
Adnan Sharif ◽  
Javeria Peracha ◽  
David Winter ◽  
Raoul Reulen ◽  
Mike Hawkins

IntroductionSolid organ transplant patients are counselled regarding increased risk of cancer (principally due to their need for lifelong immunosuppression) and it ranks as one of their biggest self-reported worries. Post-transplantation cancer is common, associated with increased healthcare costs and emerging as a leading cause of post-transplant mortality. However, epidemiology of cancer post-transplantation remains poorly understood, with limitations including translating data from different countries and national data being siloed across different registries and/or data warehouses.Methods and analysisStudy methodology for Epidemiology of Cancer after Solid Organ Transplantation involves record linkage between the UK Transplant Registry (from NHS Blood and Transplant), Hospital Episode Statistics (for secondary care episodes from NHS Digital), National Cancer Registry (from cancer registration data hosted by Public Health England) and the National Death Registry (from NHS Digital). Deterministic record linkage will be conducted by NHS Digital, with a fully anonymised linked dataset available for analysis by the research team. The study cohort will consist of up to 85 410 solid organ transplant recipients,who underwent a solid organ transplant in England between 1 January 1985 and 31 December 2015, with up-to-date outcome data.Ethics and disseminationThis study has been approved by the Confidentiality Advisory Group (reference: 16/CAG/0121), Research Ethics Committee (reference: 15/YH/0320) and Institutional Review Board (reference: RRK5471). The results of this study will be presented at national and international conferences, and manuscripts with results will be submitted for publication in high-impact peer-reviewed journals. The information produced will also be used to develop national evidence-based clinical guidelines to inform risk stratification to enable risk-based clinical follow-up.Trial registration numberNCT02991105.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4227-4227
Author(s):  
Michael D Jain ◽  
Ryan Lam ◽  
Rashmi S Goswami ◽  
Krystyna Tybinkowski ◽  
Parneet K Cheema ◽  
...  

Abstract Background: Post-transplant lymphoproliferative disorder (PTLD) is an uncommon, heterogeneous disease that occurs in the setting of immune suppression following solid organ transplantation. As the transplant population ages over time, the spectrum of PTLD histologies and their treatment has evolved; we report here our recent experience with PTLD from a large multi-organ transplant program. Methods: We identified patients from the Multi-Organ Transplant Program at University Health Network (UHN) who were diagnosed with PTLD between January 1, 2000 and December 31, 2015. We describe the characteristics and outcomes of this cohort, with a focus on the outcome of patients with the diffuse large B cell (DLBCL) subtype of PTLD treated in the rituximab era. Results: A total of 140 patients were diagnosed with PTLD at UHN during this time period (Table 1): 38% were female and median age at time of diagnosis was 50 (interquartile range, IQR Q1/Q3, 37 to 62 years). The most commonly implicated transplants were liver and kidney (33% and 32%), as well as lung (20%) and heart (7%). The median time from organ transplantation to PTLD diagnosis was 61 months (IQR 9 to 136), with 70% of cases occurring more than 12 months following solid organ transplant. Pathologically, the majority of the patients had monomorphic PTLD, with DLBCL (n = 86) being most common. Where classifiable by the Hans algorithm (n = 68), the majority of the DLBCL types were of the non-germinal center B cell type (non-GCB, 76.5%). Of 24 DLBCL patients with available FISH, 7 had a MYC translocation (29%). Treatment and outcome varied by PTLD subtype (Table 2). For the overall cohort (n = 140), the median OS was 5.1 years. Highlighting competing risks, less than half of patients died of PTLD, with the remainder of mortality due to complications of solid organ transplantation, or less commonly, due to treatment-related mortality. Polymorphic PTLD (n = 17) was treated in a variety of ways ranging from reduction in immunosuppression (RIS) alone to R-CHOP; median OS was 10.3 years. Less common histologic subtypes (Hodgkin, Burkitt, T cell) were treated with therapies specific to those lymphomas. For DLBCL (n = 86), treatment consisted of RIS alone (10.5%; OS 4.4 years) or RIS followed by local treatment (involved field radiation or surgical resection) (7.0%; OS not reached); single agent rituximab (R) (22.1%; OS not reached); sequential R followed by CHOP (11.6%; OS 1.5 years), or upfront R-CHOP (43.0%; OS 3.4 years). Median OS for patients classified as non-GCB was not worse than those classified as GCB (OS 6.2 vs. 4.7 years, p = 0.93). In the DLBCL cohort, 20 patients had progression during or after first line therapy, with 14 patients receiving additional treatment. Patients with early relapse during initial therapy or within the first 3 months (n = 13) did poorly compared to patients with later relapse occurring after 3 months (n = 7; median OS 0.7 vs 5.6 years, p < 0.01). This was similar to the entire cohort, where 40 patients relapsed and early relapsed/refractory patients also had poor outcomes compared to late relapsing patients (median OS 0.8 vs. 5.1 years, p <0.01). Six patients in the overall cohort had an autologous stem cell transplant for progressive disease; 4 remain in remission after 5 years (range, 1.3 to 5.8 years follow-up). Conclusion: In this recent retrospective cohort, PTLD was generally late onset and the median OS of all patients was 5 years. The most common histology was DLBCL (non-GCB subtype), but cell of origin did not influence outcome. Patients with early relapse or refractory disease had poor overall survival. Due to competing risks and comorbidities, many PTLD patients continue to have poor outcomes despite modern treatment strategies. Disclosures Jain: Roche Canada: Research Funding. Prica:Janssen: Honoraria. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria. Kuruvilla:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4067-4067
Author(s):  
Pavan Tenneti ◽  
Jiaxian He ◽  
Peter Lalli ◽  
Pranav Tenneti ◽  
Michael R. Grunwald ◽  
...  

