Cutting edge of genetically modified pigs targeting complement activation for xenotransplantation.

In the quest to address the critical shortage of donor organs for transplantation, xenotransplantation stands out as a promising solution, offering a more abundant supply of donor organs. Yet, its widespread clinical adoption remains hindered by significant challenges, chief among them being immunological rejection. Central to this issue is the role of the complement system, an essential component of innate immunity that frequently triggers acute and chronic rejection through hyperacute immune responses. Such responses can rapidly lead to transplant embolism, compromising the function of the transplanted organ and ultimately causing graft failure. This review delves into three key areas of xenotransplantation research. It begins by examining the mechanisms through which xenotransplantation activates both the classical and alternative complement pathways. It then assesses the current landscape of xenotransplantation from donor pigs, with a particular emphasis on the innovative strides made in genetically engineering pigs to evade complement system activation. These modifications are critical in mitigating the discordance between pig endogenous retroviruses and human immune molecules. Additionally, the review discusses pharmacological interventions designed to support transplantation. By exploring the intricate relationship between the complement system and xenotransplantation, this retrospective analysis not only underscores the scientific and clinical importance of this field but also sheds light on the potential pathways to overcoming one of the major barriers to the success of xenografts. As such, the insights offered here hold significant promise for advancing xenotransplantation from a research concept to a viable clinical reality.

Efficacy and safety of single-dose anti-thymocyte globulin versus basiliximab induction therapy in pediatric kidney transplant recipients: A retrospective comparative cohort study.

BACKGROUND: This study aimed to compare the efficacy and safety of basiliximab (BAS) versus a single dose of anti-thymocyte globulin (r-ATG) induction therapy in pediatric kidney transplant recipients (KTRs). METHODS: This single-center retrospective comparative cohort study included all pediatric KTRs from May 2013 to April 2018 and followed up to 12 months. In the first period, all recipients received BAS, while from May 2016, a single 3 mg/kg dose of r-ATG was instituted. Maintenance therapy consisted of a calcineurin inhibitor plus prednisone plus azathioprine or mycophenolate. RESULTS: A total of 227 patients were included (BAS, n = 113; r-ATG, n = 114). The main combination of immunosuppressive drugs was tacrolimus, prednisone, and azathioprine in both groups (87% vs. 88%, p = .718). Patients receiving r-ATG showed superior survival-free of the composite endpoint (acute rejection, graft loss, or death; 76% vs. 61%, p = .003; HR 2.08, 1.29-3.34, p = .003) and lower incidence of biopsy-proven acute rejection (10% vs. 21%, p = .015). There was no difference in the overall incidence of CMV infection (33% vs. 37%, p = .457), PTLD (1% vs. 3%, p = .309), 30-day hospital readmissions (24% vs. 23%, p = .847), and kidney function at 12 months (86 ± 29 vs. 84 ± 30 mL/min/1.73m2, p = .614). CONCLUSIONS: These data suggest that induction therapy with a single 3 mg/kg dose of r-ATG is associated with higher efficacy for preventing acute rejection and similar safety profile compared to BAS.

Intragraft memory-like CD127hiCD4+Foxp3+ Tregs maintain transplant tolerance.

CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in suppressing transplant rejection, but their role within the graft and heterogeneity in tolerance are poorly understood. Here, we compared phenotypic and transcriptomic characteristics of Treg populations within lymphoid organs and grafts in an islet xenotransplant model of tolerance. We showed Tregs were essential for tolerance induction and maintenance. Tregs demonstrated heterogeneity within the graft and lymphoid organs of tolerant mice. A subpopulation of CD127hi Tregs with memory features were found in lymphoid organs, presented in high proportions within long-surviving islet grafts, and had a transcriptomic and phenotypic profile similar to tissue Tregs. Importantly, these memory-like CD127hi Tregs were better able to prevent rejection by effector T cells, after adoptive transfer into secondary Rag-/- hosts, than naive Tregs or unselected Tregs from tolerant mice. Administration of IL-7 to the CD127hi Treg subset was associated with a strong activation of phosphorylation of STAT5. We proposed that memory-like CD127hi Tregs developed within the draining lymph node and underwent further genetic reprogramming within the graft toward a phenotype that had shared characteristics with other tissue or tumor Tregs. These findings suggested that engineering Tregs with these characteristics either in vivo or for adoptive transfer could enhance transplant tolerance.

