The Role of Uremic Retention Solutes in the MIA Syndrome in Hemodialysis Subjects.

INTRODUCTION: In chronic kidney disease (CKD), the high morbidity and mortality risk for cardiovascular disease (CVD) are not easily explained only on the basis of traditional factors. Among nontraditional ones involved in CKD, malnutrition, inflammation, and atherosclerosis/calcification have been described as the "MIA syndrome." METHODS: In this pilot study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in a population of dialysis patients. RESULTS: As expected, we found a direct correlation between serum albumin and both phosphate and total cholesterol (r = 0.54 and 0.37, respectively; p < 0.05). Moreover, total cholesterol and phosphate directly correlate (r = 0.40, p < 0.05). The relationship between malnutrition and inflammation is highlighted by the correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = -0.56, r = -0.39, respectively; p < 0.05). Moreover, the relation between inflammation and atherosclerosis/calcification is supported by the correlation of IL-6 with VEGF levels and vascular smooth muscle cell high-Pi in vitro calcification (r = 0.81, r = 0.66, respectively; p < 0.01). CONCLUSION: We found significant correlations between several uremic retention solutes and malnutrition, inflammation, and atherosclerosis/calcification. Our findings support the hypothesis of a central role of the uremic milieu in the MIA syndrome and ultimately in the pathogenesis of CKD-specific CVD risk factors.

The role of activin: the other side of chronic kidney disease-mineral bone disorder?

Chronic kidney disease-mineral bone disorder (CKD-MBD) plays a pivotal role in the excess of cardiovascular morbidity and mortality associated with CKD. There is now a growing awareness that pathways involved in CKD-MBD, like canonical Wnt signalling, are activated from the earliest stages of CKD, playing a role in the development of adynamic bone disease with unknown consequences on vasculature. These changes occur before the classic changes in mineral metabolism: secondary hyperparathyroidism, calcitriol deficiency and hyperphosphataemia. Furthermore, vascular calcification is frequently associated and evolves with decreased bone mineral density and deranged bone turnover, while bone and arterial mineralization share common pathways. Therefore, results of clinical trials focused on mineral bone disorder, aimed at preserving bone and cardiovascular health, are considered unsatisfactory. In order to identify more effective therapeutic strategies, it is necessary to clarify the pathways modulating the cross-talk between bone and vasculature and identify new mediators involved in the pathogenesis of CKD-MBD. Much attention has been paid recently to the role of the transforming growth factor-beta superfamily members in renal disease, and in particular of activin A (ActA). Preclinical studies demonstrate an upgrade of ActA signalling in kidney, skeleton, vasculature and heart during CKD. This supports the idea that an endocrine factor produced in the kidney during renal disease, in addition to promoting the progression of kidney damage, deranges other organs' homoeostasis and participates in CKD-MBD. In this review, we analyse the contribution of ActA to kidney fibrosis and inflammation as well as its role in the development of CKD-MBD.

COVID-19 in Chronic Kidney Disease: The Impact of Old and Novel Cardiovascular Risk Factors.

Cardiovascular disease is a frequent complication and the most common cause of death in patients with CKD. Despite landmark medical advancements, mortality due to cardiovascular disease is still 20 times higher in CKD patients than in the general population, which is mainly due to the high prevalence of risk factors in this group. Indeed, in addition to traditional cardiovascular risk factors, CKD patients are exposed to nontraditional ones, which include metabolic, hormonal, and inflammatory alterations. The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has brought novel challenges for both cardiologists and nephrologists alike. Emerging evidence indicates that coronavirus disease 2019 (COVID-19) increases the risk of cardiovascular events and that several aspects of the disease may synergize with pre-existing cardiovascular risk factors in CKD patients. A better understanding of these mechanisms is pivotal for the prevention and treatment of cardiovascular events in this context, and we believe that additional clinical and experimental studies are needed to improve cardiovascular outcomes in CKD patients with COVID-19. In this review, we provide a summary of traditional and nontraditional cardiovascular risk factors in CKD patients, discussing their interaction with SARS-CoV-2 infection and focusing on CO-VID-19-related cardiovascular complications that may severely affect short- and long-term outcomes in this high-risk population.

