mTOR-Inhibition and COVID-19 in Kidney Transplant Recipients: Focus on Pulmonary Fibrosis

Kidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities (e.g., cardiovascular disease, diabetes) and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis

The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation

Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response. In addition to their role in anti-viral and anti-tumor defense, they also regulate several aspects of the allo-immune response in kidney transplant recipients. Growing evidence suggests a key role of NK cells in the pathogenesis of immune-mediated graft damage in kidney transplantation. Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss. Moreover, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. Finally, activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection. In this review, we will describe how these cells can influence the innate and the adaptive immune response in kidney transplantation and how immunosuppression can modulate NK behavior

Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney’s excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16ink4a, Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function

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

Malattia renale policistica autosomica dominante. Nuovi approcci terapeutici "Ottimisti per diritto"

La malattia renale policistica autosomica dominante (Autosomal Dominant Polycystic Kidney Disease, ADPKD), è la più comune forma di malattia renale cistica e rappresenta, nel mondo, la causa di terapia sostitutiva emodialitica nel 7–10% dei pazienti. Sono noti due tipi di malattia policistica: il tipo I è causato da mutazioni del gene PKD1, che codifica per la policistina-1, è la forma più diffusa e aggressiva e colpisce soggetti di età giovane; il tipo II è causato da mutazioni del gene PKD2 che codifica per la policistina-2 e rappresenta il 10–15% dei casi, a evoluzione più lenta. Clinicamente, le cisti si svilup-pano a livello renale, epatico, pancreatico e intestinale. Il dolore cronico, la chirurgia palliativa, l'insufficienza renale, la dialisi, il trapianto, come anche la morte, sono tutte conseguenze di questa malattia genetica che non ha ancora una terapia medica per rallentare o arrestare la sua progressione. Di grande interesse per il suo potenziale terapeutico, è la dimostrazione che la Policistina-1, formando un complesso con la tuberina (la proteina la cui mutazione causa la sclerosi tuberosa), agisce come un inibitore endogeno dell'attività del mammalian Target of Rapamycin (mTOR). Se mutato, come nell'ADPKD, tale meccanismo inibitorio viene compromesso e ciò favorirebbe lo sviluppo delle cisti. I recenti discordanti risultati di alcuni studi nell'uomo sull'uso di un inibitore di mTOR in pazienti affetti da ADPKD, possono generare interrogativi e confusione, ma diverse e molteplici possono essere le ragioni per cui tali studi hanno portato a conclusioni diverse fra di loro. A questo punto, è d'obbligo porsi l'interrogativo se questi risultati siano la fine o possano essere l'inizio di nuovi studi. Agli Autori piace considerare la seconda ipotesi, in quanto tutti gli studi di biologia molecolare, quelli preclinici, e su animali, hanno confermato la "bontà" del percorso intrapreso. Questa rassegna viene proposta per fare chiarezza sui risultati di tali studi e per dare una speranza concreta, secondo l'opinione degli Autori, sulla possibilità di riuscire a scoprire una cura per tale patologia

Rapamycin promotes autophagy cell death of Kaposi’s sarcoma cells through P75NTR activation

The mammalian target of rapamycin inhibitor (mTOR-I) Rapamycin, a drug widely used in kidney transplantation, exerts important anti-cancer effects, particularly in Kaposi's Sarcoma (KS), through several biological interactions. In this in vivo and in vitro study, we explored whether the activation of the autophagic pathway through the low-affinity receptor for nerve growth factor, p75NTR, may have a pivotal role in the anti-cancer effect exerted by Rapamycin in S. Our Kimmunohistochemistry results revealed a significant hyper-activation of the autophagic pathway in KS lesions. In vitro experiments on KS cell lines showed that Rapamycin exposure reduced cell viability by increasing the autophagic process, in the absence of apoptosis, through the transcriptional activation of p75NTR via EGR1. Interestingly, p75NTR gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75NTR activation promoted the upregulation of phosphatase and tensin homolog (PTEN), a tumour suppressor that modulates the PI3K/Akt/mTOR pathway. In conclusion, our in vitro data demonstrated, for the first time, that in Kaposi's sarcoma, autophagy triggered by Rapamycin through p75NTR represented a major mechanism by which mTOR inhibitors may induce tumour regression. Additionally, it suggested that p75NTR protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi's sarcoma

