mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients.

Kidney transplant recipients (KTRs) have been considered as patients at higher risk of SARS-CoV-2-related disease severity, thus COVID-19 vaccination was highly recommended. However, possible interferences of different immunosuppression with development of both humoral and T cell-mediated immune response to COVID-19 vaccination have not been determined. Here we evaluated the association between mTOR-inhibitors (mTOR-I) and immune response to mRNA BNT162b2 (Pfizer-BioNTech) vaccine in KTR. To this aim 132 consecutive KTR vaccinated against COVID-19 in the early 2021 were enrolled, and humoral and T cell-mediated immune response were assessed after 4-5 weeks. Patients treated with mTOR-I showed significantly higher anti-SARS-CoV-2 IgG titer (p = .003) and higher percentages of anti-SARS-CoV-2 S1/RBD Ig (p = .024), than those without. Moreover, SARS-CoV-2-specific T cell-derived IFNγ release was significantly increased in patients treated with mTOR-I (p < .001), than in those without. Multivariate analysis confirmed that therapy with mTOR-I gained better humoral (p = .005) and T cell-mediated immune response (p = .005) in KTR. The presence of mTOR-I is associated with a better immune response to COVID-19 vaccine in KTR compared to therapy without mTOR-I, not only by increasing vaccine-induced antibodies but also by stimulating anti-SARS-CoV-2 T cell response. These finding are consistent with a potential beneficial role of mTOR-I as modulators of immune response to COVID-19 vaccine in KTR.

Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies.

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.

Iliac Pseudoaneurysm, Only a Manifestation With More Causes: A Case Report.

Pseudoaneurysm is due to a disruption in arterial wall continuity. It forms a sac that communicates with the vessel lumen and is surrounded by the compressed, surrounding tissues and not by the wall of the artery from which the lesion arises. Many causes can predispose to the formation of a pseudoaneurysm such as trauma, surgical procedures, anticoagulation. In our patient another important risk factor for the formation of a pseudoaneurysm is ADPKD (autosomal dominant polycystic kidney disease) that can cause vascular complication. The mechanisms leading to the genesis of the pseudoaneurysms in our patient are unknown, but the clinicians should bear in mind when evaluating this type of patients that ADPKD may have a various range of systemic cardiovascular manifestation.

Rapamycin Inhibitors for Eye Squamous Cell Carcinoma after Renal Transplantation: A Case Report.

INTRODUCTION: The immunosuppressive efficiency obtained in the last decades in kidney transplantation significantly improved graft survival. However, there is still a high risk and incidence of cancer in transplant patients strongly and directly related to the type of immunosuppression. An increasing body of evidence suggests that the PI3K/Akt/mTOR pathway may play a pivotal role in the development and progression of several neoplastic diseases. CASE PRESENTATION: We describe a 47-year-old male patient who received a cadaveric primary renal transplant in November 2008 developing a poorly differentiated infiltrating and ulcerated squamous cell carcinoma (SCC) at the eye level. In this patient, the modification of an immunosuppressive regimen with introduction of rapamycin (mTOR) inhibitors and withdrawal of calcineurin inhibitors (CNIs) led to the resolution of this severe condition. CONCLUSION: The introduction of mTOR inhibitors and withdrawal of CNIs in kidney-transplanted patients with de novo eye SCC should be considered in this clinical setting.

Local device infection successfully treated without pacemaker removal in a neonate: a case report.

AIMS: Local device infection is a serious complication, especially in neonates. Complete device removal is the gold standard treatment for cardiac device infection; however, in selected cases alternative strategies could be adopted. We describe a case of a 14-day-old neonate, weighing 2.5kg, who had undergone epicardial double chamber pacemaker implantation for a congenital complete atrioventricular block. The generator pocket was created in the epigastric area below the rectus abdominis. At six days after implantation, pocket infection was found; blood cultures and the transoesophageal echocardiogram were normal. Due to the low weight of the neonate, and the limited possibility of finding a new comfortable site for housing the generator far from the infected area, we opted for a conservative strategy. We successfully applied a combination of antibiotic therapy, a vacuum-assisted wound closure system (KCI, Germany) for 40 days, and then skin transfer flap from the right flank without device removal. At one-year follow-up there were no local or systemic signs of infection.