Implications of an Altered Gut Microbiome in Rat Experimental Vascularized Composite Transplantation.

OBJECTIVES: Vascularized composite allotransplantation is a reconstructive option after severe injury but is fraught with complications, including transplant rejection due to major histocompatibility complex mismatch in the context of allogeneic transplant, which in turn is due to altered immuno-inflammation secondary to transplant. The immunosuppressant tacrolimus can prevent rejection. Because tacrolimus is metabolized predominantly by the gut, this immunosuppressant alters the gut microbiome in multiple ways, thereby possibly affecting immunoinflammation. MATERIALS AND METHODS: We performed either allogeneic or syngeneic transplant with or without tacrolimus in rats. We quantified protein-level inflammatory mediators in the skin, muscle, and plasma and assessed the diversity of the gut microbiome through 16S RNA analysis at several timepoints over 31 days posttransplant. RESULTS: Statistical analysis highlighted a complex interaction between major histocompatibility complex and tacrolimus therapy on the relative diversity of the microbiome. Time-interval principal component analysis indicated numerous significant differences in the tissue characteristics of inflammation and gut microbiome that varied over time and across experimental conditions. Classification and regression tree analysis suggested that both inflammatory mediators in specific tissues and changes in the gut microbiome are useful in characterizing the temporal dynamics of posttransplant inflammation. Dynamic network analysis highlighted unique changes in Methanosphaera that were correlated with Peptococcusin allogeneic transplants with and without tacrolimus versus Prevotella in syngeneic transplant with tacrolimus, suggesting that alterations in Methanosphaera might be a biomarker of vascularized composite allotransplant rejection. CONCLUSIONS: Our results suggest a complex interaction among major histocompatibility complex, local and systemic immuno-inflammation, and tacrolimus therapy and highlight the potential for novel insights into vascularized composite allotransplant from computational approaches.

Factors Associated with Chronic Rejection in Liver Transplant Recipients: A Retrospective Cohort Study From Shiraz Organ Transplant Center.

OBJECTIVES: Identification of chronic rejection risk factors in liver transplant recipients is critical for early detection and prevention of further graft loss. We investigated characteristics of liver transplant recipients who had experienced chronic rejection and the associated risk factors versus patients without chronic rejection. MATERIALS AND METHODS: Data from 3022 adult liver transplant recipients between 2011 and 2018 were analyzed; of these, 80 patients had experienced chronic rejection. The control group included 98 randomly selected liver transplant recipients who did not have chronic rejection. RESULTS: The age of the recipients and the donors was significantly lower in the group with chronic rejection versus the group without chronic rejection.The results indicated that chronic rejection was significantly associated with the sex of the recipients (hazard ratio 3.2, 95% CI 1.77-6.08; P < .001) and with the sex concordance between the recipients and donors (hazard ratio 2.93, 95% CI 1.67-5.13; P < .001, respectively). Also, in the group without chronic rejection, there were no male donors; however, the group with chronic rejection had mostly male donors (P <.001). Cold ischemia time was longer in patients with chronic rejection versus that shown in the control group (P = .031), and there was a significant difference between the 2 groups in acute rejection frequency (P < .001). CONCLUSIONS: Recipient sex and sex concordance were independent risk factors for chronic rejection. Most transplantrecipients with chronic rejection responded to medicaltreatment, and the rate of graftloss was low among our recipients.

Long-Term Outcomes with Prolonged-Release Tacrolimus in Kidney Transplantation: A Retrospective Real-World Data Analysis.

