Use of Tocilizumab in the treatment of chronic active antibody-mediated rejection in pediatric kidney transplant recipients.

Chronic active antibody-mediated rejection is one of the leading causes of graft failure and traditional therapies have unclear efficacy. Recent studies suggested that Tocilizumab could stabilize renal function and improve microvascular inflammation. Here we report the outcomes of Tocilizumab therapy in 6 pediatric kidney transplant recipients with biopsy-proven chronic active antibody-mediated rejection resistant to standard treatments. All patients received monthly Tocilizumab infusions for 6 months and were monitored for renal function (creatinine, estimated glomerular filtration rate (eGFR), proteinuria) and Human Leukocyte Antigens (HLA) and non-HLA antibodies at baseline and 3 and 6 months after Tocilizumab initiation. For each patient, a follow-up biopsy was scheduled at the end of the treatment. Renal function did not show stabilization or improvement (mean eGFR 37 ml/min/1.73 m2 pre-Tocilizumab and 27 ml/min/1.73 m2 3 months after-Tocilizumab) and proteinuria remained stable. Moreover, Tocilizumab had no impact on HLA and non-HLA antibodies. Graft loss was observed in 3 patients (50 %) and 4 patients who underwent post-treatment biopsy showed a worsening in overall chronicity scores. In our pediatric series, rescue therapy with Tocilizumab did not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection.

Calcification of surgical aortic bioprostheses and its impact on clinical outcome.

AIMS: Aortic valve calcification (AVC) of surgical valve bioprostheses (BP) has been poorly explored. We aimed to evaluate in-vivo and ex-vivo BP AVC and its prognosis value. METHODS AND RESULTS: Between 2011 and 2019, AVC was assessed using in-vivo computed tomography (CT) in 361 patients who had undergone surgical valve replacement 6.4±4.3 years earlier. Ex-vivo CT scans were performed for 37 explanted BP. The in-vivo CT scans were interpretable for 342 patients (19 patients [5.2%], were excluded). These patients were 77.2±9.1 years old and 64.3% were male. Mean in-vivo AVC was 307±500 Agatston unit (AU). The AVC was 562±570 AU for the 183 (53.5%) patients with structural valve degeneration (SVD) and 13±43 AU for those without SVD (p<0.0001). In-vivo and ex-vivo AVC were strongly correlated (r=0.88, p<0.0001). An in-vivo AVC>100 AU (n=147, 43%) had a specificity of 96% for diagnosing Stage 2-3 SVD (area under the curve=0.92). Patients with AVC>100 AU had a worse outcome compared with those with AVC≤100 AU (n=195). In multivariable analysis, AVC was a predictor of overall mortality (hazard ratio [HR] and 95% confidence interval=1.16[1.04-1.29]; p=0.006), cardiovascular mortality (HR=1.22[1.04-1.43]; p=0.013), cardiovascular events (HR=1.28 [1.16-1.41]; p<0.0001), and re-intervention (HR=1.15 [1.06-1.25]; p<0.0001). After adjustment for Stage 2-3 SVD diagnosis, AVC remained a predictor of overall mortality (HR=1.20 [1.04-1.39]; p=0.015) and cardiovascular events (HR=1.25 [1.09-1.43]; p=0.001). CONCLUSION: CT scan is a reliable tool to assess BP leaflet calcification. An AVC>100 AU is tightly associated with SVD and it is a strong predictor of overall mortality and cardiovascular events.

Current challenges in xenotransplantation.

PURPOSE OF REVIEW: In recent years, the xenotransplantation science has advanced tremendously, with significant strides in both preclinical and clinical research. This review intends to describe the latest cutting-edge progress in knowledge and methodologies developed to overcome potential obstacles that may preclude the translation and successful application of clinical xenotransplantation. RECENT FINDINGS: Preclinical studies have demonstrated that it is now possible to extend beyond two years survival of primate recipients of life saving xenografts. This has been accomplished thanks to the utilization of genetic engineering methodologies that have allowed the generation of specifically designed gene-edited pigs, a careful donor and recipient selection, and appropriate immunosuppressive strategies.In this light, the compassionate use of genetically modified pig hearts has been authorized in two human recipients and xenotransplants have also been achieved in human decedents. Although encouraging the preliminary results suggest that several challenges have yet to be fully addressed for a successful clinical translation of xenotransplantation. These challenges include immunologic, physiologic and biosafety aspects. SUMMARY: Recent progress has paved the way for the initial compassionate use of pig organs in humans and sets the scene for a wider application of clinical xenotransplantation.

Association of Angiotensin II Receptor Type 1 and Endothelin-1 Receptor Type A Agonistic Autoantibodies With Adverse Remodeling and Cardiovascular Events After Acute Myocardial Infarction.

BACKGROUND: The left ventricular remodeling (LVR) process has limited the effectiveness of therapies after myocardial infarction. The relationship between autoantibodies activating AT1R-AAs (angiotensin II receptor type 1-AAs) and ETAR-AAs (autoantibodies activating endothelin-1 receptor type A) with myocardial infarction has been described. Among patients with ST-segment-elevation myocardial infarction, we investigated the relationship between these autoantibodies with LVR and subsequent major adverse cardiac events. METHODS AND RESULTS: In this prospective observational study, we included 131 patients with ST-segment-elevation myocardial infarction (61±11 years of age, 112 men) treated with primary percutaneous coronary intervention. Within 48 hours of admission, 2-dimensional transthoracic echocardiography was performed, and blood samples were obtained. The seropositive threshold for AT1R-AAs and ETAR-AAs was >10 U/mL. Patients were followed up at 6 months, when repeat transthoracic echocardiography was performed. The primary end points were LVR, defined as a 20% increase in left ventricular end-diastolic volume index, and major adverse cardiac event occurrence at follow-up, defined as cardiac death, nonfatal re-myocardial infarction, and hospitalization for heart failure. Forty-one (31%) patients experienced LVR. The prevalence of AT1R-AAs and ETAR-AAs seropositivity was higher in patients with versus without LVR (39% versus 11%, P<0.001 and 37% versus 12%, P=0.001, respectively). In multivariable analysis, AT1R-AAs seropositivity was significantly associated with LVR (odds ratio [OR], 4.66; P=0.002) and represented a risk factor for subsequent major adverse cardiac events (OR, 19.6; P=0.002). CONCLUSIONS: AT1R-AAs and ETAR-AAs are associated with LVR in patients with ST-segment-elevation myocardial infarction. AT1R-AAs are also significantly associated with recurrent major adverse cardiac events. These initial observations may set the stage for a better pathophysiological understanding of the mechanisms contributing to LVR and ST-segment-elevation myocardial infarction prognosis.