Management of the kidney transplant recipient

The short-term outcomes of kidney transplant recipients have improved dramatically in the past 20 years, in large part resulting from the availability of more potent immunosuppressive drugs capable of preventing or treating acute allograft rejection. Ironically, side effects from these same immunosuppressants play a role in the long-term morbidity and mortality of this patient population. As kidney transplant recipients survive for longer periods of time with functioning allografts, primary care physicians will likely become more involved in their management, mandating at least a basic understanding of immunosuppression and its complications.     

Marking a path to transplant tolerance

Long-term allograft survival requires lifelong immunosuppression, which comes with serious side effects. Inducing immune tolerance to the transplant would enable immunosuppression withdrawal and revolutionize the quality of life of transplant recipients. In this issue of the JCI, Martínez-Llordella et al. identify a profile of biomarkers that predict tolerance in liver transplant recipients (see the related article beginning on page 2845). These findings translate into a new means for prospectively selecting liver transplant patients who would benefit from immunosuppression withdrawal and ultimately may guide development of tolerogenic therapies that allow for allograft acceptance without the use of long-term immunosuppression.     

Why do we need biomarkers in solid organ transplantation

Immunosuppressive therapy is administered to all solid organ transplant recipients to help prevent acute rejection and the loss of allograft function. Adequate immunosuppression is a delicate balance between rejection rates and chronic allograft dysfunction on the one hand and immunological and nonimmunological side effects on the other hand. The general strategy is to minimize the toxicity associated with triple immunosuppressive regimens and possibly enhance long-term allograft survival without compromising short-term allograft survival. There are no criteria that enable the clinician to predict who will do well with the decrease or complete avoidance of immunosuppression. It becomes more and more clear that randomized controlled trials will not be able to solve the problem of defining the optimal immunosuppression for a given individual. The most promising road to achieve this goal and to improve chronic allograft survival may be personalized immunosuppression guided by biomarkers complementary to conventional drug monitoring strategies.     

Identification of a B cell signature associated with renal transplant tolerance in humans

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.     

46例移植肾切除回顾性分析

目的:探讨移植肾切除的原因和手术安全性。方法:回顾分析复旦大学附属中山医院25年来626例肾移植患者中46例移植肾切除的原因和并发症。结果:切除的46例移植肾中急性排斥反应20例(45.20%),慢性排斥反应16例(34.78%),加速排异2例,动脉栓塞1例,感染4例,肾破裂2例和肾动脉破裂1例。感染和出血为术后最多见的并发症,共9例(19.56%),死亡2例(4.34%)。环孢素A(CsA)使用后移植肾切除率7.72%,与CsA使用前的27.78%相比移植肾切除率明显减少(P<0.01)。结论:移植肾切除的主要原因是急慢、性排斥反应。CsA的使用是移植肾切除减少的原因之一。移植肾切除手术风险大,并发症多,手术前后合理的处理可增加手术安全性。     

Management of patients after cardiac transplantation.

During the past decade, the morbidity and mortality associated with cardiac transplantation have decreased dramatically. The current survival for patients who undergo orthotopic cardiac transplantation is 80 to 90% at 1 year and 70 to 80% at 5 years; these results are attributed chiefly to improved immunosuppression and the consequent decrease in infectious illnesses and rejection. Because surgical mortality and technique have not changed appreciably during the past 20 years, improved survival can be ascribed to advances in the medical management of recipients of cardiac transplants. Medical problems frequently encountered in such patients include allograft rejection, allograft vasculopathy, hypertension, renal dysfunction, hyperlipidemia, hyperglycemia, malignant disorders, general surgical disease, and osteopenic bone disease. Hence, the expertise needed for management of patients who undergo cardiac transplantation is not confined to a particular specialty--optimal care necessitates the integrated efforts of a team, including transplant physicians and personnel to provide broad subspecialty and laboratory support. Meticulous management with proactive intervention and minimal effective immunosuppression will prevent or ameliorate many problems and contribute to increased survivorship and improved quality of life. For additional substantive improvement in long-term survival and quality of life for recipients of cardiac allografts, multicenter, prospective, and placebo-controlled clinical investigations will be necessary.     

