Can direct oral anticoagulants be used in kidney transplant recipients?

BACKGROUND: Kidney transplant recipients(KTRs) are at an increased risk of venous thromboembolism (VTE) and atrial fibrillation(AF). Direct oral anticoagulants (DOACs) have shown important advantages over vitamin K antagonists; however, in KTRs, concerns regarding interactions and use in severe kidney disease may limit their use. This evaluation describes a large UK kidney transplant center's experience of DOACs in KTRs with CrCl > 15 mL/min. METHODS: Electronic records were reviewed for all adult KTRs at Manchester University Foundation Trust Hospitals taking DOACs between January 2018 and October 2020 with VTE or AF. The primary outcome was trough and peak DOAC levels within the expected reference ranges and secondary outcomes included bleeding and thrombotic events. RESULTS: In 31 KTRs taking DOACS, eight patients had a CrCl < 30 mL/min. Overall, 94% (62/66) of DOAC levels were within the recommended ranges. There were no thrombotic events and four bleeding events (two major and two clinically relevant non-major bleeds). The overall bleeding rate was 6.9 per 100 patient-years at risk. CONCLUSIONS: There was no evidence of a significant interaction of apixaban or rivaroxaban with CNIs based on expected DOAC and CNI levels. Their use was found to be safe and effective with no VTE events and bleeding episodes similar to published trial data.

Talaromycosis in a renal transplant recipient returning from South China.

Talaromycosis is a fungal infection endemic in Southeast Asia. We report a case of a renal transplant recipient who developed infection after a trip to South China. She presented with constitutional symptoms and was found to have an FDG-avid lung mass. Histopathology demonstrated small yeast cells and culture grew Talaromyces marneffei. The patient was treated with 2 weeks of liposomal amphotericin B followed by itraconazole. The dose of tacrolimus was significantly reduced because of the interaction with itraconazole. Mycophenolate mofetil was discontinued. After 12 months of treatment, the mass had completely resolved. Talaromycosis has mainly been reported in patients with AIDS and is uncommon among solid organ transplant recipients. The immune response against T. marneffei infection is mediated predominantly by T cells and macrophages. The diagnosis may not be suspected outside of endemic areas. We propose a therapeutic approach in transplant patients by extrapolating the evidence from the HIV literature and following practices applied to other endemic mycoses.

A role for human leucocyte antigens in the susceptibility to SARS-Cov-2 infection observed in transplant patients.

We analysed data from 80 patients who tested positive for SARS-CoV-2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA- DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94-3.22) and infection. A bias towards an increased representation of HLA-A*26, HLA-DRB1*15, HLA-DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA-A*02, HLA-B*44 and HLA-C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS-CoV-2 pandemic and potentially in risk-assessing staff interactions with infected patients.

A single-center experience of post-transplant lymphomas involving the central nervous system with a review of current literature.

BACKGROUND: Central Nervous System (CNS) lymphoma is a rare presentation of post-transplantation lymphoproliferative disorder (PTLD). METHODS: This single center retrospective study reviewed presentations, management and outcomes of CNS lymphomas in kidney transplant patients transplanted 1968 to 2015, and reviews relevant current literature. RESULTS: We identified 5773 adult kidney transplant recipients of who 90 had a PTLD diagnosis confirmed. CNS disease was diagnosed in 6/90 (7%). Median age at presentation was 60 years and time from transplant 4.5 years. Immunosuppression at diagnosis included mycophenolate mofetil and prednisolone without calcineurin inhibitor in 5/6 patients. Histological analysis diagnosed monomorphic disease in 5/6, and one polymorphic case with tissue positive for Epstein-barr virus (EBV) in 5/6 cases. Despite this 2/4 EBV positive cases had no detectable EBV in peripheral blood or CSF at diagnosis. Treatment strategies included reduction in immunosuppression in all, chemotherapy (n=5), radiotherapy (n=3), Cytotoxic T-Lymphocytes and Craniotomy (n=2). Patient survival was 40% at 1 year with CTL treated patients surviving beyond three years from diagnosis. CONCLUSION: This study supports observational data suggesting MMF treated patients without CNI may have increased risk of disease. Peripheral blood screening for EBV DNAemia does not seem helpful in early identification of those at risk.

Post-transplant lymphoproliferative disorder in adult renal transplant recipients: survival and prognosis.

Post-transplant lymphoproliferative disorder (PTLD) is a rare, serious complication following solid organ transplantation, with an incidence of 2.6 cases per 1000 patient years. Optimal treatment strategies and risk stratifications specific to kidney transplantation are lacking and PTLD mortality remains high. This study investigated survival and prognosis in 89 cases of PTLD presenting over 44 years at Manchester Royal Infirmary. Patient survival following diagnosis was 72% at 6 months, 67% at 1 year and 54% at 3 years. In multivariate analysis, a poorer 3 year survival was associated with acute kidney injury at diagnosis (p = 0.0001), impaired renal function (p = 0.04), early onset (p = 0.02), T cell disease (p = 0.02) and previous treatment with anti-thymocyte globulin (p = 0.04). The inclusion of graft function adds prognostic value to risk stratification and should be explored further. Strategies to improve survival should include timing and choice of immuno-chemotherapy, preparation for dialysis and aggressive surveillance for sepsis and treatment toxicity.

