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.

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.

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.

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.

Acute Kidney Injury in Kidney Transplant Patients in Intensive Care Unit: From Pathogenesis to Clinical Management.

Kidney transplantation is the first-choice treatment for end-stage renal disease (ESRD). Kidney transplant recipients (KTRs) are at higher risk of experiencing a life-threatening event requiring intensive care unit (ICU) admission, mainly in the late post-transplant period (more than 6 months after transplantation). Urosepsis and bloodstream infections account for almost half of ICU admissions in this population; in addition, potential side effects related to immunosuppressive treatment should be accounted for cytotoxic and ischemic changes induced by calcineurin inhibitor (CNI), sirolimus/CNI-induced thrombotic microangiopathy and posterior reversible encephalopathy syndrome. Throughout the ICU stay, Acute Kidney Injury (AKI) incidence is common and ranges from 10% to 80%, and up to 40% will require renal replacement therapy. In-hospital mortality can reach 30% and correlates with acute illness severity and admission diagnosis. Graft survival is subordinated to baseline estimated glomerular filtration rate (eGFR), clinical presentation, disease severity and potential drug nephrotoxicity. The present review aims to define the impact of AKI events on short- and long-term outcomes in KTRs, focusing on the epidemiologic data regarding AKI incidence in this subpopulation; the pathophysiological mechanisms underlying AKI development and potential AKI biomarkers in kidney transplantation, graft and patients' outcomes; the current diagnostic work up and management of AKI; and the modulation of immunosuppression in ICU-admitted KTRs.

The risks associated with percutaneous native kidney biopsies: a prospective study.

BACKGROUND: The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. METHODS: The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. RESULTS: Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08-1.17], liver disease (OR 2.27, 95% CI 1.21-4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07-1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92-0.99) were protective. CONCLUSIONS: This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

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.

Pre-Transplant Expression of CCR-2 in Kidney Transplant Recipients Is Associated With the Development of Delayed Graft Function.

Background: Delayed graft function (DGF) leads to a reduced graft survival. Donors' features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the recipients' characteristics in the development of DGF. Methods: We enrolled 932 kidney graft recipients from 466 donors; 226 recipients experienced DGF. In 290 donors, both recipients presented with early graft function (EGF, group A), in 50 both recipients experienced DGF (group B), and in 126 one recipient presented with DGF and the other with EGF (group C). In group C, we selected 7 couples of DGF/EGF recipients and we evaluated the transcriptomic profile by microarray on circulating mononuclear cells harvested before transplantation. Results were validated by qPCR in an independent group of 25 EGF/DGF couples. Findings: In the whole study group, DGF was associated with clinical characteristics related to both donors and recipient. In group C, DGF was significantly associated with body mass index, hemodialysis, and number of mismatches. In the same group, we identified 411 genes differently expressed before transplantation between recipients discordant for the transplant outcome. Those genes were involved in immune dysfunction and inflammation. In particular, we observed a significant increase in DGF patients in the expression of C-C chemokine receptor type 2 (CCR2), the monocyte chemoattractant protein-1 (MCP-1) receptor. CCR-2 upregulation was confirmed in an independent cohort of patients. Conclusions: Our results suggest that recipients' clinical/immunological features, potentially modulated by dialysis, are associated with the development of DGF independently of donors' features.

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.

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.

Role of Complement in Regulating Inflammation Processes in Renal and Prostate Cancers.

For decades, the complement system, the central pillar of innate immune response, was recognized as a protective mechanism against cancer cells and the manipulation of complement effector functions in cancer setting offered a great opportunity to improve monoclonal antibody-based cancer immunotherapies. Similarly, cellular senescence, the process of cell cycle arrest that allow DNA and tissue repair has been traditionally thought to be able to suppress tumor progression. However, in recent years, extensive research has identified the complement system and cellular senescence as two main inducers of tumour growth in the context of chronic, persistent inflammation named inflammaging. Here, we discuss the data describing the ambivalent role of senescence in cancer with a particular focus on tumors that are strongly dependent on complement activation and can be understood by a new, senescence-related point of view: prostate cancer and renal cell carcinoma.

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.

Emerging biomarkers of delayed graft function in kidney transplantation.

Delayed Graft Function (DGF) is one of the most common early complications in kidney transplantation, associated with poor graft outcomes, prolonged post-operative hospitalization and higher rejection rates. Given the severe shortage of high-quality organs for transplantation, DGF incidence is expected to raise in the next years because of the use of nonstandard kidneys from Extended Criteria Donors (ECD) and from Donors after Circulatory Death (DCD). Alongside conventional methods for the evaluation of renal allograft [e.g. serum creatinine Glomerular Filtration Rate (GFR), needle biopsy], recent advancements in omics technologies, including proteomics, metabolomics and transcriptomics, may allow to discover novel biomarkers associated with DGF occurrence, in order to identify early preclinical signs of renal dysfunction and to improve the quality of graft management. Here, we gather contributions from basic scientists and clinical researchers to describe new omics studies in renal transplantation, reporting the emerging biomarkers of DGF that may implement and improve conventional approaches.