Belatacept : a new biological agent for maintenance immunosuppression in kidney transplantation

INTRODUCTION: Over the past decades, calcineurin inhibitors (CNIs) have become the cornerstone of transplant immunosuppression. CNIs can exert negative effects on chronic allograft function along with cardiovascular (CV) and metabolic adverse effects. Belatacept , a selective co-stimulation blocker of T cells, is the first US FDA (06/2011) and EMEA (06/2011) approved biologic agent for maintenance immunosuppression in renal transplantation. AREAS COVERED: The authors critically reviewed the literature over the last few years comparing belatacept with current standard of maintenance immunosuppression including CNIs in kidney transplantation. EXPERT OPINION: Despite the increased incidence and severity of acute rejection with belatacept in Phase II and III studies, a better preservation of GFR and reduced incidence of chronic allograft nephropathy was observed as compared with CNIs. Patient and graft survivals were similar over 3- and 5-year follow-up post-transplantation. Incidence of adverse events were similar between the groups, but the risk of post-transplant lymphoproliferative disorder, predominantly involving CNS, was higher in Epstein-Barr virus seronegative recipients on belatacept, especially with a more intensive regimen. CV and metabolic end points were more favorable in belatacept versus CNI groups with similar incidences of diabetes after transplantation. Belatacept seems to be a promising drug for the future, but long-term outcomes are awaited.     

Extracorporeal photochemotherapy: a treatment for organ graft rejection.

Extracorporeal photochemotherapy (ECPC) has been investigated experimentally and in clinical conditions in transplant rejection treatment and prevention. Repeated injections of photochemically modified syngeneic alloreactive T cells prior to transplant significantly delay rejection in a mouse skin graft model as well as in a heterotopic heart transplant model in rats. In the latter, we found this effect to be dependent on 3 main parameters, i.e., treatment intensity (number of injections), schedule (injections before and after transplant), and associated immunosuppression (because there is no detectable effect in animals without immunosuppression). In human beings, ECPC was first used for the treatment of acute rejection episode after heart transplantation. At least 2 studies provided evidence that ECPC is as effective as high dose corticosteroids in controlling moderate acute rejections, and several case reports showed that ECPC could be effective in recurrent and/or steroid resistant rejections. ECPC has also been investigated in an open trial to prevent rejection episodes after heart transplantation in patients at high risk of acute rejection because of human leukocyte antigen (HLA) immunization and/or a second or third transplant and found to be successful. In heart transplant recipients at standard risk of rejection episodes, a small scale randomized trial showed a reduction in both rejection episodes and infections in the ECPC treated vs. the standard group. Beyond these studies and other isolated case reports, several large scale randomized trials in heart, lung, and even kidney transplantations (some of them already ongoing), will enable us to define the role of ECPC in the management of transplant recipients.     

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes.     

Coronavirus disease 2019 and renal transplantation

Ever since the severe acute respiratory syndrome virus causing coronavirus disease 2019 (COVID-19) struck the world, global health strategies have changed significantly. According to the Centers for Disease Control and Prevention, kidney transplant recipients are stratified as being high risk of developing fatal illness from COVID-19 infection. Kidney transplant is the gold-standard treatment for end-stage kidney disease subjects. During the pandemic, significant concerns have emerged regarding continuation of kidney transplant surgeries and management of kidney transplant recipients post-transplant. The added risk of immunosuppression in this cohort was and remains a theoretical concern, posing a potential risk of transplantation rather than benefit. This comprehensive review aims to cover most of the faced challenges in kidney transplantation in different stages of the pandemic. In addition, it will elucidate the epidemiology, nature, course of the disease, surgical consideration in donors and recipients as well as role of immunosuppression and management of COVID-19 infected kidney transplant recipients during these extraordinary circumstances.     

Cardiac transplantation: a review for critical care nurses

Advances in immunology, immunosuppressive therapy, and preservation techniques have contributed to making cardiac transplantation an accepted therapy for end-stage heart disease. One-year survival rates now exceed 90% at some transplant centers. However, serious complications, such as infection, rejection, coronary artery disease, and malignancies, continue to plague long-term survival rates in this patient population. Balancing the immune system between infection and rejection requires the special expertise of experienced cardiologists and immunologists. An improved understanding of the immune system promises to increase long-term survival rates of cardiac transplant recipients. Critical care nurses require special assessment skills to meet the demanding challenges of cardiac transplant recipients in the immediate postoperative period. The impact of cardiac denervation, immunosuppression, and the risk for acute rejection add a different perspective for nursing interventions in the critical care environment. With mortality rates remaining at 8 to 10% for the first month following cardiac transplantation, the skill of critical care nurses is crucial to decreasing morbidity and increasing survival during the acute perioperative period.     

Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4⁺/CD8⁺ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.     

Review of the Clinical and Economic Burden of Antibody-Mediated Rejection in Renal Transplant Recipients

Antibody-mediated rejection (AbMR) is a leading cause of late graft loss in kidney transplant recipients, accounting for up to 60% of late graft failures. AbMR manifests as two distinct phenotypes: the first occurs in the immediate post-transplant period in sensitized patients; the second occurs in the late post-transplant period and has been associated with non-adherence to immunosuppression. The present review summarizes the current treatment options for AbMR, its clinical and economic burden, and approaches for reducing the risk of AbMR. While AbMR is typically refractory to treatment with corticosteroids, there are numerous other approaches focused on removal, inhibition or neutralization of donor-specific antibodies, or inhibition of complement-mediated allograft damage. AbMR treatment is generally expensive with one US study reporting costs of USD 49,000–155,000 per episode. However, leaving AbMR untreated puts patients at high risk of capillaritis, microangiopathy, necrosis and graft failure, which may ultimately result in much greater costs associated with a return to dialysis. Given the barriers to treatment, which include the high cost and the fact that pharmacologic treatments are currently used off-label, prevention of AbMR is important, with improvement in patient adherence to immunosuppression a key strategic approach that may be worthy of further evaluation. Funding: Astellas Pharma EMEA Limited.     

供者特异性活化T细胞频度预测肾移植急性排斥反应

背景:提高移植后排斥反应风险预报的准确性,可为移植后个体化使用免疫抑制剂提供参考。目的:寻找一种能定量分析供受者间免疫反应强度的方法来预测急性排斥反应。方法:对同种异体尸肾移植的患者115例采用前瞻性分析,用ELISPOT法检测移植前分泌γ-干扰素的供者特异性活化T细胞的频度,观察随访期内有无急性排斥及肺部感染,并观察HLA错配与急性排斥的关系。结果与结论:115例群体反应性抗体阴性肾移植受者中有25例发生急性排斥反应,发生急性排斥反应患者的供者特异性活化T细胞频度高于未发生急性排斥反应者(P<0.01),而HLA-I、II及总的错配数比较,差异均无显著性意义(P>0.05)。提示,通过移植前对产生γ-干扰素的供者特异性活化T细胞频度的检测,可预测急性排斥反应,对潜在供者进行选择。     

Risks and benefits of kidney and pancreas transplantation for diabetic patients

Type 1 diabetic patients with end-stage renal disease can choose dialysis or transplantation for renal replacement therapy. For patients choosing transplantation, a kidney from a living related donor is associated with longer allograft and patient survival. When a living donor is not available, then a combined cadaveric kidney and pancreas transplant can be considered. The addition of a pancreas transplant incurs greater morbidity and may require higher levels of immunosuppression. However, there may be substantial benefits, including improvement in quality of life and stabilization of neuropathy. Patients with type 1 diabetes younger than 45 years with little or no atherosclerotic vascular disease are ideal candidates for a combined kidney and pancreas transplant. Patients who do not meet these criteria but who have life-threatening hypoglycemia may also wish to consider pancreas transplantation, but have an increased risk of serious complications. The risks and benefits of combined kidney and pancreas transplantation are outlined in this review and should be carefully considered by potential transplant recipients and their physicians.     

A primer for managing cardiac transplant patients in the emergency department setting

BackgroundCardiac transplant is an effective long-term management option for several severe cardiac diseases. These cardiac transplant patients may present to the emergency department with a range of issues involving the cardiac transplantation, including complications due to their transplant as well as altered presentations of disease resulting from their transplant.ObjectiveThis narrative review provides a focused guide to the evaluation and management of patients with cardiac transplantation and its complications.DiscussionCardiac transplant is an effective therapy for end-stage heart failure. A transplanted heart varies both anatomically and physiologically from a native heart. Several significant complications may occur. Graft failure, rejection, and infection are common causes of morbidity and mortality within the first year of transplant. As these patients are on significant immunosuppressive medication regimens, they are at risk of infection, but inadequate immunosuppression increases the risk of acute rejection. A variety of dysrhythmias such as atrial fibrillation and ventricular dysrhythmias may occur. These patients are also at risk of acute coronary syndrome, cardiac allograft vasculopathy, and medication adverse events. Importantly, patients with acute coronary syndrome can have an altered presentation with the so-called “painless” myocardial infarction. Consultation with the transplant physician is recommended, if available, for these patients to assist in evaluation and management.ConclusionsAn understanding of the presentations and various complications that may affect patients with cardiac transplant will assist emergency clinicians in the care of these patients.     

