Showing papers by "Nassim Kamar published in 2020"

Insertions and Duplications in the Polyproline Region of the Hepatitis E Virus.

Abstract: Recombinant strains of hepatitis E virus (HEV) with insertions of human genomic fragments or HEV sequence duplications in the sequence encoding the polyproline region (PPR) were previously described in chronically infected patients. Such genomic rearrangements confer a replicative advantage in vitro but little is known about their frequency, location, or origin. As the sequences of only a few virus genomes are available, we analyzed the complete genomes of 114 HEV genotype 3 strains from immunocompromised (n = 85) and immunocompetent (n = 29) patients using the single molecular real-time sequencing method to determine the frequency, location, and origin of inserted genomic fragments, plus the proportions of variants with genomic rearrangements in each virus quasispecies. We also examined the amino acid compositions and post-translational modifications conferred by these rearrangements by comparing them to sequences without human gene insertions or HEV gene duplications. We found genomic rearrangements in 7/114 (6.1%) complete genome sequences (4 HEV-3f, 1 HEV-3e, 1 HEV-3 h, and 1 HEV-3chi-new), all from immunocompromised patients, and 3/7 were found at the acute phase of infection. Six of the seven patients harbored virus-host recombinant variants, including one patient with two different recombinant variants. We also detected three recombinant variants with genome duplications of the PPR or PPR + X domains in a single patient. All the genomic rearrangements (seven human fragment insertions of varying origins and three HEV genome duplications) occurred in the PPR. The sequences with genomic rearrangements had specific characteristics: increased net load (p < 0.001) and more ubiquitination (p < 0.001), phosphorylation (p < 0.001), and acetylation (p < 0.001) sites. The human fragment insertions and HEV genome duplications had slightly different characteristics. We believe this is the first description of HEV strains with genomic rearrangements in patients at the acute phase of infection; perhaps these strains are directly transmitted. Clearly, genomic rearrangements produce a greater net load with duplications and insertions having different features. Further studies are needed to clarify the mechanisms by which such modifications influence HEV replication.

Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections.

Abstract: Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails.

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study

Abstract: Background Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. Methods Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months. Results After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. Conclusions This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.

Hepatitis E virus replication in human intestinal cells.

Abstract: Objective Hepatitis E virus (HEV), one of the most common agent of acute hepatitis worldwide, is mainly transmitted enterically, via contaminated water for HEV genotypes 1 (HEV1) and HEV2, or by eating raw or undercooked infected meat for HEV genotype 3 (HEV3) and HEV4. However, little is known about how the ingested HEV reaches the liver or its ability to replicate in intestinal cells. Design We developed human primary cultures of small intestine epithelial cells and intestinal explants obtained from small bowel resections. The epithelial cells were also polarised on transwells. Cells were infected with Kernow-p6 strain or clinically derived virions. Results Primary intestinal cells supported the growth of Kernow-p6 strain and HEV1 and HEV3 clinically derived virions. Polarised enterocytes infected with HEV1 and HEV3 strains released HEV particles vectorially: mostly into the apical compartment with a little basally. Iodixanol density gradient centrifugation of enterocyte-derived HEV virions gave bands at a density of 1.06–1.08 g/cm3, corresponding to that of quasi-enveloped HEV particles. Ribavirin therapy inhibited HEV excretion from the basal surface but not from the apical side of infected human enterocytes. HEV virions also infected intestinal tissue explants. Lastly, HEV RNA and antigen were detected in the intestinal crypts of a chronically infected patient. Conclusion HEV can replicate in intestinal cells and reaches the liver as quasi-enveloped virions.

IL6-R blocking with tocilizumab in critically ill patients with hemophagocytic syndrome