Prospective Validation of Pentraxin-3 as a Novel Serum Biomarker to Predict the Risk of Prostate Cancer in Patients Scheduled for Prostate Biopsy.

PURPOSE: To test and internally validate serum Pentraxin-3 (PTX3) levels as a potential PCa biomarker to predict prostate biopsy (PBx) results. MATERIALS AND METHODS: Serum PSA and serum PTX3 were prospectively assessed in patients scheduled for PBx at our Institution due to increased serum PSA levels or abnormal digital rectal examination. Uni- and multivariable logistic regression analysis, area under the receiver operating characteristic curve (AUC), and decision curve analysis (DCA), were used to test the accuracy of serum PTX3 in predicting anyPCa and clinically significant PCa (csPCa) defined as Gleason Grade (GG) ≥ 2. RESULTS: Among the 455 eligible patients, PCa was detected in 49% and csPCa in 25%. During univariate analysis, PTX3 outperformed other variables in predicting both anyPCa and csPCa. The addition of PTX3 to multivariable models based on standard clinical variables, significantly increased each model's predictive accuracy for anyPCa (AUC from 0.73 to 0.82; p < 0.001) and csPCa (AUC from 0.79 to 0.83; p < 0.001). At DCA, PTX3, and PTX3, density showed higher net benefit than PSA and PSA density and increased the net benefit of multivariable models in deciding when to perform PBx. CONCLUSIONS: Serum PTX3 levels might be of clinical utility in predicting prostate biopsy results. Should our findings be confirmed, this novel reflex test could be used to reduce the number and burden of unnecessary prostate biopsies.

mTOR inhibition improves mitochondria function/biogenesis and delays cardiovascular aging in kidney transplant recipients with chronic graft dysfunction.

CVD remains the major cause of mortality with graft functioning in Kidney transplant recipients (KTRs), with an estimated risk of CV events about 50-fold higher than in the general population. Many strategies have been considered to reduce the CV risk such as the use of mTOR inhibitors. We evaluate whether chronic mTOR inhibition might influence CV aging in KTRs studying the molecular mechanisms involved in this effect. We retrospectively analyzed 210 KTRs with stable graft function on therapy with CNI and mycophenolic acid (Group A, 105 pts.), or with CNI and mTORi (Everolimus, Group B, 105 pts.). The presence of mTOR inhibitor in immunosuppressive therapy was associated to increase serum levels of Klotho with concomitant reduction in FGF-23, with a significant decrease in left ventricular mass. In addition, KTRs with mTORi improved mitochondrial function/biogenesis in PBMC with more efficient oxidative phosphorylation, antioxidant capacity and glutathione peroxidase activity. Finally, group B KTRs presented reduced levels of inflammaging markers such as reduced serum pentraxin-3 and p21ink expression in PBMC. In conclusion, we demonstrated that mTOR inhibition in immunosuppressive protocols prevents the occurrence and signs of CV aging in KTRs.

On-line hemodiafiltration modulates atherosclerosis signaling in peripheral lymphomonocytes of hemodialysis patients.

BACKGROUND: Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. METHODS: The transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20). RESULTS: Eight hundred and forty-seven genes were differentially expressed in patients treated with  on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial Growth Factor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis  were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis. CONCLUSIONS: Our data suggest that type of dialysis (on-line hemodiafiltration versus bicarbonate hemodialysis) may modulate the expression of several genes involved in the pathogenesis of atherosclerotic disease.

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.

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.

SARS-CoV-2 and Viral Sepsis: Immune Dysfunction and Implications in Kidney Failure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), first emerged in Wuhan, China. The clinical manifestations of patients infected with COVID-19 include fever, cough, and dyspnea, up to acute respiratory distress syndrome (ARDS) and acute cardiac injury. Thus, a lot of severe patients had to be admitted to intensive care units (ICU). The pathogenic mechanisms of SARS-CoV-2 infection are mediated by the binding of SARS-CoV-2 spikes to the human angiotensin-converting enzyme 2 (ACE-2) receptor. The overexpression of human ACE-2 is associated with the disease severity in SARS-CoV-2 infection, demonstrating that viral entry into cells is a pivotal step. Although the lung is the organ that is most commonly affected by SARS-CoV-2 infection, acute kidney injury (AKI), heart dysfunction and abdominal pain are the most commonly reported co-morbidities of COVID-19. The occurrence of AKI in COVID-19 patients might be explained by several mechanisms that include viral cytopathic effects in renal cells and the host hyperinflammatory response. In addition, kidney dysfunction could exacerbate the inflammatory response started in the lungs and might cause further renal impairment and multi-organ failure. Mounting recent evidence supports the involvement of cardiovascular complications and endothelial dysfunction in COVID-19 syndrome, in addition to respiratory disease. To date, there is no vaccine, and no specific antiviral medicine has been shown to be effective in preventing or treating COVID-19. The removal of pro-inflammatory cytokines and the shutdown of the cytokine storm could ameliorate the clinical outcome in severe COVID-19 cases. Therefore, several interventions that inhibit viral replication and the systemic inflammatory response could modulate the severity of the renal dysfunction and increase the probability of a favorable outcome.