BACKGROUND Long-term real-world outcomes data for kidney transplant recipients (KTRs) converting from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT) are limited. MATERIAL AND METHODS A retrospective, non-interventional review of adult KTRs treated with PRT for ≥1 month was conducted in Germany. Data were extracted from time of transplant (2008-2014) to 2018. Primary composite endpoints (graft loss, biopsy-confirmed acute rejection, graft dysfunction) and secondary endpoints (all-cause mortality, kidney function course, and tacrolimus dose/trough levels) were analyzed for sub-cohorts: de novo PRT, early conversion from IRT (within 6 months post-transplant), and late conversion (7 months to 3 years). RESULTS Analysis included 163 patients (101 de novo, 12 early converters, and 50 late converters). The overall Kaplan-Meier estimate of freedom from efficacy failure through 5 years was 0.537, (95% confidence interval (CI) 0.455-0.612) (de novo: 0.512 [0.407-0.608]; early converters: 0.500 [0.208-0.736]; late converters: 0.594 [0.443-0.717]). The overall survival rate was 0.925 (95% CI 0.872-0.957) (de novo: 0.900 [0.823-0.945]; early converters: 0.917 [0.539-0.988]; late converters: 0.977 [0.846-0.997]). During follow-up, there was a gradual reduction in tacrolimus dose and trough levels; kidney function remained stable in all cohorts. Multivariable analysis found re-transplantation, organ donor quality, best estimated glomerular filtration rate 8-12 weeks after transplant, and treatment center (between-center differences in age, sex, donor status/quality) were significantly associated with efficacy failure. CONCLUSIONS There was no difference in long-term survival profiles between KTRs who received PRT de novo vs those who converted from IRT, with 5-year survival remaining high in both groups.

Back to the future: the uncharted role of T cells in chronic and unexplained microvascular inflammation.

The 2022 Banff classification for kidney allograft pathology introduced the category "microvascular inflammation DSA-negative and C4d-negative" for cases without evidence of a humoral cause. Many questions remain about the etiology, prognosis, and treatment of this phenotype. Cristoferi et al. performed a molecular comparison of chronic active antibody-mediated rejection and its seronegative counterpart and suggest a central role for T cells in chronic donor-specific antibody-negative, C4d-negative microvascular inflammation. These results further question how we should classify rejection.

Current use of antithymoglobulin as induction regimen in kidney transplantation: A review.

Currently, various immunosuppressive drugs are used in organ transplantation. In particular, antithymoglobulin is a widely used drug in kidney transplantation in Korea, accounting for 20% of all induction therapy. According to existing studies, antithymoglobulin induction therapy has several advantages and disadvantages compared with other immunotherapies depending on the kidney transplant situation (dead donor, living donor, low-risk recipient, and high-risk recipient) or antithymoglobulin dose. In this review, we summarize the research conducted so far on antithymoglobulin and hope that antithymoglobulin research on kidney transplantation will be actively conducted in the future.

The role of anticomplement therapy in the management of the kidney allograft.

As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.

Impact of early immunosuppression on pediatric liver transplant outcomes within 1 year.

OBJECTIVES: The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes. METHODS: We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries. RESULTS: We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only. CONCLUSIONS: Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.

Conversion from twice-daily everolimus to once-daily sirolimus in long-term stable liver transplant recipients.

BACKGROUND: After organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients. METHODS: We included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR). RESULTS: The median age at the time of conversion was 68.9 years (range: 26.1-83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3-31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5-4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5-3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%. CONCLUSION: The results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

Treatment of a MyD88 inhibitor alleviates rejection and inflammation in xenotransplantation by inhibiting dendritic cells activation and trained immunity in macrophages.