Abstract: To the Editor, Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hematological disorder characterized by uncontrolled activation of CD8 T cells and NK cells, cytokine storm (including overproduction of interleukine6 (IL6)), and uncontrolled hemophagocytosis leading to severe organ dysfunction [1]. Several causes of HLH have been identified, including infection, cancer, drugs, and autoimmune diseases [1]. Diagnosis of HLH is challenging, and the H-score may help to better identify patients with reactive HLH [2]. A combination of dexamethasone, etoposide, and treatment of the underlying cause is the cornerstone of treatment for severe forms of HLH [1]. Because some patients may develop refractory or relapsing HLH, alternative treatments targeting specific immune pathways or cytokine signaling have been tested [1]. These approaches also aim to avoid long-lasting etoposide-induced neutropenia in patients with bone marrow failure or after transplantation. Tocilizumab, a monoclonal antibody targeting the receptor of IL6, fully reverses the multi-organ failure and the cytokine profile of the CAR-T cell-induced cytokinerelease syndrome [3]. This prompted some groups including ours to treat severe HLH secondary to acute autoimmune disease with tocilizumab [4]. Targeting one of the major cytokines that orchestrate the cytokine storm may be an alternative to etoposide in patients with HLH not related to hematological malignancies. In the herein study, we reviewed the outcomes of nine critically ill patients who received tocilizumab to treat HLH (Table 1). Eight of them received at least one organ support. Median H-score was 208 (probability of HLH according to the score, 92.5%), and all patients had at least 4 to 7 criteria of the modified 2009 HLH criteria (genetic testing and NK cell activity were not available; sCD25 was tested in one patient). Causes of HLH were multiples: autoimmune diseases in four, infection (bacterial or viral) in three, and idiopathic in two. In addition to tocilizumab (8mg/kg once, intravenously), five patients received concomitant treatment with dexamethasone (n = 4), cyclophosphamide (n = 2), or intravenous immunoglobulins (n = 1). Remission was observed in 8/9 patients after tocilizumab (88.9%) whereas one developed refractory HLH, also unresponsive to rescue therapy with etoposide. Ferritin progressively decreased over the first 2 weeks (Fig. 1). One patient relapsed during the hospitalization and successfully received etoposide, but she ultimately died from unrelated gut ischemia. No patient developed profound neutropenia (< 500 cells/mm), except one who had also received cyclophosphamide. During the hospitalization, four patients died (sepsis-related multi-organ failure n = 1; refractory HLH n = 1; organ support limitation n = 2). None developed HLH relapse beyond the current hospitalization. Cytomegalovirus prophylaxis was pursued at least 3months in transplant recipients. In critically ill patients with severe forms of HLH, etoposide rapidly reverses cytokine storm and improves

Tocilizumab for Hemophagocytic Syndrome in a Kidney Transplant Recipient With COVID-19.

Abstract: Transplant Recipient With COVID-19 Background: A subset of patients with coronavirus disease 2019 (COVID-19) will develop acute respiratory distress syndrome and require mechanical ventilation. Studies suggest that many patients with COVID-19 and acute respiratory distress syndrome experience a cytokine storm characterized by fever; hyperferritinemia; and a massive release of inflammatory cytokines, including interleukin-6, tumor necrosis factor, and monocyte chemoattractant proteins (1). These findings led to the hypothesis that biological agents targeting specific cytokine or inflammatory pathways may improve the respiratory outcomes of patients with the most severe forms of COVID-19 (2). Objective: To describe a patient with COVID-19 and overt hemophagocytic syndrome whose response to treatment was consistent with this hypothesis. Case Report: A 51-year-old man who had received a kidney transplant was referred to our intensive care unit for cough, fever, and shortness of breath leading to the presumptive diagnosis of COVID-19. On day 1, acute respiratory failure required mechanical ventilation and prone positioning. Therapy with dexamethasone (5 mg twice daily), ceftriaxone (2 g/d), and spiramycin (1.5 million units 3 times daily) was initiated. Tacrolimus and mycophenolate mofetil were withdrawn. On day 2, the patient developed refractory multiorgan failure characterized by an inflammatory state, heart failure, stage 3 acute-on-chronic kidney injury, acute liver failure, nonregenerative anemia, thrombocytopenia, and lactic acidosis. The C-reactive protein level was 262 mg/L, and the ferritin level was 52 005 μg/L. We considered a diagnosis of hemophagocytic syndrome because the patient had underlying immunosuppression; fever (temperature, 39 °C); a serum ferritin level above 6000 μg/L; a hemoglobin level below 92 g/L; a platelet count below 110 × 10 cells/L; high levels of serum triglycerides; and aspartate aminotransferase with an HScore of 253, which indicated that the probability of having hemophagocytic syndrome was 99.5% (3). Bone marrow aspiration and liver biopsy confirmed the presence of hemophagocytosis (Figure). Polymerase chain reaction identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in bronchoalveolar fluid (cycle threshold 21) and blood. Given the salutary effects of interleukin-6 receptor inhibition in the treatment of secondary hemophagocytic syndromes (4) and chimeric antigen receptor T-cell–related cytokine release syndromes (5), we treated the patient with tocilizumab (8 mg/kg intravenously, once) as salvage therapy, instead of etoposide, and we withdrew dexamethasone. Tocilizumab administration was followed by dramatic improvement of the respiratory, hemodynamic, and liver conditions and correction of the ferritin levels (Table). Three days after tocilizumab administration, we observed normalization of circulating levels of CD3 CD16 CD56 natural killer cells and effector CD8 CD56 and CD8 CD57 perforin-positive, granzyme-positive T cells. Discussion: In this report, we describe an immunocompromised patient with COVID-19 and a related hemophagocytic syndrome whom we treated with tocilizumab. The cytokine storm and multiorgan failure rapidly reversed, and the patient made a speedy recovery. On hospital day 30, the LETTERS