HA-ving lymphatics improves lung transplantation

Lung allografts are prone to rejection, even though recipients undergo aggressive immunosuppressive therapy. Lymphatic vessels serve as conduits for immune cell trafficking and have been implicated in the mediation of allograft rejection. In this issue of the JCI, Cui et al. provide compelling evidence that lymphatic vessel formation improves lung allograft survival in a murine transplant model. Moreover, their data suggest a potential mechanism for the beneficial effects of lymphatics that does not involve immune cell or antigen transport. Together, the results of this study provide new insight into the role of lymphatic vessels in transplant tolerance.     

Complications infectieuses graves chez le transplanté rénal en réanimation

Kidney transplantation is the most frequent solid organ transplantation. Thanks to the advances in immunosuppressive therapy and the development of new immunosuppressive drugs, eligibility criteria of donors and recipients have expanded, incidence of acute rejection has decreased, and long-term graft survival has improved. However, despite a better management of antimicrobial prophylaxis, transplantation of patients with more comorbid conditions and use of more potent immunosuppressive regimens have led to an increase in the incidence of infectious complications. They represent the first reason for admission to the intensive care unit (ICU) among kidney transplant recipients. In 20–30% of cases, ICU admission is preceded by the treatment of an acute rejection. Moreover, the reactivation of cytomegalovirus, which could promote the occurrence of infections by its immunomodulatory properties, is found before or during ICU admission in 16–36% patients. Infected sites and pathogens depend on the time between transplantation and ICU admission, but especially on the severity of immune depression. Pneumonia, which is bacterial in two-third of cases, is the leading cause. Pneumocystis jirovecii is the most frequent opportunistic pathogen. Inhospital mortality range between 20 and 60%. Chronic allograft dysfunction is observed in 40% of survivors. Therefore, intensivists should be aware of epidemiology, risk factors, clinical presentation, and treatment of the main infectious complications following kidney transplantation.     

Time to reach tacrolimus maximum blood concentration,mean residence time, and acute renal allograft rejection: an open-label, prospective, pharmacokinetic study in adult recipients

OBJECTIVES: The aims of this study were to determine whether disposition-related pharmacokinetic parameters such as T(max) and mean residence time (MRT) could be used as predictors of clinical efficacy of tacrolimus in renal transplant recipients, and to what extent these parameters would be influenced by clinical variables. METHODS: We previously demonstrated, in a prospective pharmacokinetic study in de novo renal allograft recipients, that patients who experienced early acute rejection did not differ from patients free from rejection in terms of tacrolimus pharmacokinetic exposure parameters (dose interval AUC, preadministration trough blood concentration, C(max), dose). However, recipients with acute rejection reached mean (SD) tacrolimus T(max) significantly faster than those who were free from rejection (0.96 [0.56] hour vs 1.77 [1.06] hours; P < 0.001). Taking into account that neither differences in tacrolimus steady-state clearance nor T(1/2) could explain this unusual finding, we used data from the previous study to calculate MRT from the concentration-time curves. RESULTS: As part of the previous study, 100 patients (59 male, 41 female; mean [SD] age, 51.4 [13.8] years;age range, 20-75 years) were enrolled in the study The calculated MRT was significantly shorter in recipients with acute allograft rejection (11.32 [031] hours vs 11.52 [028] hours; P = 0.02), just like T(max) was an independent risk factor for acute rejection in a multivariate logistic regression model (odds ratio, 0.092 [95% CI, 0.014-0.629]; P = 0.01). Analyzing the impact of demographic, transplantation-related, and biochemical variables on MRT, we found that increasing serum albumin and hematocrit concentrations were associated with a prolonged MRT (P < 0.05). Conversely, serum albumin and hematocrit concentrations were significantly lower in recipients with acute rejection (P < (101). CONCLUSIONS: In this selected population of de novo renal allograft recipients, a shorter tacrolimus T(max) and calculated MRT were associated with a higher incidence of early acute graft rejection. These findings suggest that a shorter transit time of tacrolimus in certain tissue compartments, rather than failure to obtain a maximum absolute tacrolimus blood concentration, might lead to inadequate immunosuppression early after transplantation.