Endothelial cells in tumor microenvironment: insights and perspectives.

The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

The use of extracorporeal blood purification therapies and sequential extracorporeal support in patients with septic shock (EROICASS): a study protocol for a national, non-interventional, observational multicenter, prospective study.

BACKGROUND: Septic shock, a critical condition characterized by organ failure, presents a substantial mortality risk in intensive care units (ICUs), with the 28-day mortality rate possibly reaching 40%. Conventional management of septic shock typically involves the administration of antibiotics, supportive care for organ dysfunction, and, if necessary, surgical intervention to address the source of infection. In recent decades, extracorporeal blood purification therapies (EBPT) have emerged as potential interventions aimed at modulating the inflammatory response and restoring homeostasis in patients with sepsis. Likewise, sequential extracorporeal therapy in sepsis (SETS) interventions offer comprehensive organ support in the setting of multiple organ dysfunction syndrome (MODS). The EROICASS study will assess and describe the utilization of EBPT in patients with septic shock. Additionally, we will evaluate the potential association between EBPT treatment utilization and 90-day mortality in septic shock cases in Italy. METHODS: The EROICASS study is a national, non-interventional, multicenter observational prospective cohort study. All consecutive patients with septic shock at participating centers will be prospectively enrolled, with data collection extending from intensive care unit (ICU) admission to hospital discharge. Variables including patient demographics, clinical parameters, EBPT/SETS utilization, and outcomes will be recorded using a web-based data capture system. Statistical analyses will encompass descriptive statistics, hypothesis testing, multivariable regression models, and survival analysis to elucidate the associations between EBPT/SETS utilization and patient outcomes. CONCLUSIONS: The EROICASS study provides valuable insights into the utilization and outcomes of EBPT and SETS in septic shock management. Through analysis of usage patterns and clinical data, this study aims to guide treatment decisions and enhance patient care. The implications of these findings may impact clinical guidelines, potentially improving survival rates and patient outcomes in septic shock cases.

Vascular access for hemodialysis in Italy: What a national survey reveals.

BACKGROUND: Since in Italy there are no official data on vascular access (VA) for hemodialysis the Vascular Access Project Group (VAPG) of the Italian Society of Nephrology (SIN) designed a national survey. METHODS: A 35-question survey was designed and sent it to the Italian facilities through the SIN website. The basic questions were the prevalence, the location, and the surveillance of VA, the bedside use of ultrasound, the use of fluoroscopy for central venous catheter (CVC) placement, and of buttonhole technique, the role of nephrologist in the access creation. RESULT: The questionnaire was completed in June 2022 by 161 facilities. The survey registered 15,499 patients, approximately one-third of the Italian dialysis population. The prevalence of arteriovenous fistula (AVF), arteriovenous Graft (AVG), and CVC were 61.8%, 3.7%, and 34.5% respectively. The AVF location was 50% in distal forearm, 20% in meanproximal forearm, 30% in upper arm. For AVF creation, nephrologists were involved in 72% of facilities while for CVC placement in 62%. As regards VA monitoring, 21% of the facilities did not have a surveillance protocol; 60% did not register AVF thrombosis and 53% did not register CVC infections. Most of facilities use the fluoroscope during CVC placement, 37% when needed, and 22% never. Ultrasound-guided puncture of complex AVFs was used by 80% of facilities. Buttonhole puncture was used in 5% of patients. CONCLUSIONS: Some considerations emerge from the survey data: (1) The increasing CVC prevalence compared to DOPPS 5 study. (2) The low rate of AVG prevalence. (3) The nephrologist is the operator in many VA procedures. (4) The fluoroscopy for CVC placement and the US-guide puncture of the complex AVF are widely used in most facilities. (5) The practice of the buttonhole is not widespread. (6) When the operator is the nephrologist more distal fistulas are performed.

[Chronic Kidney Disease and Cancer: Ethical Choices].

Cancer and chronic kidney disease prevalence both increase with age. As a consequence, physicians are more frequently encountering older people with cancer who need dialysis, or patients on dialysis diagnosed with cancer. Decisions in this context are particularly complex and multifaceted. Informed decisions about dialysis require a personalised care plan that considers the prognosis and treatment options for each condition while also respecting patient preferences. The concept of prognosis should include quality-of-life considerations, functional status, and burden of care. Close collaboration between oncologists, nephrologists, geriatricians and palliativists is crucial to making optimal treatment decisions, and several tools are available for estimating cancer prognosis, prognosis of renal disease, and general age-related prognosis. Decision regarding the initiation or the termination of dialysis in patients with advanced cancer have also ethical implications. This last point is discussed in this article, and we delved into ethical issues with the aim of providing a pathway for the nephrologist to manage an elderly patient with ESRD and cancer.