Abstract INTRODUCTION Graft vs host disease (GVHD) is a rare complication after solid organ transplantation ( ̴ 1-2% with liver and ̴ 5.6% with intestines), but is associated with high mortality (70-80%). In contrast to GVHD following hemopoietic stem cell transplant, bone marrow infiltration by donor T lymphocytes leading to cytopenia ( ̴ 80%) is a common manifestation of GVHD after solid organ transplantation (Murali et. al., 100(12), Transplantation, January 2016). The risk factors associated with GVHD occurring after solid organ transplantation have not been well characterized, but single institution studies have suggested donor/recipient (D/R) HLA mismatch, ABO incompatibility and gender mismatch playing important roles. However, some studies have identified that similarities in HLA type which permit mismatches unrecognized by the recipient as a common mechanism preventing rejection of donor lymphocytes, which then can cause GVHD in the recipient. In order to evaluate potential risk factors, we reviewed the transplant data of patients in whom GVHD was listed as the cause of death from United Network of Organ transplant database (UNOS), the database that contains all US organ transplant data. METHODS From the UNOS database we obtained information of patients that underwent liver or intestinal transplantation between 1987-2020 in the US. The patients for whom GVHD was reported as the cause of death were identified. Baseline D/R and transplant variables were collected. Patient or transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Chi-square test for categorical variables and two-sample t-test for continuous variables. The incidence of mortality caused by GVHD was estimated using the cumulative incidence method, accounting for non-GVHD related death as a competing risk. All statistical tests were two sided, and a P-value &lt; 0.05 was considered significant. RESULTS Of a total of 179,355 patients that underwent liver transplantation, 216 (0.1%) patients had GVHD identified as the primary cause of death (GVHD group). The HLA mismatch information was available in 86,434 patients (48.2%). HLA mismatch was grouped into low level (0-3) and high level (4-6). Low level HLA mismatch was 24.6% in the GVHD group compared to 16.2% in patients that are alive or died of non-GVHD related causes (non-GVHD group). High level mismatch was 75.4% in GVHD group and 83.8% in the non-GVHD group (P=0.013). Other risk factors including gender mismatch (40.3% vs 42.5%, P=0.536), ABO incompatibility between D/R (0.5% vs 1.4%, P=0.42) and use of live donors (1.9% vs 4.3%, p= 0.09) were similar between the two groups. Patients in the GVHD group were older with median age of recipient being 59 years compared to 53 years in the non-GVHD (P&lt;0.001). Graft failure was more common in the GVHD group compared to non-GVHD group (33.8% vs 17.1%, P&lt;0.001). Of a total of 3,153 patients that underwent intestinal transplantation, 20 (0.6%) patients had GVHD identified as the primary cause of death (GVHD group). The HLA mismatch information was available in 2859 patients (90.6%).The high-level HLA mismatch (83.3% vs 84.7%, P=0.749), gender mismatch (40% vs 47.1%, P=0.655) and ABO incompatibility (0% vs 0.2%, P=0.757) between D/R were similar between the GVHD group and non-GVHD group among intestinal transplant patients. Conclusions In patients that undergo hematopoietic stem cell transplant, HLA and gender mismatch between D/R have been recognized as risk factors for GVHD. Based on the largest analysis of solid organ transplant database, traditionally considered GVHD risk factors like HLA and gender mismatch between D/R do not appear to be significantly associated with severe GVHD leading to death. Recipient age and graft failure are significantly associated with GVHD related deaths in liver transplant patients. These findings suggest that other risk factors for severe GVHD leading to death after solid organ transplant than those previously reported in single institution studies should be examined and underscore the need for additional studies. Figure 1 Figure 1. Disclosures Grunwald: Med Learning Group: Other; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Research Funding; Amgen: Consultancy; Pfizer: Consultancy; PRIME: Other; PER: Other; Karius: Consultancy; Sierra Oncology: Consultancy; Blueprint Medicines: Consultancy; Incyte: Consultancy, Research Funding; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; Stemline: Consultancy; Gilead: Consultancy; Cardinal Health: Consultancy; Trovagene: Consultancy; MDEdge: Other. Copelan: Amgen: Consultancy.