The genetic contribution to recurrent autoimmune nephritis.

Glomerulonephritis is a significant cause of chronic kidney disease requiring renal replacement therapy. For patients receiving a transplant, it is known that specific primary pathologies such as membranous nephropathy, IgA nephropathy and FSGS have a high risk of recurrence in the transplant but the reasons for this are unknown and the ability to predict recurrence is poor. The recent discovery that primary MN is an autoimmune disease characterised by an autoantibody to phospholipase A2 receptor 1 and the identification of two genes, PLA2R1 and DQA1 which account for the genetic susceptibility to the disease, open up the potential to understand the mechanism of recurrent MN and therefore to design and manage therapy to prevent recurrence. Transplantation offers a unique ethical experimental context in which to explore the genetic contribution to recurrent autoimmune membranous nephropathy. By analysing the genetic changes in the kidney transplant in the context of anti-PLA2R status post transplant, it may be possible to link genetic markers, anti-PLAR regulation with recurrence and non-recurrence of disease. If successful, similar strategies may help unravel mechanisms of recurrent IgA nephropathy and FSGS.

Epidemiology of posttransplantation lymphoproliferative disorder in adult renal transplant recipients.

BACKGROUND: There is little information in the literature describing the relationship between posttransplantation lymphoproliferative disorder (PTLD) incidence and presentation with both recipient Epstein-Barr virus (EBV) serostatus and EBV status of PTLD histology, particularly in the late posttransplantation period. METHODS: This study reports the largest UK single-center, single-organ analysis of PTLD to date in a retrospective cohort study of 80 cases occurring in 4189 adult renal transplant recipients. RESULTS: The incidence rate was 2.6 cases per 1000 patient-years (95% confidence interval [95% CI], 2.1-3.2) for PTLD, 1.8 (95% CI, 1.4-2.4) for non-Hodgkin's lymphoma, and 0.2 (95% CI, 0.07-4.2) for Hodgkin's lymphoma. Non-Hodgkin's lymphoma occurred at a rate 7.6 times that of the adult general population in England, whereas the rate for Hodgkin's lymphoma was 5.9 times. The incidence of PTLD was highest during the 10th to 14th posttransplantation years. Early-onset disease was associated with EBV-seronegative recipient status, EBV-positive histology, and the involvement of extranodal sites. PTLD occurring in EBV-seronegative recipients was associated with EBV nuclear antigen antibody deficiency, polymorphic disease, and the involvement of extranodal sites. EBV-negative histology occurred in 32% of cases at a median time to presentation of 109 months. PTLD involving the allograft, central nervous system, and skin was uncommon and occurred late. CONCLUSION: The incidence of PTLD is highest in the late posttransplantation period. Close clinical surveillance and education for transplant recipients is required for the duration of time while immunosuppressed. Failure to detect EBV DNA in blood should not reassure, particularly in patients with symptoms such as abdominal pain, oropharyngeal complaints, neck lumps, and B-symptoms.

Factors associated with major infections in patients with granulomatosis with polyangiitis and systemic lupus erythematosus treated for deep organ involvement.

This study is an audit and a comparison of major infective complications in patients with granulomatosis with polyangiitis (GPA) and systemic lupus erythematosis (SLE). Data were collected on consecutive patients attending a single treatment approach, multidisciplinary vasculitis centre who met diagnostic criteria for GPA and SLE from 01/01/2006 to 30/06/2006. Immunosuppressive treatment is used in this clinic with guidelines targeting avoidance of neutropenia. For each patient, documentation was made of disease presentation, organ involvement and therapy used. A history of major infections requiring hospital admission and intravenous antimicrobials pre- and post-diagnosis was recorded. Patients with GPA received a higher cumulative dose of cyclophosphamide, had a higher median age, shorter period of follow-up and had lower mean and nadir absolute lymphocyte counts and nadir neutrophil counts. GPA patients had more major infections per patient years (P = 0.0027) and respiratory tract infections (P = 0.0031) per patient years. Relative risk (RR) of major infection was significantly increased with methylprednisolone, RR 11.1 (P = <0.0001), cyclophosphamide, RR 2.0 (P = 0.0246) and the intensive phase of treatment, RR 13.3 (P = <0.0001). Marked lymphopenia was common in both groups during follow-up and was associated with an increased risk of major infection (P = 0.0020). Major infections, in particular respiratory tract infections, are more common in those treated for GPA than SLE. This may be due to a combination of factors including greater doses and duration of methyprednisolone and cyclophosphamide. We recommend treatment strategies that aim not only to avoid neutropenia but that also identify lymphopenia as a risk factor for major infection.