Does HEV-3 subtype play a role in the severity of acute hepatitis E?

Abstract: Hepatitis E virus genotype 3 (HEV-3) is a major aetiologic agent of acute hepatitis in industrialized countries. Two main HEV-3 subtypes are found in Europe: subtypes 3c and 3f. We have analysed the clinical and biological parameters from 100 French immunocompetent patients with an HEV subtype 3f or subtype 3c infection, included in a prospective multicentre study. Stepwise regression analysis found that infections with HEV subtype 3f were associated with fever (OR: 6.1 95%CI: 1.4-26.1), have a greater virus load (OR: 7.4; 95%CI: 1.3-42.2) and require more frequent hospitalization (OR: 7.6; 95%CI: 1.1-51.4) than those infected with subtype 3c. The directed acyclic graph strengthens the multivariate analyses indicating a direct link between the HEV subtype, HEV RNA concentration, fever and hospitalization. Further studies on patients in other European countries are needed to confirm this relationship and determine the underlying mechanism.

Long-Term Kidney Transplant Outcomes: Role of Prolonged-Release Tacrolimus.

Abstract: Tacrolimus has significantly improved outcomes for kidney transplant patients and remains the cornerstone of immunosuppressive therapy. While improvements in short-term outcomes in transplantation have been achieved in recent years, maintaining long-term graft survival remains a challenge in kidney transplantation. Minimizing risk factors for poor long-term kidney graft function and survival, and modifying tacrolimus regimens in the early and maintenance phases post-transplantation are essential to maintain long-term kidney transplant outcomes. Tacrolimus has a narrow therapeutic window, resulting in a tightly defined range of optimal drug exposure. Underimmunosuppression is associated with long-term risks, such as the development of donor-specific antibodies and antibody-mediated rejection, with a high possibility of a decline in kidney function and progression to graft failure. Conversely, prolonged overimmunosuppression carries a risk of drug-related adverse events. This review provides an overview of the differences in the formulation, delivery, and pharmacokinetic profiles between immediate- and prolonged-release tacrolimus and evaluates the effect of prolonged-release tacrolimus on the risk factors for poor outcomes in kidney transplantation. Recent evidence is used to provide guidance on target tacrolimus trough levels in the early and maintenance phases post-transplantation, with a view to improving long-term kidney graft function.

An extension of the RITUX‐ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody‐mediated rejection after renal transplantation

Abstract: The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.

Prospects for improved glomerular filtration rate estimation based on creatinine-results from a transnational multicentre study.

Abstract: Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved.MethodsIn a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmo revised equation (LMR) and the Full Age Spectrum equation.Results7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%.ConclusionsNone of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated. (Less)

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients

Abstract: The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Validation of a Capillary Dry Blood Sample MITRA-Based Assay for the Quantitative Determination of Systemic Tacrolimus Concentrations in Transplant Recipients.

Abstract: Background Tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dosing based on systemic exposure. MITRA microsampling offers a convenient, minimally invasive approach for the collection of capillary blood samples from a finger prick versus conventional venous blood sampling for quantitation of tacrolimus blood concentrations. However, the suitability of MITRA microsampling for the determination of tacrolimus concentrations requires assessment in clinical settings. Methods Paired venous (2 mL) and capillary (10 μL) blood samples were collected pre-tacrolimus dose and 1 and 3 hours postdose during routine outpatient visits from stable adult liver or kidney transplant patients receiving prolonged-release tacrolimus. Tacrolimus concentrations were determined by liquid chromatography-tandem mass spectrometry, and the concentrations obtained by the 2 sampling methods were compared by linear regression and Bland-Altman agreement analyses. Results Samples were available for 82 transplant recipients (kidney, n = 41; liver, n = 41). A high correlation was observed between tacrolimus concentrations in capillary and venous blood samples (Pearson correlation coefficient, 0.97; Lin concordance coefficient, 0.87; slope of the fitted line, >1.0). Tacrolimus concentrations in capillary samples were 22.5% higher on average than in the corresponding venous blood samples (95% limits of agreement, 0.5%-44.6%). Similar results were observed in both transplant subgroups. Conclusions MITRA finger prick sampling provides a convenient alternative to venipuncture for therapeutic drug monitoring in transplant recipients maintained on prolonged-release tacrolimus. When using the finger prick MITRA method, the positive bias in tacrolimus concentrations observed with this technique, when compared with venipuncture, needs to be taken into consideration.