BACKGROUND: Acute vascular rejection (AVR) and systemic inflammation in xenograft recipients (SIXR) negatively impact the xenografts survival, and novel immunosuppressants are required to improve survival outcomes. We previously reported that TJ-M2010-5, a myeloid differentiation factor 88 (MyD88) inhibitor, exerts excellent anti-rejection effects in allogeneic transplantation. The aim of the present study was to evaluate the efficacy of TJ-M2010-5 in preventing AVR and SIXR and to investigate whether combined treatment of TJ-M2010-5 with anti-CD154 antibody (MR1) could prolong xenograft survival furthermore. METHODS: A model involving heart transplantation from Sprague-Dawley rats to BALB/c mice was established in vivo, and the xenografts developed typical AVR. Bone marrow-derived dendritic cells and macrophages were cultured to study the underlying mechanisms induced by rat cardiomyocyte lysate stimulation in vitro. RESULTS: TJ-M2010-5 monotherapy prolonged xenograft survival, although combination treatment with MR1 further enhanced the anti-AVR and anti-SIXR effects with about 21 days graft survival, compared to monotherapy. TJ-M2010-5 reduced dendritic cell and macrophage activation induced by xenotransplantation, downregulated CD80/CD86 expression, suppressed B-cell activation and anti-donor antibody generation, reduced pro-inflammatory cytokine production and tissue factor expression, and attenuated epigenetic modifications underlying interleukin-6 and tumor necrosis factor-α production in macrophages by inhibiting nuclear factor kappa B nuclear translocation. CONCLUSIONS: TJ-M2010-5 attenuated AVR and SIXR and contributed to xenograft survival by inhibiting dendritic cell and macrophage activation. A dual-system inhibition strategy combining TJ-M2010-5 with anti-CD154 antibody achieved better results in xenotransplantation.

[Renal xenotransplantation : state of the art]. / Xénotransplantation rénale†: état actuel et perspectives.

Xenotransplantation could be an inexhaustible source of organs and change the life of end-stage kidney disease patients with reduction of morbidity and mortality. Through genetic engineering it is now possible to reduce the risk of hyperacute and acute graft rejection and improve the overall immune compatibility between two different species. Some experiments have already brought promising perspectives. Nevertheless, there are still difficulties to overcome. The risk of animal-related infectious diseases, ethnic limitations, safety, and applicability of large-scale xenotransplantation should be assessed. We still need to improve the technical aspects and define the purpose of these procedures: definitive replacement or temporary solution?

La xénotransplantation pourrait être une source inépuisable d'organes et changer la vie des patients atteints d'une maladie rénale terminale en diminuant la morbidité et la mortalité. Grâce au génie génétique, il est maintenant possible de réduire le risque de rejet hyperaigu et aigu et d'améliorer la compatibilité immunitaire globale entre deux espèces différentes. Certains travaux ont déjà apporté des perspectives prometteuses. Néanmoins, il reste de nombreuses difficultés à surmonter. Le risque de maladies infectieuses liées aux animaux, les considérations ethniques, la sécurité et l'applicabilité de la xénotransplantation à grande échelle devraient être évalués. Nous devons encore améliorer les aspects techniques et définir le but de ces procédures : remplacement définitif ou solution temporaire ?

Kidney Retransplantation in Children.

Pediatric kidney transplant recipients will likely require a retransplant in their lifetime. Although the significant advances in clinical management and newer immunosuppressive agents have had a significant effect to improve short-term allograft function, it is apparent that long-term allograft function remains suboptimal. Therefore, it is likely that most pediatric renal allograft recipients will require 1 or more retransplants during their lifetime. In the West, an increasing number of patients on the deceased donor wait list are awaiting a retransplant; in the US, 15% of current annual transplants are retransplants. Unfortunately, the use of a second or subsequent grafts in pediatric recipients has inferior long-term graft survival rates compared with initial grafts, with decreasing rates with each subsequent graft. Multiple issues influence the outcome of retransplant, with the most significant being the cause of the prior transplant failure. Nonadherenceassociated graft loss poses unresolved ethical issues that may affect a patient's access to retransplant. Graft nephrectomy prior to retransplant may benefit selected patients, but the effect of an in situ failed graft on the development of panel reactive antibodies remains to be definitively determined. It is important that these and other factors discussed in this presentation be taken into consideration during the counseling of families on the optimal approach for their child who requires a retransplant.

Immunology Status of Patients During Kidney Transplant.

