Posttransplant lymphoproliferative disorders in renal allograft recipients: report of 53 cases of a French multicenter study

Abstract New immunosuppressive therapies are currently being developed in renal transplantation and their relative risk in terms of post‐transplant lymphoproliferative disorders (PTLD) must be carefully evaluated. For this purpose, a French registry of PTLD occurring after renal transplantation was set up. Among 10000 patients presently followed up in 30 French renal transplantation centers, we prospectively identified 53 new PTLD (0.5 %) since January 1998. Patients (34 male, 19 female) ranged from 3 to 72 years (mean age: 46 years), and the median time between grafting and diagnosis of PTLD was 63 months (2 months to 14 years). Ninety percent of recipients were Epstein‐Barr virus (EBV) positive before transplantation. Most patients received a quadruple sequential therapy with polyclonal anti‐lymphocyte globulin. Sites involved in PTLD were isolated lymph nodes in 13 cases, stomach or bowel in 10 cases, allograft in 14 cases, central nervous system in 6 cases, oropharynx in 4 cases, and skin or mucosa in 4 cases. Only three PTLD expressed markers of T lineage. Out of 40 studied tumors, 31 (78%) were EBV positive. Tumors were classified as polymorph in 26 cases and monomorph in 23 cases. Genotype studies in 18 PTLD showed a monoclonal pattern in 13 cases. In most patients, treatment consisted of reduction of immune suppression, 21 patients were given additional anti‐viral therapy, 13 patients had anti‐CD20, 23 patients underwent chemotherapy, and 4 patients were given cerebral radiotherapy. Five patients underwent transplantectomy. Sixteen patients (30 %) died within the 1st year and 7 patients returned to dialysis (13 %). The outcome of patients with PTLD remains poor, and the optimal approach to therapy is largely unknown. This ongoing registry is not only a national observatory but also a task force designed to improve the treatment strategy of PTLD.     

Post-transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment

Abstract:  We performed histopathological and immunohistochemical studies, in situ hybridization (ISH) for Epstein–Barr virus (EBV) and molecular genetic analysis using the PCR method for the immunoglobulin heavy chain gene in six patients with post-transplant lymphoproliferative disorders (PTLD) to clarify these problems. In two patients, PTLD developed in the graft, and in the remaining four it developed in systemic lymphoid tissues or organs. In terms of morphological classification, lesions in the graft of two patients were polymorphic with features of rejection in the background. In the other four patients, three of them presented monomorphic lesions and the remaining one presented features of reactive lymphoid hyperplasia. All the patients were positive for EBV as determined by ISH. The molecular genetic study could be performed for four patients, the cells in lesions of two patients were found to be monoclonal and those of the remaining two were polyclonal in IgH as determined by PCR. We conclude that PTLD are of two types, namely, intragraft PTLD and extra-graft PTLD. In the cases of intragraft PTLD their diagnosis is relatively difficult, because lesions are mixed with features of rejection. Molecular genetic analysis and detection of EBV by ISH are useful for diagnosis. In contrast, the diagnosis of extra-graft PTLD is easier than that of intragraft PTLD, by basing of the latest classification of malignant lymphoma. Grading of severity of PTLD should be carried out according to the newest system and protocols for treatment based on the grade of the lesion should be established as soon as possible.     

CAR-T therapy in solid organ transplant recipients with treatment refractory posttransplant lymphoproliferative disorder

Chimeric antigen receptor T cells (CAR-T) are genetically modified T cells with a chimeric antigen receptor directed against a specific tumor-associated antigen like CD19 in lymphoma. CAR-T cells have shown encouraging activity against recurrent and refractory diffuse large B cell lymphomas (DLBCL). However concurrent use of immunosuppressive agents was prohibited in most CAR-T trials effectively excluding patients with prior solid organ transplantation (SOT) and posttransplant lymphoproliferative disorders (PTLD). We report the outcomes for three patients with PTLD refractory to immunochemotherapy 10-20 years after SOT who received CAR-T therapy between January 2018 and December 2019. One patient had an orthotopic heart transplant, the second had a deceased donor kidney transplant, and the third had a pancreas after kidney transplant (PAK). All patients developed complications of CAR-T therapy such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and acute kidney injury requiring renal replacement therapy in the two out of three patients. All patients expired after withdrawal of care due to lack of response to CAR-T therapy. In addition, the PAK patient developed acute pancreatitis after CAR-T therapy. This case series identifies the challenges of using CAR-T therapy to manage refractory PTLD in SOT recipients and its possible complications.     