Uremic Patients with Increased Vascular Calcification Score Have Serum with High Calcific Potential: Role of Vascular Smooth Muscle Cell Osteoblastic Differentiation and Apoptosis.

BACKGROUND/AIMS: Uremic patients experience premature vascular ageing that causes cardiovascular morbidity. In this study, we investigated the relationship between uremic serum calcific potential induced by high phosphate (Pi) and vascular calcification score (VCS). METHODS: Vascular smooth muscle cells (VSMCs) were cultured with 3.5 mM Na3PO4 (Pi) with 10% uremic serum and calcium deposition, markers of osteoblastic transformation, and apoptosis were evaluated. RESULTS: Culture with uremic serum and high-Pi significantly induced calcification (0.21 ± 0.03 vs. 8.05 ± 0.6; ctr vs. Pi; OD/mg protein; p < 0.01). We next stratified patients with respect of the degree of VCS in 2 groups: absence of vascular calcification (VC) "no VC group" and presence of VC "VC group". We found that there was a significant correlation between VCS and uremic serum calcific potential induced by high Pi in vitro (p < 0.01). Interestingly, uremic sera of the "VC group" were more effective than sera from the "no VC group", in downregulating α-actin and SM22α, after treatment with high-Pi (41.3 ± 4.7 vs. 23.3 ± 2.9 and 25.6 ± 6.8 vs. 8.14 ± 2.3; VC vs. no VC group, α-actin and SM22α respectively; Δ intensity area; p < 0.01). Similarly, sera from "VC group" were more effective than sera from "no VC group" in adjuvanting the high-Pi effect of increasing osteoblastic markers, such as bone morphogenic protein 2 (BMP2), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2; 39.1 ± 11.3 vs. 5.0 ± 2.6 BMP2; 12.2 ± 4.2 vs. 1.7 ± 0.3 OC; 2.9 ± 0.4 vs. 1.2 ± 0.2 RUNX2; VC vs. no VC group respectively; p < 0.05). We found a similar pattern with significantly higher apoptosis and necrosis induction by sera from the "VC group" compared to the "no VC group" (2.05 ± 0.33 vs. 1.29 ± 0.13 and 54.1 ± 19.5 vs. 27.4 ± 10.6; Pi; VC group vs. no VC group; enrichment factor of apoptotic or necrotic fragments, respectively; p < 0.05). CONCLUSIONS: We conclude that VCS of end-stage renal disease patients significantly correlates with serum-calcific potential induced by high Pi. In addition, uremic patients with higher VCS have sera with a higher potential to induce VSMC osteoblastic trans-differentiation, apoptosis, and necrosis.

HABITAT: An IoT Solution for Independent Elderly.

In this work, a flexible and extensive digital platform for Smart Homes is presented, exploiting the most advanced technologies of the Internet of Things, such as Radio Frequency Identification, wearable electronics, Wireless Sensor Networks, and Artificial Intelligence. Thus, the main novelty of the paper is the system-level description of the platform flexibility allowing the interoperability of different smart devices. This research was developed within the framework of the operative project HABITAT (Home Assistance Based on the Internet of Things for the Autonomy of Everybody), aiming at developing smart devices to support elderly people both in their own houses and in retirement homes, and embedding them in everyday life objects, thus reducing the expenses for healthcare due to the lower need for personal assistance, and providing a better life quality to the elderly users.

Percutaneous microwave ablation of renal angiomyolipomas in tuberous sclerosis complex to improve the quality of life: preliminary experience in an Italian center.

AIM: To evaluate efficacy, safety and quality of life of the patients with renal angiomyolipomas (AMLs) associated with tuberous sclerosis complex (TSC) treated with percutaneous microwave ablation (MWA). MATERIALS AND METHODS: Nine patients (7 females and 2 males; mean age 27.6 years, range 23-34), with 10 renal AMLs with a mean size of 6.3 cm (range 4.5-8.5) were treated with image-guided percutaneous MWA. Indications for treatment were the risk of rupture/hemorrhage due to size greater than 4 cm and symptomatology; in one case, a previous hemorrhage was the indication for treatment. During follow-up, the volume of the ablated AMLs and its relationship with the relief of symptoms were registered. Technical and clinical success, safety, and quality of life (QOL) were evaluated in a mean follow-up of 9 months (range 3-12). RESULTS: Technical success was obtained in all cases. Clinical success was obtained in all cases; the volume of the ablated AMLs was not related with symptoms relief; all patients referred a significant improvement in their QOL, with a regularization of daily activities. There were no major procedural complications or delayed adverse events. A small self-limited post-procedural subcapsular hematoma was registered. Post-ablation syndrome was registered in 5 cases and was self-limited in all cases. CONCLUSIONS: Symptoms relief, lower risk of hemorrhage and a normalized QOL were obtained in all patients with a safe and mini-invasive procedure.