OBJECTIVES: The immunology status of a patient has a crucial role in kidney transplant. We investigated the effectiveness of a desensitization protocol, guided by the immunology status of patients, for kidney transplant candidates. MATERIALS AND METHODS: Antibody screening for human leukocyte antigens was conducted with the Luminex single-antigen microsphere bead assay method for 34 patients from June 2021 to June 2022. Donor human leukocyte antigen genotypes at 8 loci (A*, B*, С*, DRB1*, DQA1*, DQB1*, DPA1*, and DPB1*) were determined, to correlate the specificities of recipient human leukocyte antigen antibodies with donor antigens and identify unacceptable donor antigen combinations. Specialized immunology studies measured panel reactive antibody levels and human leukocyte antigen class I and class II antibodies. A crossmatch compatibility test using complementdependent cytotoxicity was conducted. RESULTS: Of the 34 patients, 10 completed all 3 stages of the desensitization therapy. Most patients experienced decreased sensitization to human leukocyte antigen class I and class II antibodies. Two patients achieved complete clearance of A1 and DQ5 antibodies, respectively, whereas 1 patient exhibited an increase in donor-specific antibody mean fluorescence intensity. Prior to desensitization therapy, the crossmatch compatibility test yielded positive results with T and B lymphocytes. After completing the therapy, the crossmatch test showed negative results in 4 cases with T lymphocytes and positive results with B lymphocytes. Plasmapheresis sessions effectively reduced circulating antibodies. However, the combination of rituximab and plasmapheresis alone did not achieve a negative crossmatch test required for kidney transplant. CONCLUSIONS: It is crucial to assess the reduction of donor-specific antibody quantity, considering both the percentage and the mean fluorescence intensity. To avoid false-positive results in crossmatch analysis, drug half-life must be considered. Laboratories should have various crossmatch techniques, such as flow cytometry and single-antigen microsphere bead assay technology, available for research and urgent cases that require crossmatch analysis.

The Challenge of Preoperative Panel Reactive Antibody Positivity in Parathyroid Transplantation.

OBJECTIVES: Identifying suitable recipient criteria and matching recipients with appropriate donors are required to increase survival for parathyroid transplant. This study was undertaken to evaluate transplant survival rates while comparing preoperative panel reactive antibody positivity. MATERIALS AND METHODS: The study included 14 hypoparathyroidism patients who presented to our clinic for parathyroid transplant. Preoperative ABO compatibility and negative cross-match tests were prioritized for recipient-donor matching, and panel reactive antibody screening tests were performed. During the 24-month follow-up, we evaluated medication use and serum calcium, phosphorus, and parathormone levels of patients. RESULTS: Preoperative panel reactive antibody positivity was assessed in 3 groups. The HLA class I-positive group (mean fluorescence intensity range, 179-1770) showed decreased medication use and stability in serum calcium levels. The HLA class IIpositive (mean fluorescence intensity range, 85-3959) showed decreased medication use by 25% to 50% and returned to their former prescription doses after 12 months. An opposite pattern was observed in 2 patients with panel reactive antibody positivity for both HLA classes (mean fluorescence intensity range, 462-2289), with 1 patient requiring medication for continuing symptoms and the other patient occasionally taking additional magnesium supplementation, despite decreased medication doses after 12 months. Serum calcium levels remained normal, and parathormone and phosphorus levels were elevated. CONCLUSIONS: Improving patient symptoms and having no requirement for intravenous calcium replacement are priorities, and monitoring serum levels is the next important step. Varied panel reactive antibody positivities and survival rates indicate a requirement, and each HLA class could require a proper limitation for the mean fluorescence intensity. Preoperative mean fluorescence intensity cut-off value should be <900. Higher mean fluorescence intensity values in panel reactive antibody screenings could increase risk of short-term graft survival after parathyroid transplant. Further studies should include immunological risk assessments by individualizing the outcome with donor-specific antibodies.

Management of Tacrolimus-Induced Toxicity With Normal Serum Levels After Liver Transplant.