Graft outcomes following diagnosis of post‐transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study

Data related to graft outcomes following post‐transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow‐up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED‐PTLD‐2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet‐PHL C1. In four patients, donor‐specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody‐mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range‐based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B‐cell‐depleting therapy of PTLD with rituximab.     

Pregnancy outcomes in simultaneous pancreas and kidney transplant recipients: a national French survey study

Simultaneous pancreas and kidney transplantation (SPK) is currently the best therapeutic option for patients with type 1 diabetes and terminal renal failure. Renal transplantation restores fertility enabling women to pursue pregnancies. However, scarcity of available data on pregnancy outcomes in SPK impedes fair medical counseling. Medical files of all pregnancies that lasted ≥3 months among recipients of functional SPK performed between 1990 and 2015 in France were retrospectively analyzed. Twenty‐six pregnancies in 22 SPK recipients were identified. Main maternal complications included gestational hypertension (53.8%) and infections (50%). Cesarean section was performed in 73% of cases. Overall fetal survival was 92.6% with a mean gestational age of 34.2 ± 3 weeks. Four children (16.7% of live births) had a birth weight <10th percentile. Endocrine pancreas graft function remained stable during pregnancy. An acute kidney rejection occurred in two patients, one of which resulting in graft loss. Kidney and pancreas graft survival was, respectively, 96% and 100% at 1 year postconception and did not differ from controls. Pregnancy in SPK is feasible, but patients should be informed of the risks for the fetus, the mother, and the grafts. Planning of pregnancy in SPK women is key to allow a personalized multidisciplinary monitoring, which represents the most straightforward approach to optimize outcomes.     

Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota

Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal complications of solid organ transplantation. The natural history of PTLD varies considerably among the different types of organs transplanted. While lung transplant recipients are highly susceptible to PTLD, there are only a few small studies that detail PTLD in this setting. We undertook this study to better describe the characteristics and treatment response in PTLD after lung transplantation. We conducted a retrospective chart review of lung and heart/lung-transplant recipients between 1985 and 2008. A total of 32 cases (5%) of PTLD were identified in 639 patients. The median interval after transplantation to the diagnosis was 40 (3-242) months. Eight patients (25%) were diagnosed within one yr of transplantation and had PTLD predominantly within the thorax and allograft. Twenty-four patients (75%) were diagnosed more than one yr after transplantation and their tumors mainly affected the gastrointestinal tract. Monomorphic PTLD, diffuse large B-cell lymphoma, was diagnosed in 91%. Treatment of PTLD varied according to stage and clinical circumstances. Twenty-four patients (75%) have died. The median overall survival was 10 (0-108) months. PTLD after lung transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome.     

Post‐transplant lymphoproliferative disorder in adult liver transplant recipients: a South American multicenter experience

Post‐transplant lymphoproliferative disorder (PTLD) is a major and potentially life‐threatening complication after solid‐organ transplantation. The aim of this study was to describe the disease characteristics, clinical practices, and survival related to PTLD in adult orthotopic liver transplant (OLT) recipients in South America. We conducted a survey at four different transplant groups from Argentina, Brazil, and Chile. Among 1621 OLT recipients, 27 developed PTLD (1.7%); the mean age at diagnosis was 53.7 (±14) yr with a mean time of 39.7 (±35.2) months from OLT to PTLD diagnosis. Initial therapy included reduction in immunosuppression alone in 23.1% of the patients. Either rituximab or chemotherapy was employed as initial or second‐line therapy in 76.9% of the patients. PTLD location was frequently extranodal (80.7%) and mostly involving the transplanted liver (59.3%). The overall survival at one and five yr post‐PTLD diagnosis was 53.8% and 46.2%, respectively. Significant univariate risk factors for post‐PTLD mortality included lactate dehydrogenase ≥250 U/L (HR 9.66, p = 0.02), stage III/IV PTLD (HR 5.34, p = 0.004), and HCV infection (HR 7.68, p = 0.01). In conclusion, PTLD in OLT adult recipients is predominantly extranodal, and although mortality is high, long‐term survival is possible.     