T cell reconstitution after lymphocyte depletion features a different pattern of inhibitory receptor expression in ABO- versus HLA-incompatible kidney transplant recipients.

Abstract: Chronic antigen stimulation can lead to immune exhaustion (a state of T cell dysfunction). Several phenotypical signatures of T cell exhaustion have been described in various pathological situations, characterized by aberrant expression of multiple inhibitory receptors (IR). This signature has been barely studied in the context of allogenic organ transplantation. We undertook a cross-sectional analysis of the expression of IR [CD244, CD279, T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) and CD57] and their correlation with cytokine-producing functions in T cells reconstituting after lymphocyte depletion in patients transplanted from living donors, with preformed donor-specific antibodies. After ABO incompatible transplantation, T cells progressively acquired a phenotype similar to healthy donors and the expression of several IR marked cells with increased functions, with the exception of TIGIT, which was associated with decreased cytokine production. In stark contrast, T cell reconstitution in patients with anti-human leukocyte antigen (HLA) antibodies was characterized with an increased co-expression of IR by T cells, and specifically by an increased expression of TIGIT. Furthermore, expression of these receptors was no longer directly correlated to cytokine production. These results suggest that T cell alloreactivity in HLA-incompatible kidney transplantation drives an aberrant T cell reconstitution with respect to IR profile, which could have an impact on the transplantation outcome.

Outcomes of solid organ transplant recipients with invasive aspergillosis and other mold infections.

Abstract: Objectives To characterize the clinical presentation and outcomes of invasive mold infections (IMI) in solid organ transplant (SOT) recipients. Methods Inclusion of all SOT recipients with IMI diagnosed between 2008 and 2016 at a referral center for SOT. Univariable analyses identified factors associated with death at one year, and logistic regression models retained independent predictors. Results Of the 1739 patients that received a SOT during this period, 68 developed IMI (invasive aspergillosis [IA] in 58). Cumulative incidence of IMI at 1 year ranged from 1.2% to 18.8% (kidney and heart transplantation, respectively). At baseline, compared with other IMI, the need for vasoactive drugs was more frequent in patients with IA. During follow-up, 35 patients (51%) were admitted to the ICU and required mechanical ventilation (n = 27), vasoactive drugs (n = 31), or renal replacement therapy (n = 31). The need for vasoactive drugs (OR 7.34; P = .003) and a positive direct examination (OR 10.1; P = .004) were independently associated with the risk of death at 1 year in patients with IA (n = 33; 57%) CONCLUSIONS: Characteristics of IMI at presentation varied according to the underlying transplanted organ and the mold species. Following IA, one-year mortality may be predicted by the need for hemodynamic support and initial fungal load.

Living-donor kidney transplantation: comparison of sequential and simultaneous surgical organizations.

Abstract: The objective of this study was to compare living-donor kidney transplantation (LDKT) performed either sequentially, in one operating room, leading to extended cold ischemia time (CIT) or simultaneously, in two different operating room, with shorter CIT. We retrospectively included all living-donor nephrectomies and kidney transplantations, performed from March 2010 to March 2014, in three French university centers. In the first one (C1), LDKTs were performed in sequential manner (Sequential group) and in C2 and C3, LDKTs were performed in simultaneous manner (Simultaneous group). A total of 324 LDKT were performed: 176 LDKT in Sequential group and 148 LDKT in Simultaneous group. Patients characteristics were equivalent between groups, except nephrectomy side, ABO mismatch rate and previous kidney transplantation rate. CIT, rewarming time, transfusion and delayed graft function (DGF) were significantly higher in Sequential group. Overall survival and graft survival of kidney transplant recipients were similar in the Sequential and Simultaneous groups. 5-year eGFR was similar between groups. In univariate analysis, number of graft arteries, recipient BMI, previous kidney transplantation status and CIT were significant predictors of DGF. Only previous kidney transplantation status was an independent predictive factor of DGF in the multivariate analysis. Sequential surgical organization results in the same functional results as simultaneous surgical organization. DGF was higher for LDKT performed sequentially but at 5-year overall survival, graft survival and eGFR were similar between these two types of transplant organizations.