Drug-induced liver injury after liver transplant occurs in 1.7% of patients. Tacrolimus is an effective immunosuppressant that is used to treat acute rejection. Although rare, it can cause toxicity, which is demonstrated by cholestatic liver injury. Here, we present a case of a young male patient who was diagnosed with Wilson disease, had penicillaminechelating therapy, and underwent living related liver transplant. Within 1 month posttransplant, he developed deranged, predominantly cholestatic pattern liver function tests. Laboratory parameters showed total bilirubin of 1.12 mg/ dL, alanine aminotransferase of 553 IU/L, gammaglutamyltransferase of 624 IU/L, and tacrolimus level of 10.2 ng/mL. After thorough evaluation, a liver biopsy was performed. Liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. However, with normal level of tacrolimus, the biopsy was suggestive of drug-induced liver injury. Thus, tacrolimus dose was reduced, resulting in improved liver function tests and patient discharge from the hospital. Tacrolimus is an effective immunosuppressant after liver transplant and has the ability to treat early acute rejection. The patient's liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. Cholestatic liver injury after tacrolimus usually resolves after dose reduction or by switching to another agent. With demonstrated tacrolimus-induced toxicity in liver transplant recipients, despite normal serum levels, transplant physicians should keep high index of suspicion regarding toxicity in the posttransplant setting.

Management of the sensitized pediatric renal transplant candidate.

Kidney transplantation is the treatment of choice for patients with ESRD as it is associated with improved patient survival and better quality of life, especially in children. There are several barriers to a successful transplant including organ shortage, anatomic barriers, and immunologic barriers. One of the biggest immunologic barriers that precludes transplantation is sensitization, when patients have antibodies prior to transplantation, resulting in positive crossmatches with donor. 30%-40% of adult patients on the wait list are sensitized. There is a growing number of pediatric patients on the wait list who are sensitized. This poses a unique challenge to the pediatric transplant community. Therefore, attempts to perform desensitization to remove or suppress pathogenic HLA antibodies resulting in acceptable crossmatches, and ultimately a successful transplant, while reducing the risk of acute rejection, are much needed in these children. This review article aims to address the management of such patients both prior to transplantation, with strategies to overcome sensitization, and after transplantation with monitoring for allograft rejection and other complications.

Pharmacotherapy in the heart transplant recipient: A primer for nurse clinicians and pharmacists.

Heart transplantation (HT) is the definitive treatment for eligible patients with end-stage heart disease. A major complication of HT is allograft rejection which can lead to graft dysfunction and death. The guiding principle of chronic immunosuppression therapy is to prevent rejection of the transplanted organ while avoiding oversuppression of the immune system, which can cause opportunistic infections and malignancy. The purpose of this review is to describe immunosuppressive management of the HT recipient-including agent-specific pharmacology and pharmacokinetics, outcomes data, adverse effects, clinical considerations, and recent guideline updates. We will also provide recommendations for medical prophylaxis of immunosuppressed patients based on the most recent clinical guidelines. Additionally, we highlight the importance of medical therapy adherence and the effect of social determinants of health on the long-term management of HT. HT recipients are a complex and high-risk population. The objective of this review is to describe basic pharmacotherapy in HT and implications for nurses and pharmacists.

Effectiveness of combined plasma cell therapy and costimulation blockade based desensitization regimen in heart transplant candidates.

BACKGROUND: Desensitization is one of the strategies to reduce antibodies and facilitate heart transplantation in highly sensitized patients. We describe our center's desensitization experience with combination of plasma cell (PC) depletion therapy (with proteasome inhibitor or daratumumab) and costimulation blockade (with belatacept). METHODS: We reviewed five highly sensitized patients who underwent desensitization therapy with plasma cell depletion and costimulation blockade. We evaluated the response to therapy by measuring the changes in cPRA, average MFI, and number of positive beads > 5000MFI. RESULTS: Five patients, mean age of 56 (37-66) years with average cPRA of 98% at 5000 MFI underwent desensitization therapy. After desensitization, mean cPRA decreased from 98% to 70% (p = .09), average number of beads > 5000 MFI decreased from 59 to 37 (p = .15), and average MFI of beads > 5000 MFI decreased from 16713 to 13074 (p = .26). CONCLUSION: Combined PC depletion and CoB could be a reasonable strategy for sustained reduction in antibodies in highly sensitized patients being listed for heart transplantation.