Recurrent Glomerulonephritis after Renal Transplantation: The Clinical Problem.

Glomerulonephritis (GN) continues to be one of the main causes of end-stage kidney disease (ESKD) with an incidence rating from 10.5% to 38.2%. Therefore, recurrent GN, previously considered to be a minor contributor to graft loss, is the third most common cause of graft failure 10 years after renal transplantation. However, the incidence, pathogenesis, and natural course of recurrences are still not completely understood. This review focuses on the most frequent diseases that recur after renal transplantation, analyzing rate of recurrence, epidemiology and risk factors, pathogenesis and bimolecular mechanisms, clinical presentation, diagnosis, and therapy, taking into consideration the limited data available in the literature. First of all, the risk for recurrence depends on the type of glomerulonephritis. For example, recipient patients with anti-glomerular basement membrane (GBM) disease present recurrence rarely, but often exhibit rapid graft loss. On the other hand, recipient patients with C3 glomerulonephritis present recurrence in more than 50% of cases, although the disease is generally slowly progressive. It should not be forgotten that every condition that can lead to chronic graft dysfunction should be considered in the differential diagnosis of recurrence. Therefore, a complete workup of renal biopsy, including light, immunofluorescence and electron microscopy study, is essential to provide the diagnosis, excluding alternative diagnosis that may require different treatment. We will examine in detail the biomolecular mechanisms of both native and transplanted kidney diseases, monitoring the risk of recurrence and optimizing the available treatment options.

Dendritic Cells: A Bridge between Tolerance Induction and Cancer Development in Transplantation Setting.

Dendritic cells (DCs) are a heterogeneous group of antigen-presenting cells crucial for fostering allograft tolerance while simultaneously supporting host defense against infections and cancer. Within the tumor microenvironment, DCs can either mount an immune response against cancer cells or foster immunotolerance, presenting a dual role. In immunocompromised individuals, posttransplant malignancies pose a significant health concern, with DCs serving as vital players in immune responses against cancer cells. Both recipient- and donor-derived DCs play a critical role in the rejection process, infiltrating the transplanted organ and sustaining T-cell responses. The use of immunosuppressive drugs represents the predominant approach to control this immunological barrier in transplanted organs. Evidence has shed light on the immunopharmacology of these drugs and novel strategies for manipulating DCs to promote allograft survival. Therefore, comprehending the mechanisms underlying this intricate microenvironment and the effects of immunosuppressive therapy on DCs is crucial for developing targeted therapies to reduce graft failure rates. This review will delve into the fundamental immunobiology of DCs and provide a detailed exploration of their clinical significance concerning alloimmune responses and posttransplant malignancies.

Hypoxic Inducible Factor Stabilization in Pericytes beyond Erythropoietin Production: The Good and the Bad.

The paracrine signaling pathways for the crosstalk between pericytes and endothelial cells are essential for the coordination of cell responses to challenges such as hypoxia in both healthy individuals and pathological conditions. Ischemia-reperfusion injury (IRI), one of the causes of cellular dysfunction and death, is associated with increased expression of genes involved in cellular adaptation to a hypoxic environment. Hypoxic inducible factors (HIFs) have a central role in the response to processes initiated by IRI not only linked to erythropoietin production but also because of their participation in inflammation, angiogenesis, metabolic adaptation, and fibrosis. While pericytes have an essential physiological function in erythropoietin production, a lesser-known role of HIF stabilization during IRI is that pericytes' HIF expression could influence vascular remodeling, cell loss and organ fibrosis. Better knowledge of mechanisms that control functions and consequences of HIF stabilization in pericytes beyond erythropoietin production is advisable for the development of therapeutic strategies to influence disease progression and improve treatments. Thus, in this review, we discuss the dual roles-for good or bad-of HIF stabilization during IRI, focusing on pericytes, and consequences in particular for the kidneys.