The Role of Plant-Based Diets in Preventing and Mitigating Chronic Kidney Disease: More Light than Shadows.

Chronic kidney disease (CKD) is a non-communicable disease that affects >10% of the general population worldwide; the number of patients affected by CKD is increasing due in part to the rise in risk factors such as obesity, hypertension, and diabetes mellitus. As many studies show, diet can be an important tool for preventing and mitigating the onset of non-communicable diseases. Plant-based diets (PBDs) are those that emphasize the consumption of plant foods and may or may not include small or moderate amounts of animal foods. Recently, these diets have received increasing interest because they have been associated with favourable effects on health and also appear to protect against the development and progression of CKD. PBDs, which are associated with protein restrictions, seem to offer adjunctive advantages in patients with chronic kidney disease, as compared to conventional low-protein diets that include animal proteins. The principal aims of this review are to provide a comprehensive overview of the existing literature regarding the role of plant-based diets and low-protein, plant-based diets in the context of chronic kidney disease. Moreover, we try to clarify the definition of plant-based diets, and then we analyse possible concerns about the use of PBDs in patients with chronic kidney disease (nutritional deficiency and hyperkalaemia risk). Finally, we offer some strategies to increase the nutritional value of plant-based low-protein diets. In the Materials and Methods section, many studies about plant-based diets and low-protein plant-based diets (e.g., the very-low-protein diet and vegan low-protein diet, LPD) in chronic kidney disease were considered. In the Results and Conclusion section, current data, most from observational studies, agree upon the protective effect of plant-based diets on kidney function. Moreover, in patients with advanced CKD, low-protein plant-based options, especially a very-low-protein diet supplemented with heteroanalogues (VLPDs), compared to a conventional LPD appear to offer adjunctive advances in terms of delaying dialysis and mitigating metabolic disturbances. However, further studies are necessary to better investigate the possible metabolic and cardiovascular advantages of plant-based LPDs versus conventional LPDs.

Impact of belimumab therapy on the quality of life in patients with systemic lupus erythematosus: A cohort study.

Systemic lupus erythematosus (SLE) is a chronic and extremely disabling connective-tissue autoimmune disease with a tremendous impact on the quality of life (QoL). Belimumab, a B-lymphocyte-stimulator-specific inhibitor, is the first biologic drug approved as add-on therapy in patients with active, refractory auto-antibody-positive SLE.The impact of belimumab on the QoL of SLE patients was evaluated using a generic questionnaire short-form health survey 36 (SF-36) and the disease-specific questionnaire SLE-specific quality of life (SLEQoL).The Italian version of the SLEQoL and the SF-36 were administered to 46 SLE patients before and after 6 months of belimumab therapy. The control population consisted of 40 age-matched healthy individuals. The questionnaires were completed before and after belimumab treatment and the results were compared using the Wilcoxon signed-rank test. In addition, data from healthy controls and SLE patients were compared using the Mann-Whitney test. Dichotomous variables were compared using Fisher's exact test.For SLE patients, the addition of belimumab to their therapeutic regimen significantly improved their health-related QoL (HRQoL), according to the results of the SF-36 and SLEQoL. The comparison of the data obtained before and after belimumab treatment showed a decrease in all six SLEQoL domains and an increase in all eight SF-36 domains. Moreover, treatment led to a reduction in the median prednisone dose, to 0 mg/day (IQR 0-4.5 mg/day). Before belimumab therapy, SLE patients had a worse HRQoL than the control group, based on both questionnaires, but after belimumab treatment the outcome scores between SLE patients and controls were similar, suggesting that belimumab therapy resulted in a strong improvement in HRQoL. These findings were supported by a decrease in the SELENA-SLEDAI score, a measure of disease activity.In addition to clinical remission and low disease activity, the goals of an innovative therapeutic strategy for SLE should include the attainment of a good HRQoL. Our study demonstrates that the combined use of the SF-36 and SLEQoL questionnaires can provide clinicians with a better understanding of the HRQoL of SLE patients.

Nutritional and Dietary Management of Chronic Kidney Disease Under Conservative and Preservative Kidney Care Without Dialysis.

While dialysis has been the prevailing treatment paradigm for patients with advanced chronic kidney disease (CKD), emphasis on conservative and preservative management in which dietary interventions are a major cornerstone have emerged. Based on high-quality evidence, international guidelines support the utilization of low-protein diets as an intervention to reduce CKD progression and mortality risk, although the precise thresholds (if any) for dietary protein intake vary across recommendations. There is also increasing evidence demonstrating that plant-dominant low-protein diets reduce the risk of developing incident CKD, CKD progression, and its related complications including cardiometabolic disease, metabolic acidosis, mineral and bone disorders, and uremic toxin generation. In this review, we discuss the premise for conservative and preservative dietary interventions, specific dietary approaches used in conservative and preservative care, potential benefits of a plant-dominant low-protein diet, and practical implementation of these nutritional strategies without dialysis.

