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.

Evaluating the Clinical Relevance of Antibodies against Non-Human Leukocyte Antigen in Kidney Transplantation.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher's exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The 'high frequency' non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

Body weight-based initial dosing of tacrolimus in renal transplantation: Is this an ideal approach?

BACKGROUND: Tacrolimus dosing immediately posttransplant is based on body weight. Recent studies have highlighted that the dosing of tacrolimus purely based on weight may not be appropriate, particularly in individuals who are obese. OBJECTIVES: This study aimed to estimate the effect of body mass index (BMI) and the weight-based dosing on tacrolimus trough levels in recipients of renal transplants. DESIGN AND PARTICIPANTS: This study was conducted on 400 of the 863 patients registered in the Salford, UK, renal transplant database between 2012 and 2019 who had complete and analysable datasets. Data were collected at baseline (first tacrolimus trough level after transplantation), after 1 month and 6 months posttransplantation. The cohort was split into three groups based on BMI (kg/m2 ; Group 1 ≤ 25, Group 2 > 25-30 and Group 3 > 30) which were compared with respect to tacrolimus dose, plasma levels and concentration/dose (C/D) ratio at the three-time points. RESULTS: Patients in the higher BMI group (Group 3) had significantly higher baseline tacrolimus trough levels despite receiving a lower initiation dose per kilogram of body weight. After 1 and 6-months posttransplant, the higher BMI group were receiving a significantly lower tacrolimus dose relative to their body weight, with a significant negative correlation between body weight and tacrolimus/kg body weight. There was no adverse relationship evident between tacrolimus dosing or concentration and graft function. CONCLUSIONS: Our study showed that standard dosing of tacrolimus based on body weight in individuals who were obese did not adversely affect their tacrolimus concentrations or transplant function.

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.

Outcomes of peritoneal dialysis patients and switching to hemodialysis: a competing risks analysis.

BACKGROUND: We performed a review of a large incident peritoneal dialysis cohort to establish the impact of current practice and that of switching to hemodialysis. METHODS: Patients starting peritoneal dialysis between 2004 and 2010 were included and clinical data at start of dialysis recorded. Competing risk analysis and Cox proportional hazards model with time-varying covariate (technique failure) were used. RESULTS: Of 286 patients (median age 57 years) followed for a median of 24.2 months, 76 were transplanted and 102 died. Outcome probabilities at 3 and 5 years respectively were 0.69 and 0.53 for patient survival (or transplantation) and 0.33 and 0.42 for technique failure. Peritonitis caused technique failure in 42%, but ultrafiltration failure accounted only for 6.3%. Davies comorbidity grade, creatinine and obesity (but not residual renal function or age) predicted technique failure. Due to peritonitis deaths, technique failure was an independent predictor of death hazard. When successful switch to hemodialysis (surviving more than 60 days after technique failure) and its timing were analyzed, no adverse impact on survival in adjusted analysis was found. However, hemodialysis via central venous line was associated with an elevated death hazard as compared to staying on peritoneal dialysis, or hemodialysis through a fistula (adjusted analysis hazard ratio 1.97 (1.02 - 3.80)). CONCLUSIONS: Once the patients survive the first 60 days after technique failure, the switch to hemodialysis does not adversely affect patient outcomes. The nature of vascular access has a significant impact on outcome after peritoneal dialysis failure.