Safety and efficacy of tixagevimab/cilgavimab for pre-exposure prophylaxis in kidney transplant recipients: a multicenter retrospective cohort study.

BACKGROUND: Immunocompromised patients show an impaired vaccine response and remain at high risk of severe COVID-19, despite vaccination. Neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed for prophylaxis and treatment. The combination tixagevimab/cilgavimab (AZD7442) has been authorized for emergency use as pre-exposure prophylaxis for COVID-19, but data on safety and efficacy in kidney transplant recipients during the Omicron period are limited. METHODS: We conducted a multicenter retrospective cohort study including 253 kidney transplant recipients, of whom 98 were treated with tixagevimab/cilgavimab 150 mg/150 mg and 155 who received only four doses of the BNT162b2 mRNA vaccine. RESULTS: Only 13.3% of patients developed SARS-CoV-2 infection after the administration of tixagevimab/cilgavimab; in comparison, 34.2% of patients had been infected after the fourth dose of vaccine (p = 0.00013). Most infected patients in the AZD7442 group remained asymptomatic (92.3% vs 54.7%), 7.7% had mild symptoms and none had severe disease, need for hospitalization or died, while in the control group, 9.4% of patients had moderate or severe disease (p = 0.04). Using Kaplan-Meier curves we demonstrated that the controls presented early infection compared to the AZD7442 group (p = 0.000014). No changes in eGFR or proteinuria, assessed before and after the administration, were observed. CONCLUSIONS: In conclusion, our study showed that tixagevimab/cilgavimab 150/150 mg is effective and safe in preventing infection and severe disease when administered to patients with weak or no response to COVID-19 vaccine.

mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation.

The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.

Hypoxic State of Cells and Immunosenescence: A Focus on the Role of the HIF Signaling Pathway.

Hypoxia activates hypoxia-related signaling pathways controlled by hypoxia-inducible factors (HIFs). HIFs represent a quick and effective detection system involved in the cellular response to insufficient oxygen concentration. Activation of HIF signaling pathways is involved in improving the oxygen supply, promoting cell survival through anaerobic ATP generation, and adapting energy metabolism to meet cell demands. Hypoxia can also contribute to the development of the aging process, leading to aging-related degenerative diseases; among these, the aging of the immune system under hypoxic conditions can play a role in many different immune-mediated diseases. Thus, in this review we aim to discuss the role of HIF signaling pathways following cellular hypoxia and their effects on the mechanisms driving immune system senescence.

A large basal left ventricular pseudoaneurysm following pediatric cardiac surgery.

Left ventricular pseudoaneurysm (LV-PSA) is a rare complication in children, usually developing after cardiac surgery, percutaneous procedures, infections, or trauma. Herein, we report a case of large basal submitral LV-PSA in a 36-day-old baby, detected 26 days after cardiac operation for hypoplastic arch, aortic coarctation, and small ventricular septal defect. No complications occurred in the first postoperative course, and early postoperative echocardiograms were normal. Despite large dimension of pseudoaneurysm, the baby presented with only mild tachypnea. The baby was successfully operated. Pseudoaneurysm, besides rare, could have an extremely broad and insidious clinical presentation and had to be considered in post-cardiac surgery follow-up echocardiogram at any time lapse.

Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus.

Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.

Nutrition-Based Management of Inflammaging in CKD and Renal Replacement Therapies.

Access to renal transplantation guarantees a substantial improvement in the clinical condition and quality of life (QoL) for end-stage renal disease (ESRD) patients. In recent years, a greater number of older patients starting renal replacement therapies (RRT) have shown the long-term impact of conservative therapies for advanced CKD and the consequences of the uremic milieu, with a frail clinical condition that impacts not only their survival but also limits their access to transplantation. This process, referred to as "inflammaging," might be reversible with a tailored approach, such as RRT accompanied by specific nutritional support. In this review, we summarize the evidence demonstrating the presence of several proinflammatory substances in the Western diet (WD) and the positive effect of unprocessed food consumption and increased fruit and vegetable intake, suggesting a new approach to reduce inflammaging with the improvement of ESRD clinical status. We conclude that the Mediterranean diet (MD), because of its modulative effects on microbiota and its anti-inflammaging properties, may be a cornerstone in a more precise nutritional support for patients on the waiting list for kidney transplantation.