Benign Prostatic Hyperplasia Endoscopic Surgical Procedures in Kidney Transplant Recipients: A Comparison Between Holmium Laser Enucleation of the Prostate, GreenLight Photoselective Vaporization of the Prostate, and Transurethral Resection of the Prostate.

Abstract: Purpose: The main objective of this multicentric retrospective pilot study was to evaluate the 1-year follow-up safety (i.e., minor [Clavien–Dindo I–II] and major [Clavien–Dindo ≥III] complications...

The FcγRIIIA-158 VV genotype increased the risk of post-transplant lymphoproliferative disorder in T-cell-depleted kidney transplant recipients - a retrospective study.

Abstract: Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication in organ transplant recipients. The use of T lymphocyte-depleting antibodies (TLDAb), especially rabbit TLDAb, contributes to PTLD, and the V158F polymorphism of Fc gamma receptor IIIA (FcγRIIIA) also named CD16A could affect the concentration-effect relationship of TLDAb. We therefore investigated the association of this polymorphism with PTLD in kidney transplant recipients. We characterized the V158F polymorphism in two case-control cohorts (discovery, n = 196; validation, n = 222). Then, we evaluated the binding of rabbit IgG to human FcγRIIIA-158V and FcγRIIIA-158F. The V158F polymorphism was not linked to PTLD in the overall cohorts, but risk of PTLD was increased in VV homozygous recipients receiving TLDAb compared with F carriers in both cohorts, especially in recipients receiving TLDAb without muromonab (discovery: HR = 2.22 [1.03-4.76], P = 0.043, validation: HR = 1.75 [1.01-3.13], P = 0.049). In vitro, we found that the binding of rabbit IgG to human NK-cell FcγRIIIA was increased when cells expressed the 158-V versus the 158-F allotype. While the 158-V allotype of human FcγRIIIA binds rabbit immunoglobulin-G with higher affinity, the risk of PTLD was increased in homozygous VV kidney transplant recipients receiving polyclonal TLDAb.

Cardiac impact of arteriovenous fistulas: what tools to assess?

Abstract: The relationship between arteriovenous access flow (Qa) and cardiovascular changes is complex. Several studies have shown cardiac remodeling and symptoms of heart failure for high-flow arteriovenous fistulas (AVF). To evaluate the early cardiovascular impact of AVF. Forty-seven patients with an AVF, hospitalized for the evaluation of high-flow AVF or a pre-kidney transplant assessment were included. We collected clinical and biological data. We also collected data of the assessment by transthoracic echocardiography, functional evaluation by 6-min-walk test and peak oxygen consumption, and measurement of coronary flow reserve by dynamic myocardial perfusion imaging. The measurement of Qa was performed by color Doppler ultrasound and then indexed to the body surface area (Qai) and to the cardiac output (CO) (Qa/CO). Patients were poorly symptomatic (18 and 1 patients NYHA stage 2 and 3, respectively). There was no correlation between Qa, Qai, or Qa/CO and functional status, assessed by peak oxygen consumption (P = 0.891; P = 0.803; P = 0.939, respectively). Symptomatic patients did not have higher Qa, Qai or Qa/CO than asymptomatic (2260 vs 2197 mL/min, P = 0.402; 1257 vs 1256 mL/min/m2, P = 0.835; and 34% vs 37%, P = 0.701, respectively). There was no correlation between Qa, Qai or Qa/CO and left ventricular end-diastolic volume or left ventricular ejection fraction. There was no correlation between coronary flow reserve and these 3 parameters of vascular access flow. However, the global longitudinal strain (GLS) was correlated with Qa and Qa/CO (R = 0.331, P = 0.023 and R = 0.380, P = 0.008, respectively). Increase of Qa or Qa/CO was associated with an alteration of the GLS. A cut-off value of 2250 mL/min for Qa allowed 83% sensitivity and 63% specificity for detecting an alteration of the GLS > − 18%. A cut-off value of 33% for Qa/CO allowed 92% sensitivity and 65% specificity. Impact of AVF on cardiac parameters is weak. However, GLS is the first parameter to be impacted by the flow of the fistula. Systematic transthoracic echocardiography evaluation with measurement of GLS should be proposed for all patients with Qa > 2250 mL/min or Qa/CO > 33%, to detect those at higher risk of cardiac impact of the AVF.