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S948-S948
Author(s):  
Lynne Strasfeld ◽  
Ricardo M La Hoz ◽  
Gabe Vece ◽  
Cameron R Wolfe ◽  
Marian G Michaels

Abstract Background Donor-derived toxoplasmosis (DDT) is a severe and potentially life-threatening infection after solid-organ transplantation (SOT). Serologic testing for Toxoplasma gondii is required for all deceased donors per OPTN policy as of 4/6/17. To assess the impact of universal donor testing and the optimal approach to DDT prevention, we analyzed potential DDT cases reviewed by DTAC. Methods All potential Toxoplasma donor-derived transmission events adjudicated by DTAC from 2008 to 2018 were reviewed. A standardized classification algorithm was used to adjudicate each event as proven, probable, possible, unlikely, excluded or intervention without disease transmission. Results Twenty-eight potential DDT events were reported between 2008 and 2018. Proven or probable (p/p) DDT developed in 16 organ recipients from 15 donors. In the 9 years prior to the new testing requirement (January 2008–March 2017) 11 organ recipients from 10 donors had p/p DDT (0.13 transmissions per 1,000 donors); in the first 21 months of the new testing requirement 5 recipients from 5 donors had p/p DDT (0.27 transmissions per 1,000 donors), rate ratio 2.15; 95% CI 0.577, 6.90;P = 0.18. 10.2% of 18,328 donors tested between April 6, 2017 and December 31, 2018 were Toxoplasma IgG seropositive. Recipient pre-SOT serostatus was unknown in 4 of 5 and negative in 1 case of p/p DDT. Trimethoprim/sulfamethoxazole prophylaxis was either stopped at < 3 months or not used in all 5 cases. Infection was diagnosed a median of 103 days (range 42–153) post-transplant. Four of the 5 recipients died. Conclusion DDT remains a morbid infection in both heart and non-heart recipients. Despite an apparent increase in DDT reporting to DTAC, it is unlikely that the actual incidence of this donor-derived event is increasing. Rather, with universal serologic screening of deceased donors and wider access to molecular diagnostics, DDT is increasingly recognized and diagnosed. To decrease risk for illness and death related to DDT, broader pre-transplant recipient serologic testing and use of prophylaxis or monitoring for high-risk serostatus recipients (Toxoplasma D+/R−) is critical. The optimal duration of prophylaxis is uncertain at this time and warrants further study. Disclosures All authors: No reported disclosures.


2016 ◽  
Vol 3 (4) ◽  
pp. 4
Author(s):  
Mina Al-Badri ◽  
Kunam Reddy ◽  
Paru David ◽  
Raymond Heilman ◽  
Christine Snozek ◽  
...  

A 21-year-old female with end stage renal disease underwent a non-related renal transplantation from a deceased pregnant donor. The recipient had a negative serum pregnancy test prior to her surgery. However postoperatively, a rise in her serum human chorionic gonadotrophin (hCG) level, which lasted several days, was documented. Solid organ transplantation is known to transmit various infections, malignant cells and antibodies from donor to recipient but no previous reports described transmission of hCG. This case report highlights the importance of considering this possibility when managing post-transplantation hormonal disturbances. Further research is warranted to evaluate the different mechanisms through which transmission occurs between donor and recipient.


2021 ◽  
pp. 22-52
Author(s):  
Lainie Friedman ◽  
J. Richard Thistlethwaite, Jr

This chapter provides a brief history of solid organ transplantation. Although the focus is on the living donor, the history of living donor solid organ transplantation is intertwined with the history of deceased donor solid organ transplantation. This is particularly true in the early years of solid organ transplantation when the earliest success for some solid organ transplants began with living donors, e.g. kidney, and began with deceased donors for other solid organ transplants, e.g. liver. The history of each solid organ in which living donors have supplied grafts (kidney, liver, lung, pancreas, intestines, and uterus) is described even though some are rarely if ever performed today, e.g. lung, intestine, pancreas. We also discuss the living domino donor—a candidate-recipient (most commonly the recipient of a deceased donor liver or heart) whose own organ is not discarded but is transplanted into another person.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2859-2859
Author(s):  
Thomas M. Habermann ◽  
Matthew J Maurer ◽  
Kay Ristow ◽  
William R. Macon ◽  
Timothy S Larson ◽  
...  