Abdominal involvement in pediatric heart and lung transplant recipients with posttransplant lymphoproliferative disease increases the risk of mortality

Background

Posttransplant lymphoproliferative disease (PTLD) is a serious complication in transplant recipients. Abdominal PTLD has been reported, but the prognosis remains undefined. The purpose of this study was to identify the incidence, predisposing factors, and outcome of abdominal PTLD in pediatric cardiothoracic transplant patients.

Methods

Retrospective chart review of 134 transplant patients (50 heart, 77 lung, 7 heart/lung) at our institution (1995-2005).

Results

Posttransplant lymphoproliferative disease was diagnosed in 14 patients. Most were Epstein-Barr virus naive initially, but all had seroconverted when diagnosed with PTLD. Eight had abdominal involvement; 4 required surgical interventions—1 for intussusception and for bowel perforation, 2 for bowel perforation, and 1 for tumor debulking. All had lifelong follow-up, with an average follow-up of 3 years. Of 8 patients with abdominal PTLD, 4 died of complications related to PTLD, whereas 1 of 6 patients with extraabdominal PTLD died of PTLD.

Conclusions

Epstein-Barr virus infection after transplantation is a major risk factor for PTLD. Pediatric patients with PTLD who present with abdominal involvement are more likely to die of PTLD than those without abdominal disease. Delay in diagnosis may contribute to the high mortality. Therefore, prompt evaluation and surveillance for possible abdominal PTLD may decrease mortality associated with this devastating problem.     

Bacteremia in kidney transplant recipients: Burden,causes, and consequences

Bacteremia is an important complication after kidney transplantation. We examined bacteremia and its outcomes in a large cohort of kidney transplant recipients. Kidney transplants from 1‐Jul‐2004 to 1‐Dec‐2014 at the Toronto General Hospital were eligible for study inclusion. Bacteremia was defined as two blood culture positives for common skin contaminants or one blood culture positive for other organisms. The cumulative incidence of first bacteremia was estimated using the Kaplan‐Meier method, and risk factors were examined in a Cox proportional hazards model. The risk of graft failure or death was assessed in a time‐dependent Cox model. Over follow‐up, 154 of 1333 patients had at least one bacteremia episode. The cumulative incidence of first bacteremia was 6.8% (6 months) and 11.9% (5 years). Risk factors included recipient diabetes mellitus, time on dialysis, dialysis modality, delayed graft function, donor age, and donor eGFR. Bacteremia increased the risk of total graft failure (hazard ratio 2.11 [95% CI: 1.50, 2.96]), death‐censored graft failure (1.73 [0.99, 3.02]), and death with graft function (2.52 [1.63, 3.89]). In conclusion, bacteremia is common after kidney transplantation and impacts both graft and patient survival. Identifying high‐risk patients for targeted preventive strategies may reduce the burden and adverse consequences of this important complication.     

Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study

Tessari G, Naldi L, Piaserico S, Boschiero L, Nacchia F, Forni A, Rugiu C, Faggian G, Dall’Olio E, Fortina AB, Alaibac M, Sassi F, Gotti E, Fiocchi R, Fagioli S, Girolomoni G. Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study.
Clin Transplant 2010: 24: 328–333. © 2009 John Wiley & Sons A/S. Abstract: Background: Primary opportunistic deep cutaneous fungal
infections may cause significant morbidity and mortality in solid organ transplant recipients (OTR), but no data exist about their incidence, timing, and clinical predictors in a long‐term follow‐up. Patients and methods: A series of 3293 consecutive OTR including 1991 kidney, 929 heart, and 373 liver transplant recipients were enrolled. Patients were regularly followed up since time at transplantation (mean 5.5 yr ±5.9 SD) and primary opportunistic fungal infections registered. Persons‐year at risk (PYs), incidence rates (IR), incidence rate ratios (IRR), and 95% confidence intervals were computed. Results: Twenty‐two cases of deep cutaneous mycoses were detected, (IR 1.2 cases per 1000 PYs) after a mean follow‐up time since transplantation of 2.5 yr ± 2.0 SD (median 1.8 yr). Six patients had subsequent systemic involvement and three patients died of systemic dissemination. A higher risk for mycoses was observed in the first two yr after transplantation, (IRR 35.9, p < 0.0001), in renal transplant recipients (IRR 5.1 p = 0.030), and in patients transplanted after the age of 50 (IRR 11.5 p = 0.020). Conclusions: Primary deep cutaneous opportunistic mycoses in OTR occur mainly in the first two yr after transplantation, in renal transplant recipients, and in older patients.     