The Contribution of Muscle Innate Immunity to Uremic Cachexia.

Protein energy wasting (PEW) is a common complication both in chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Of note, PEW is one of the stronger predictors of morbidity and mortality in this patient population. The pathogenesis of PEW involves several mechanisms, including anorexia, insulin resistance, acidosis and low-grade inflammation. In addition, "sterile" muscle inflammation contributes to PEW at an advanced CKD stage. Both immune and resident muscle cells can activate innate immunity; thus, they have critical roles in triggering "sterile" tissue inflammation. Toll-like receptor 4 (TLR4) can detect endogenous danger-associated molecular patterns generated or retained in blood in uremia and induce a sterile muscle inflammatory response via NF-κB in myocytes. In addition, TLR4, though the activation of the NLRP3 inflammasome, links the sensing of metabolic uremic stress in muscle to the activation of pro-inflammatory cascades, which lead to the production of IL-1ß and IL-18. Finally, uremia-induced accelerated cell senescence is associated with a secretory phenotype that favors fibrosis in muscle. Targeting these innate immune pathways could lead to novel therapies for CKD-related PEW.

Vegetarian Nutrition in Chronic Kidney Disease.

There is rising interest globally with respect to the health implications of vegetarian or plant-based diets. A growing body of evidence has demonstrated that higher consumption of plant-based foods and the nutrients found in vegetarian and plant-based diets are associated with numerous health benefits, including improved blood pressure, glycemic control, lipid levels, body mass index, and acid-base parameters. Furthermore, there has been increasing recognition that vegetarian and plant-based diets may have potential salutary benefits in preventing the development and progression of chronic kidney disease (CKD). While increasing evidence shows that vegetarian and plant-based diets have nephroprotective effects, there remains some degree of uncertainty about their nutritional adequacy and safety in CKD (with respect to protein-energy wasting, hyperkalemia, etc.). In this review, we focus on the potential roles of and existing data on the efficacy/effectiveness and safety of various vegetarian and plant-based diets in CKD, as well as their practical application in CKD management.

[Dialysis withdrawal and shared end-of-life management between nephrology and palliative care: our three-year experience].

Most dialysis patients with end-stage kidney disease (ESKD) lack access to palliative care services. According to the data of the Dialysis Outcomes and Practice Study (DOPPS), Italy when compared to other countries included in the study, had the lowest rates of dialysis discontinuation. Indeed, there is a growing interest in the implementation of international and national programs for the co-management between nephrology and palliative care in end-of-life decision-making for patients with ESKD. On behalf of this, since 2017, we started in the nephrology outpatient clinic and hemodialysis facilities of the Provincia Autonoma of Trento a shared program between Nephrology and Palliative Care Units to improve the end-of-life quality of care in ESKD patients in conservative and dialytic therapy. Methods:A retrospective analysis, from the 1st of January 2019 to 31st December 2021, of dialysis withdrawal in a cohort of patients undergoing hemodialysis and peritoneal dialysis. Results:Dialysis withdrawal and subsequent death, according to the integrated protocol with the Palliative Care resources, were 24 in 2019, 20 in 2020, and 28 in 2021. The mean age was 75 years in 2019, 78 years in 2020, and in 2021. Most of the patients were male. Dialysis discontinuation was higher in chronic dialysis patients (80% in 2019 and 2020, and 79% in 2021), and considering the annual rates of death of all the dialysis patients, those who died because of dialysis withdrawal were 38% in 2019, 31% in 2020 and 40% in 2021. Survival after dialysis withdrawal was in most of the cases less than 7 days; only few patients lived more than 30 days. Furthermore, the data, in the 3 years considered, showed a reduction of hospitalization and an increase of the rate of death at home. Conclusions:As described in the present study, strategies to expand palliative care by a shared protocol among nephrology and palliative care staff improved the quality of care in the end of life and reduced the hospitalization rates of admission of patients after dialysis withdrawal.

[Hyperphosphatemic pseudotumoral calcinosis due to FGF23 mutation with secondary amyloidosis].

