Malignant Transformation of an HNF1a-Inactivated Hepatocellular Adenoma to Hepatocellular Carcinoma

Hepatocellular adenomas (HCA) are rare benign tumors of the liver, occurring predominantly in females using oral contraceptives. Our case describes a 66-year-old woman presenting with a palpable mass in her upper abdomen. Contrast-enhanced computed tomography and magnetic resonance imaging showed a large exophytic mass protruding from the caudal border of liver segments IV and V, without visible metastases. Laparoscopic resection of the tumor and gallbladder was performed. Histopathological examination showed a hepatocellular carcinoma with areas of HNF1a-HCA (H-HCA). This case shows that malignant transformation is possible in H-HCA. We present our preoperative decision-making process, as well as the role of imaging techniques in this rare case

Pretransplant NT-proBNP, Dialysis Vintage, and Posttransplant Mortality in Kidney Transplant Recipients

Background. End-stage kidney disease and dialysis vintage are characterized by accelerated atherosclerosis, volume overload, and progressive left ventricular hypertrophy, leading to elevated N-terminal probrain natriuretic peptide (NT-proBNP) levels. Pretransplant dialysis vintage is associated with excess mortality after transplantation. We want to study whether pretransplant NT-proBNP is associated with posttransplantation mortality and if it explains the association of dialysis vintage with posttransplantation mortality in kidney transplant recipients (KTR). Methods. We measured plasma NT-proBNP on arrival at the hospital before kidney transplantation in 658 KTR between January 1995 and December 2005 in our center. Multivariable Cox regression analyses, adjusted for potential confounders, were used to prospectively study the associations of dialysis vintage and NT-proBNP with all-cause mortality. Results. During median 12.7 (7.8-15.6) years of follow-up after transplantation, 248 (37.7%) KTR died. Dialysis vintage was associated with an increased risk of posttransplant mortality in the fully adjusted model (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.03-1.43; P = 0.02), independent of potential confounders. The association weakened materially and lost significance after further adjustment for NT-proBNP (HR, 1.14; 0.96-1.34; P = 0.14). NT-proBNP was independently associated with all-cause mortality in the fully adjusted model (HR, 1.34; 1.16-1.55; P < 0.001). The association remained independent of adjustment for dialysis vintage (HR, 1.31; 1.13-1.52; P < 0.001). Conclusions. Our study shows that longer dialysis vintage is associated with a higher mortality risk in KTR, and this association might be explained for a considerable part by variation in pretransplant NT-proBNP at the time of transplantation

Variable EBV DNA load distributions and heterogeneous EBV mRNA expression patterns in the circulation of solid organ versus stem cell transplant recipients

Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD) is a heterogeneous and potentially life-threatening condition. Early identification of aberrant EBV activity may prevent progression to B-cell lymphoma. We measured EBV DNA load and RNA profiles in plasma and cellular blood compartments of stem cell transplant (SCT; n = 5), solid organ transplant recipients (SOT; n = 15), and SOT having chronic elevated EBV-DNA load (n = 12). In SCT, EBV DNA was heterogeneously distributed, either in plasma or leukocytes or both. In SOT, EBV DNA load was always cell associated, predominantly in B cells, but occasionally in T cells (CD4 and CD8) or monocytes. All SCT with cell-associated EBV DNA showed BARTs an

Donor genetic variants as risk factors for thrombosis after liver transplantation:A genome-wide association study

Thrombosis after liver transplantation substantially impairs graft‐ and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome‐wide association study (GWAS) and meta‐analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis‐susceptible polymorphisms. By performing a meta‐GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611‐T, p = 4.22 × 10(−05)) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696‐C, p = 2.62 × 10(−05)) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia‐related variants, are associated with increased risk of thrombosis after liver transplantation

Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney

BACKGROUND: The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement activation in active (aABMR). We quantified complement activation markers, C3, C3d, and C5b-9 in plasma of aABMR, and acute T-cell mediated rejection (aTCMR), and non-rejection kidney transplant recipients. Intra-renal complement markers were analyzed as C4d, C3d, C5b-9, and CD59 deposition. We examined in vitro complement activation and CD59 expression on renal endothelial cells upon incubation with human leukocyte antigen antibodies. METHODS: We included 50 kidney transplant recipients, who we histopathologically classified as aABMR (n=17), aTCMR (n=18), and non-rejection patients (n=15). RESULTS: Complement activation in plasma did not differ across groups. C3d and C4d deposition were discriminative for aABMR diagnosis. Particularly, C3d deposition was stronger in glomerular (P<0,01), and peritubular capillaries (P<0,05) comparing aABMR to aTCMR rejection and non-rejection biopsies. In contrast to C3d, C5b-9 was only mildly expressed across all groups. For C5b-9, no significant difference between aABMR and non-rejection biopsies regarding peritubular and glomerular C5b-9 deposition was evident. We replicated these findings in vitro using renal endothelial cells and found complement pathway activation with C4d and C3d, but without terminal C5b-9 deposition. Complement regulator CD59 was variably present in biopsies and constitutively expressed on renal endothelial cells in vitro. CONCLUSION: Our results indicate that terminal complement might only play a minor role in late aABMR, possibly indicating the need to re-evaluate the applicability of terminal complement inhibitors as treatment for aABMR

CUBN as a Novel Locus for End-Stage Renal Disease: Insights from Renal Transplantation

Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p = 0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8–9.2] years (longitudinal study) documenting ESRD in transplanted kidneys – graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p = 0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys

The prevalence of antibodies against the HLA-DRB3 protein in kidney transplantation and the correlation with HLA expression