Outcomes of kidney retransplantation in recipients with prior post‐transplant lymphoproliferative disorder

Post‐transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein–Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5–323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29–95   months) after PTLD diagnosis. After a median follow‐up of 62.5 months (range 2–125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted.     

Post-transplant lymphoproliferative disorders: clinicopathological analysis of 43 cases in a single center, 1990-2009

Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous set of complications of organ transplantation associated with poor patient prognosis. We analyzed the clinicopathological features of PTLDs in 43 adult and pediatric recipients of solid organ or bone marrow transplantation at a large transplant service in the Republic of Korea between 1990 and 2009. Of 4545 solid organ and 747 bone marrow transplant recipients, 37 (0.81%) and 6 (0.8%), respectively, developed heterogeneous types of PTLDs. The cumulative incidences of PTLDs during this period were 1.79% (4/223) for heart transplant recipients, 0.78% (17/2192) for kidney transplant recipients, and 0.77% (16/2067) for liver transplant recipients. The patterns of disease onset, histology, and patient survival were associated with the types of organs transplanted. There is a trend for shorter overall survival (OS) in recipients with early-onset PTLDs and monomorphic PTLD histology, while kidney transplant recipients showed favorable OS. This study may be the first comprehensive analysis of the characteristics of PTLDs in Korean patients.     

肝移植受者移植后淋巴组织增生性疾病的单中心诊疗经验

目的  总结肝移植受者移植后淋巴组织增生性疾病（PTLD）的发病情况和诊疗经验。方法  回顾性分析734例肝移植受者的临床资料,收集肝移植受者中PTLD的发病情况、临床症状、实验室数据及影像学资料;分析PTLD受者的病理学结果与治疗方式;分析PTLD受者的预后情况。结果  肝移植受者PTLD发生率为2.2%（16/734）, 中位术后发病时间为8（3, 46）个月。PTLD的临床表现主要为发热、淋巴结肿大,部分出现贫血、肝脾肿大、肝功能异常和消化系统症状等。16例PTLD受者中,1例他克莫司血药浓度异常升高;6例转氨酶升高;14例爱泼斯坦-巴尔病毒（EBV）DNA载量升高;5例巨细胞病毒（CMV）DNA载量升高。13例受者正电子发射计算机体层显像仪（PET/CT）检查提示相关肿大淋巴结¹⁸F-氟代脱氧葡萄糖代谢增高;2例受者颈部及腹部CT检查提示相应区域多发淋巴结肿大;1例受者仅超声提示淋巴结肿大。16例PTLD受者均行病理学检查, 其中13例受者原位杂交结果提示EBV编码的小RNA（EBER）阳性。降低免疫抑制剂水平是PTLD受者的基础治疗方案,根据不同病理类型的PTLD可联合利妥昔单抗靶向治疗及化学药物治疗;针对肿大淋巴结,给予手术及放射治疗。1例受者因PTLD治疗致移植肝衰竭死亡。结论  肝移植术后免疫抑制剂的使用可增加PTLD的患病风险,PTLD在儿童肝移植受者中发生率高于成人,尽早诊断和合理治疗可极大地改善PTLD受者的预后。     