Unusual association of transposition of great arteries with infradiaphragmatic pulmonary venous return.

A 21-day-old baby with transposition of the great arteries with intact ventricular septum, infradiaphragmatic totally anomalous pulmonary venous connection, and atrial septum defect underwent combined arterial switch operation, totally anomalous venous connection repair, and atrial septum defect closure, using a right-sided approach and temporary pulmonary veins occlusion, with no postoperative and 6-months follow-up complications. Complete anatomical correction is the most conceivable treatment for this unusual pathology; right-sided approach instead lifting the heart toward the right pleural cavity to perform left atrium-to-pulmonary veins anastomosis limits heart displacement and avoids nonphysiological three-dimensional alterations; moreover, ligation and division of vertical vein allow to obtain more tissue for anastomosis; temporary occlusion of pulmonary veins while performing anastomosis is a simple procedure that allows to avoid deep hypothermic circulatory arrest or low flow systemic perfusion. Combination of these details facilitates intra- and postoperative management, especially in combined demanding cases.

Biochemical composition and in vitro digestibility of Galdieria sulphuraria grown on spent cherry-brine liquid.

The aim of this work was to valorise an industrial food by-product and to produce a microalgal biomass rich in phytochemicals at high added value for food and nutraceutical applications. The biochemical composition, in vitro digestibility and antioxidant activity of Galdieria sulphuraria biomass grown heterotrophically on standard medium (SM) and on spent Cherry-Brine Liquid (sCBL) were assessed and compared. The biomass produced in sCBL was characterized by a lower content of proteins and lipids, while showing an increase in carbohydrates and polyphenols (5.3 vs 1.6 mg g-1). The sCBL biomass lipid moiety had a lower palmitic and linoleic acid content and a higher oleic acid concentration than SM. The total protein digestibility of Galdieria grown in SM and sCBL was 79% and 63% respectively. The antioxidant activity (AA) of G. sulphuraria biomass grown in sCBL was significantly higher than that grown in SM. Studying the AA release for sCBL biomass during the digestion, the highest value was found in the intestinal phase. In conclusion, G. sulphuraria has a valuable nutritional profile and could become a valuable source of phytochemicals, depending on the cultivation media. Cultivation on sCBL would allow an environmentally and economically sustainable process, valorising the food by-product and producing a microalgal biomass rich in cherry anthocyanins with high AA released at the intestinal level.

Inversion of the left atrial appendage following cardiac surgery.

Inversion of the left atrial appendage is a rare complication after open-heart surgery. To our knowledge only 16 cases, besides that reported herein, have been described so far. Echocardiographically, the inverted left atrial appendage appears as a mass mimicking a thrombus, a vegetation or a tumor of the left atrium. Lack of awareness of this entity can result in a misdiagnosis and unnecessary procedures. The case here reported deals with an inverted left atrial appendage occurring in an infant after repair of an atrial septal defect.

[Immature intrapericardial teratoma: a case report in a newborn]. / Teratoma immaturo intrapericardico: un caso clinico in un neonato.

We report the case of an intrapericardial teratoma, diagnosed at 38 weeks of gestation. Echocardiography revealed a 38 x 39 mm multicystic pedunculated mass compressing the right atrium and the right ventricle, but without symptoms, associated with severe anterior pericardial effusion. Surgical resection of the mass was performed after birth successfully. The histological description of the tumor after excision was reported an immature multicystic teratoma grade 2 of 3, with immature neural tissue and without yolk sac tumor cells. The baby had a favorable postoperative course.