Abstract Abstract 2859 Background: PTLD is the most common malignancy, other than melanomatous skin cancer complicating solid organ transplantation and has been one of the most commonly observed fatal consequences. The histologies are diverse and include B-cell, T-cell and Hodgkin lymphomas. Rituximab has affected the outcome in CD20+ patients with PTLD. This single institution study sought to identity the outcomes in patients of all histologies and presentations managed in the post-rituximab era. Methods: Patients with solid organ transplantation who were diagnosed with PTLD at Mayo Clinic (Rochester, MN) between December 1970 and October 2009 were identified through the Mayo Clinic Lymphoma Data Base. The rituximab era was defined as patients diagnosed after December 26, 2000, the date of diagnosis for the first patient treated with rituximab in our series. Cox proportional hazards models were used to assess the association of clinical factors and overall survival (OS). Results: 143 patients diagnosed with PTLD between December 1970 and October 2009 were identified. The median age at the time of diagnosis of PTLD was 50 years (range 15–84) with 41 patients (29%) over the age of 60. 93 were male (65%). At a median follow-up of 84 months (range 1–295), 95 patients (65%) have died. The types of organ transplant included renal (39%), liver (31%), cardiac (11%), lung (6%), renal/pancreas (6%), pancreas (4%), and multiorgan (4%). 83% of patients presented with extranodal disease. 28% had involvement of the engrafted organ. 76% of the patients developed PTLD that was EBV+ by in situ hybridization. 62% were stage 3–4. The IPI was intermediate-high in 39% of patients. Initial approaches to management included reduction in immunosuppression (45%), chemotherapy (12%), reduction in immunosuppression with rituximab (12%), rituximab (8%), and radiation therapy (6%). The overall response to therapeutic approaches was 46% in the pre-rituximab era and 56% in the post-rituximab era (chi-squared p=0.25). Patients treated with rituximab had an improved overall survival (HR = 1.66, 95% CI: 0.99–2.79). Patients treated in the rituximab era had improved 1 year survival (76%) compared to patients in the pre-rituximab era (59%) (chi-squared p=0.03). However, the survival advantage in the rituximab era was not maintained in longer follow-up. The median overall survival in the pre-rituximab era was 31 months compared to 56 months in the post-rituximab era (logrank p=0.63). Conclusion: The overall response rates and overall survival are improved with rituximab treatment in CD20+ PTLD, however, the natural history of all PTLD has not improved significantly in the post-rituximab era. New approaches are needed for the prevention and management of all the histologies of PTLD. Disclosures: No relevant conflicts of interest to declare.


2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S75-S76 ◽  
Author(s):  
Ige George ◽  
Carlos Santos

Abstract Background Coccidioidomycosis is an invasive fungal infection in solid organ transplantation (SOT) recipients with an incidence of 1.4–6.9% in endemic regions. There are no population-level data describing the incidence and outcomes of coccidioidomycosis in SOT recipients. Methods We assembled a large cohort of adult SOT recipients using ICD-9-CM billing data from the California State Inpatient Databases from 2004 to 2011. Demographics, comorbidities, coccidioidomycosis coded during hospitalization and inpatient death were identified. We used Cox proportional hazard multivariate analyses to identify risk factors for coccidioidomycosis and death. Results 20,602 SOT recipients were identified during the study period (median follow-up time = 1507 days). Eighty-seven patients (0.42%) with coccidioidomycosis were identified of whom 17 (20%) were coded with progressive/disseminated disease. Median time to diagnosis was 164 days (IQR 16–844) from transplantation. Fifty-one of 87 (58%) of these infections were diagnosed within the first year posttransplant and 29/87 (33.3%) were identified within the first month. Twenty-one of 87 (24%) of patients with coccidioidomycosis died compared with 1928/18587 (9.4%) of patients without coccidioidomycosis (P &lt; 0.001). Coccidioidomycosis was independently associated with death (HR, 3.1; 95% CI, 2.0–4.4), after adjusting for age, type of transplantation, transplant failure/rejection, and other comorbidities (Table) (Figure). Conclusion Coccidioidomycosis resulting in hospitalization is rare in an endemic region in the current era of screening and prophylactic antifungal therapy. Preventing infection in solid organ transplant recipients is imperative because overall mortality remains high. Disclosures All authors: No reported disclosures.


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