Human leukocyte antigen (HLA)-DRB3 is a functional HLA class II gene, which has a limited allele diversity in the human population. Furthermore, the HLA-DRB3 gene is only present in a subset of individuals. Therefore, in organ transplantation, this HLA molecule is frequently mismatched between patient and graft donor and thus antibodies against this mismatched HLA molecule can develop. In this study, we aimed to evaluate the prevalence and reactivity of these antibodies and aimed to identify factors that underlie antibody formation against HLA-DRB3. We showed in our patient cohort that HLA-DRB3 antibodies are identified in about 7% of all patients that were screened with solid phase assays. In these assays, we observed multiple antibody reactivity patterns indicating that HLA-DRB3 harbours multiple epitopes. In those cases, where we succeeded at tracing back the induction of these antibodies to the molecular HLA typing of the immunogenic event, we noticed a different frequency of HLA-DRB1 allele groups in the donors as compared to a control group. To a certain extent this distribution (e.g. HLA-DRB1* 11 individuals) could be linked to an altered expression level. However, it also appears that different HLA-DRB3 alleles (e.g. HLA-DRB3* 01 group) vary in their immunogenicity without having an expression difference. In conclusion, our study provides information on the immunogenicity and reactivity patterns of antibodies against HLA-DRB3 in kidney transplantation, and it points towards the possibility of HLA expression as a factor underlying antibody formation

Variable EBV DNA Load Distributions and Heterogeneous EBV mRNA Expression Patterns in the Circulation of Solid Organ versus Stem Cell Transplant Recipients

Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD) is a heterogeneous and potentially lifethreatening condition. Early identification of aberrant EBV activity may prevent progression to B-cell lymphoma. We measured EBV DNA load and RNA profiles in plasma and cellular blood compartments of stem cell transplant (SCT; n = 5), solid organ transplant recipients (SOT; n = 15), and SOT having chronic elevated EBV-DNA load (n = 12). In SCT, EBV DNA was heterogeneously distributed, either in plasma or leukocytes or both. In SOT, EBV DNA load was always cell associated, predominantly in B cells, but occasionally in T cells (CD4 and CD8) or monocytes. All SCT with cell-associated EBV DNA showed BARTs and EBNA1 expression, while LMP1 and LMP2 mRNA was found in 1 and 3 cases, respectively. In SOT, expression of BARTs was detected in all leukocyte samples. LMP2 and EBNA1 mRNA was found in 5/15 and 2/15, respectively, but LMP1 mRNA in only 1, coinciding with severe PTLD and high EBV DNA. Conclusion: EBV DNA is differently distributed between white cells and plasma in SOT versus SCT. EBV RNA profiling in blood is feasible and may have added value for understanding pathogenic virus activity in patients with elevated EBV-DNA

HLA-A*02:07 Is a Protective Allele for EBV Negative and a Susceptibility Allele for EBV Positive Classical Hodgkin Lymphoma in China

HLA-A2 protects from EBV+ classical Hodgkin lymphoma (cHL) in Western Europe, but it is unknown whether this protective effect also exists in the Chinese population. We investigated the association of HLA-A2 and specific common and well documented HLA-A2 subtypes with EBV stratified cHL patients (n = 161) from the northern part of China. Quantitative-PCR and sequence-based subtyping was performed to identify HLA-A2 positive samples and their subtypes. 67 (42%) of the cHL patients were EBV+. There were no significant differences in percentages of HLA-A2 positivity between cHL and controls (65% vs 66%) and between EBV+ and EBV− cHL patients (70% vs 61%). The frequency distribution of HLA-A2 subtypes was significantly different between EBV stratified cHL subgroups and controls. This difference was most striking for the HLA-A*02:07 type with a frequency of 38% in EBV+ cHL, 8% in EBV− cHL and 20% in controls. Significant differences were also observed for the HLA-A*02:07, HLA-A2 (non-02:07) and the A2-negative typings between EBV+ cHL vs controls (p = 0.028), EBV− cHL vs controls (p = 0.045) and EBV+ vs EBV− cHL cases (p = 2×10−5). In conclusion, HLA-A*02:07 is a predisposing allele for EBV+ cHL and a protective allele for EBV− cHL in the northern Chinese population

CCR5Δ32 Genotype Leads to a Th2 Type Directed Immune Response in ESRD Patients

BACKGROUND: In patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5Δ32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5Δ32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated with a more pronounced Th2 type immune response, suggesting that in human CCR5Δ32 carriers the immune response may be more Th2 type directed. So, in the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5Δ32 genetic variant after stimulation. METHODOLOGY/PRINCIPAL FINDINGS: We tested this hypothesis by determining the levels of IFN-γ and IL-4 and the distribution of Th1, Th2 and Th17 directed circulating CD4+ and CD8+ T cells and regulatory T cells (Tregs) after stimulation in ESRD patients with (n = 10) and without (n = 9) the CCR5Δ32 genotype. The extracellular levels of IFN-γ and IL-4 did not differ between CCR5Δ32 carriers and non carriers. However, based on their intracellular cytokine profile the percentages IL-4 secreting CD4+ and CD8+ T cells carrying the CCR5Δ32 genotype were significantly increased (p = 0.02, respectively p = 0.02) compared to non carriers, indicating a more Th2 type directed response. Based on their intracellular cytokine profile the percentages IFN-γ and IL-17 secreting T cells did not differ between carriers and non-carriers nor did the percentage Tregs, indicating that the Th1, Th17 and T regulatory response was not affected by the CCR5Δ32 genotype. CONCLUSIONS/SIGNIFICANCE: This first, functional human study shows a more pronounced Th2 type immune response in CCR5Δ32 carriers compared to non carriers. These differences may be involved in the previously observed protection from inflammation-associated mortality in ESRD patients carrying CCR5Δ32