Cementless ceramic-on-ceramic total hip replacement in children and adolescents

Background: total hip replacement (THR) is a rare surgical option in children and adolescents with disabling hip diseases. The aim of this study is to report results from a retrospective cohort of patients aged 18 years or less who underwent cementless Ceramic-on-Ceramic (CoC) THR at a single institution, investigating clinical and radiographic outcomes, survival rates, and reasons for revision of the implants. Materials and methods: we queried the Registry of Prosthetic Orthopedic Implants (RIPO) to identify all children and adolescents undergoing THR between 2000 and 2019 at a single Institution. Inclusion criteria were patients undergoing cementless CoC THR, aged less than 18 years at surgery, followed for at least 2 years. Sixty-eight patients (74 hips) matched all the inclusion criteria and were enrolled in the study. We assessed the clinical and radiographic outcomes, the rate of complications, the survival rate, and reasons for revision of the implants. Results: The mean follow-up was 6.6 ± 4.4 years (range 2–20). The most frequent reason for THR was post-traumatic or chemotherapy-induced avascular necrosis (38%). The overall survival rate of the cohort was 97.6% (95% CI: 84.9–99.7%) at 5 years of follow-up, 94.4% (95% CI: 79.8–98.6%) at 10 years and 15 years of follow-up. Two THR in two patients (2.7%) required revision. With the numbers available, Cox regression analysis could not detect any significant interaction between preoperative or intraoperative variables and implant survivorship (p-value 0.242 to 0.989).” The average HOOS was 85 ± 14.3 (range 30.6–100). Overall, 23 patients (48%) reported excellent HOOS scores (>90 points), 21 patients (44%) reported acceptable HOOS scores (60–90 points) while 4 patients (8%) reported poor outcomes (<60 points). Twenty-one patients (43%) were regularly involved into moderate-to high-intensity sport activities (UCLA ≥ 6). Conclusions: Cementless CoC THR is a successful procedure in children and teenagers, having demonstrated high implant survivorship and low rates of complications and failure. A meticulous preoperative planning and implant selection is mandatory, to avoid implant malposition, which is the main reason of failure and revision in these cases. Further studies are needed to assess the impact of the THR on the psychosocial wellbeing of teenagers, as well as risks and benefits and cost-effectiveness in comparison to the hip preserving surgical procedures

Good subjective outcomes, stable knee and high return to sport after tibial eminence avulsion fracture in children

Avulsion fracture of the tibial spine (TSA) is uncommon in children, although its incidence is increasing with the earlier practice of competitive sport activities. This study aims to report mid to long term outcomes in children who sustained a TSA, with a special focus on a return to sport activities. Skeletally immature patients with a TSA, treated in two orthopedic hospitals, were evaluated for range of motion and knee laxity using KT1000, KiRA and Rolimeter. The pediatric International Knee Documentation Committee score (Pedi-IKDC) and the Hospital for Special Surgery pediatric Functional Activity Brief Scale (Pedi-FABS) questionnaires were recorded during the latest visit. Forty-two children were included. Twenty-six were treated nonoperatively and 16 underwent surgery. At a mean follow-up of 6.9 ± 3.6 years, 36 patients completed the questionnaires and 23 patients were tested with arthrometers. Among them, 96% had normal knee laxity. The Pedi-IKDC score averaged 96.4 ± 5.7 points, while the mean Pedi-FABS was 22.2 ± 5.9 points, without statistically significant differences between groups. Twenty-eight patients (78%) returned to their previous level of sport activity (eight amateur, 13 competitive, seven elite athletes). Eight patients (22%) quit sport, mostly because of re-injury fear. If properly treated, pediatric TSAs achieve a high rate of successful healing, with complete restoration of knee stability and an early return to sport activities

CD40 cross-linking induces migration of renal tumor cell through nuclear factor of activated T cells (NFAT) activation

CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of our study was to investigate the main intracellular pathways activated by CD40 ligation and their specific involvement in RCC cell migration. CD40 ligation increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH (2)-terminal kinase (JNK) and p38 MAPK. Furthermore, CD40 crosslinking activated different transcriptional factors on RCC cell lines: AP-1, NFkB and some members of the Nuclear Factor of Activated T cells (NFAT) family. Interestingly, the specific inhibition of NFAT factors by cyclosporine A, completely blocked RCC cell motility induced by CD40 ligation. In tumor tissue, we observed a higher expression of NFAT factors and in particular an increased activation and nuclear migration of NFATc4 on RCC tumor tissues belonging to patients that developed metastases when compared to those who did not. Moreover, CD40-CD40L interaction induced a cytoskeleton reorganization and increased the expression of integrin β1 on RCC cell lines, and this effect was reversed by cyclosporine A and NFAT inhibition. These data suggest that CD40 ligation induces the activation of different intracellular signaling pathways, in particular the NFATs factors, that could represent a potential therapeutic target in the setting of patients with metastatic RCC

mTOR inhibitors effects on regulatory T cells and on dendritic cells.

The mammalian target of rapamycin (mTOR), a cytoplasmic serine/threonine kinase, represents a key biologic "switch" modulating cell metabolisms in response to environmental signals and is now recognized as a central regulator of the immune system. There is an increasing body of evidence supporting the hypothesis that mTOR inhibitors exhibit several biological properties in addition to immunosuppression, including anti-neoplastic effects, cardio-protective activities, and an array of immunomodulatory actions facilitating the development of an operational graft tolerance. The biological mechanisms explaining how mTOR inhibition can enable a tolerogenic state are still largely unclear. The induction of transplant tolerance might at the same time decrease rejection rate and minimize immunosuppression-related side effects, leading to an improvement in long-term graft outcome. In this scenario, T cell immunoregulation has been defined as the hallmark of peripheral tolerance. Two main immunologic cell populations have been reported to play a central role in this setting: regulatory T cells (Tregs) and dendritic cells (DCs). In this review we focus on mTOR inhibitors effects on Treg and DCs differentiation, activation, and function in the transplantation setting