A 44 years old man was admitted for nephrotic syndrome and rapidly progressive renal failure. Two firm, tumour-like masses were localized around the left shoulder and the right hip joint. Since the age of 8 years old, the patient had a history of metastatic calcification of the soft tissues suggesting hyperphosphatemic pseudotumoral calcinosis. Despite treatment for a long time with phosphate binders the metastatic calcinosis had to be removed with several surgeries. The patient had also a history of recurrent fever associated with pain localized toward the two masses and underwent multiple antibiotic courses. Laboratory findings at admission confirmed nephrotic syndrome. S-creatinine was 2.8 mg/dl. Calcium was 8.4 mg/dl, Phosphorus 8.2 mg/dl, PTH 80 pg/ml, 25 (OH)VitD 8 ng/ml. Serum amyloid A was slightly increased. We performed renal biopsy and we found AA amyloid deposits involving the mesangium and the tubules. The bone marrow biopsy revealed the presence of AA amyloid in the vascular walls. During the next two months renal failure rapidly progressed and the patient started hemodialysis treatment. We performed genetic analysis that confirmed homozygous mutation of the FGF23 gene. After 14 months on hemodialysis, the patient's lesions are remarkably and significantly reduced in dimension. The current phosphate binder therapy is based on sevelamer and lanthanum carbonate. Serum amyloid A is persistently slightly increased as well as C reactive protein. Proteinuria is in the nephrotic range without nephrotic syndrome.

Assessing Global Kidney Nutrition Care.

BACKGROUND AND OBJECTIVES: Nutrition intervention is an essential component of kidney disease management. This study aimed to understand current global availability and capacity of kidney nutrition care services, interdisciplinary communication, and availability of oral nutrition supplements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The International Society of Renal Nutrition and Metabolism (ISRNM), working in partnership with the International Society of Nephrology (ISN) Global Kidney Health Atlas Committee, developed this Global Kidney Nutrition Care Atlas. An electronic survey was administered among key kidney care stakeholders through 182 ISN-affiliated countries between July and September 2018. RESULTS: Overall, 160 of 182 countries (88%) responded, of which 155 countries (97%) answered the survey items related to kidney nutrition care. Only 48% of the 155 countries have dietitians/renal dietitians to provide this specialized service. Dietary counseling, provided by a person trained in nutrition, was generally not available in 65% of low-/lower middle-income countries and "never" available in 23% of low-income countries. Forty-one percent of the countries did not provide formal assessment of nutrition status for kidney nutrition care. The availability of oral nutrition supplements varied globally and, mostly, were not freely available in low-/lower middle-income countries for both inpatient and outpatient settings. Dietitians and nephrologists only communicated "sometimes" on kidney nutrition care in ≥60% of countries globally. CONCLUSIONS: This survey reveals significant gaps in global kidney nutrition care service capacity, availability, cost coverage, and deficiencies in interdisciplinary communication on kidney nutrition care delivery, especially in lower-income countries.

Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey.

BACKGROUND: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). METHODS: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1°follow-up (FU) year; secondary endpoint: response at 1°line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. RESULTS: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. CONCLUSIONS: sGIN-AKI-patients with no complete recovery at 1°line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

How to Overcome Anabolic Resistance in Dialysis-Treated Patients?

A current hypothesis is that dialysis-treated patients are "anabolic resistant" i. e., their muscle protein synthesis (MPS) response to anabolic stimuli is blunted, an effect which leads to muscle wasting and poor physical performance in aging and in several chronic diseases. The importance of maintaining muscle mass and MPS is often neglected in dialysis-treated patients; better than to describe mechanisms leading to energy-protein wasting, the aim of this narrative review is to suggest possible strategies to overcome anabolic resistance in this patient's category. Food intake, in particular dietary protein, and physical activity, are the two major anabolic stimuli. Unfortunately, dialysis patients are often aged and have a sedentary behavior, all conditions which per se may induce a state of "anabolic resistance." In addition, patients on dialysis are exposed to amino acid or protein deprivation during the dialysis sessions. Unfortunately, the optimal amount and formula of protein/amino acid composition in supplements to maximixe MPS is still unknown in dialysis patients. In young healthy subjects, 20 g whey protein maximally stimulate MPS. However, recent observations suggest that dialysis patients need greater amounts of proteins than healthy subjects to maximally stimulate MPS. Since unneccesary amounts of amino acids could stimulate ureagenesis, toxins and acid production, it is urgent to obtain information on the optimal dose of proteins or amino acids/ketoacids to maximize MPS in this patients' population. In the meantime, the issue of maintaining muscle mass and function in dialysis-treated CKD patients needs not to be overlooked by the kidney community.

[Nephrology: where we stand and where we should go].

In the last year, the Italian National Health Service as a whole and the Nephrology community have been severely challenged by the pandemic. It has been a dramatic stress test for the entire healthcare system, not only in Italy but worldwide. The general organization of our Nephrology units and our models of care were put under extreme pressure, and we had to quickly adopt unprecedented clinical practice recommendations and organizational models to overcome the impasse caused by the pandemic. The time has come to evaluate these new experiences, ask how we could have been better prepared and look for change. In this editorial, we outline a few proposals and suggestions for the future, weighing the information gathered in the 2018 Nephrology Census against the new organizational requirements imposed by the COVID-19 pandemic.