婴儿双供肾成人肾移植的改良简化术式四例

目的总结婴儿双供肾成人肾移植的改良简化术式的手术方式及临床效果。方法总结山西省第二人民医院肾移植透析中心2017年1月至2019年9月采用改良简化术式进行的4例婴儿双供肾成人肾移植资料。4例均为心死亡供者,男性3例,女性1例,年龄(54±22.69)d,体重为(5.6±0.79)kg。受者中男性1例,女性3例,年龄(41.5±5.97)岁,体重(45±3.56)kg。俢肾过程中将双侧供肾缝合固定,使双肾位置相对固定,行供肾腹主动脉瓣-受者髂外动脉、供肾下腔静脉瓣-受者髂外静脉端侧吻合,以降低手术难度、避免血流动力学紊乱。结果4例手术过程均顺利,供肾修整平均历时20 min,移植手术平均历时68.75 min。未出现血管及泌尿系统并发症,随访12个月移植肾功能恢复良好,受者及移植肾远期存活满意。结论改良简化婴儿双供肾成人整块肾移植优化了手术方式,操作简便且降低血管并发症,提高手术成功率,值得在临床实践中推广应用。     

Hydroxychloroquine and maintenance immunosuppression use in kidney transplant recipients: Analysis of linked US registry and claims data

Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory effects used to treat systemic lupus erythematosus (SLE) and scleroderma. The antiviral effects of HCQ have raised attention in the context of the COVID-19 pandemic, although safety is controversial. We examined linkages of national transplant registry data with pharmaceutical claims and Medicare billing claims to study HCQ use among Medicare-insured kidney transplant recipients with SLE or scleroderma (2008–2017; N = 1820). We compared three groups based on immunosuppression regimen 7 months-to-1 year post transplant: (a) tacrolimus (Tac) + mycophenolic acid (MPA) + prednisone (Pred) (referent group, 77.7%); (b) Tac + MPA + Pred + HCQ (16.5%); or (c) other immunosuppression + HCQ (5.7%). Compared to the referent group, recipients treated with other immunosuppression + HCQ had a 2-fold increased risk of abnormal ECG or QT prolongation (18.9% vs. 10.7%; aHR,_1.121.96_3.42, p = .02) and ventricular arrhythmias (15.2% vs. 11.4%; aHR,_1.001.81_3.29, p = .05) in the >1-to-3 years post-transplant. Tac + MPA + Pred + HCQ was associated with increased risk of ventricular arrhythmias (13.5% vs. 11.4%; aHR,_1.021.54_2.31, p = .04) and pancytopenia (35.9% vs. 31.4%; aHR,_1.031.31_1.68, p = .03) compared to triple immunosuppression without HCQ. However, HCQ-containing regimens were not associated with an increased risk of death or graft failure. HCQ may be used safely in selected kidney transplant recipients in addition to their maintenance immunosuppression, although attention to arrhythmias is warranted.     

Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes

No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single‐center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm³ in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post‐transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High‐risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18‐3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52‐1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16‐2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97‐2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients.     

CNI withdrawal for post‐transplant lymphoproliferative disorders in kidney transplant is an independent risk factor for graft failure and mortality

Post‐transplantation lymphoproliferative disorders (PTLD) are associated with poor patient and graft survival. The risk of rejection and subsequent graft loss are increased by the reduction of immunosuppression therapy, the cornerstone of PTLD treatment. This multicentre, retrospective, nonrandomized cohort study includes 104 adults who developed PTLD after renal or simultaneous renal/pancreatic transplantation between 1990 and 2007. It examines the effect of calcineurin inhibitor (CNI) withdrawal on long‐term graft and patient survival. At 10 years postonset of PTLD, the Kaplan–Meier graft loss rate was 43.9% and graft loss or death with functioning graft was 64.4%. Cox multivariate analysis determined risk factors of graft loss as PTLD stage greater than I‐II and CNI withdrawal, and for graft loss and mortality, these remained risk factors along with age over 60 years. Type and location of PTLD, year of diagnosis, and chemotherapy regime were not independent risk factors. Multivariate analysis determined CNI withdrawal as the most important risk factor for graft loss (HR = 3.07, CI 95%: 1.04–9.09; P = 0.04) and death (HR: 4.00, CI 95%: 1.77–9.04; P < 0.001). While long‐term stable renal function after definitive CNI withdrawal for PTLD has been reported, this review determined that withdrawal is associated with reduced graft and patient survival.