Cardiovascular disease in dialysis patients.

Cardiovascular disease (CVD) is a highly common complication and the first cause of death in patients with end-stage renal disease (ESRD) on haemodialysis (HD). In this population, mortality due to CVD is 20 times higher than in the general population and the majority of maintenance HD patients have CVD. This is likely due to ventricular hypertrophy as well as non-traditional risk factors, such as chronic volume overload, anaemia, inflammation, oxidative stress, chronic kidney disease-mineral bone disorder and other aspects of the 'uraemic milieu'. Better understanding the impact of these numerous factors on CVD would be an important step for prevention and treatment. In this review we focus non-traditional CVD risk factors in HD patients.

Troponin I Levels in Asymptomatic Hemodialysis Patients.

BACKGROUND: End-stage renal disease (ESRD) represents a situation in which persistently elevated levels of cardiac troponins I (cTnI) are frequently found in the absence of clinically evident cardiac disease. Moreover, the effect of hemodialysis (HD) on cTnI levels is not definitively elucidated. The aim of this study was to investigate the effects of HD on cTnI levels in ESRD patients. METHODS: We enrolled 30 asymptomatic ESRD patients on maintenance HD. All the patients were dialyzed thrice weekly. We compared each other's cTnI levels obtained before HD sessions (pre-HD) and cTnI levels obtained before and after HD sessions (post-HD). RESULTS: The median value of baseline cTnI, measured before the first dialysis session of the week, was 0.018 ng/mL (interquartile range 0.012-0.051) and elevated levels (>0.034 ng/mL) were found in 9 (30%) patients. Pre-HD cTnI levels showed a statistically significant decrease between the first and the second weekly HD sessions (from 0.018 to 0.016 ng/mL; p = 0.002), while no difference was observed between the second and the third sessions over the week. Finally, no statistically significant differences were found between pre-HD and post-HD cTnI levels, considering each HD session and the averaged cTnI values. CONCLUSIONS: Our results indicate that HD does not significantly affect cTnI levels. Even when statistically significant, the observed changes were without clinical relevance indicating that HD does not affect by itself the diagnostic accuracy of cTnI assay in ESRD patients.

Vitamin D in Kidney Transplant Recipients: Mechanisms and Therapy.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and post-transplantation bone disease (PTBD) are potential effectors of both graft and vascular aging. Reduced 25(OH)D levels are highly prevalent in KTRs. Experimental and clinical evidence support the direct involvement of deranged vitamin D metabolism in CKD-MBD among KTRs. This review analyzes the pathophysiology of vitamin D derangement in KTRs and its fall out on patient and graft outcome, highlighting the roles of both nutritional and active vitamin D compounds to treat PTBD, cardiovascular disease (CVD) and graft dysfunction. Fibroblast growth factor-23-parathyroid hormone (PTH)-vitamin D axis, immunosuppressive therapy and previous bone status have been associated with PTBD. Although several studies reported reduced PTH levels in KTRs receiving nutritional vitamin D, its effects on bone mineral density (BMD) remain controversial. Active vitamin D reduced PTH levels and increased BMD after transplantation, but paricalcitol treatment was not accompanied by benefits on osteopenia. Vitamin D is considered protective against CVD due to the widespread pleiotropic effects, but data among KTRs remain scanty. Although vitamin deficiency is associated with lower glomerular filtration rate (GFR) and faster estimated GFR decline and data on the anti-proteinuric effects of vitamin D receptor activation (VDRA) in KTRs sound encouraging, reports on related improvement on graft survival are still lacking. Clinical data support the efficacy of VDRA against HPTH and show promising evidence of VDRA's effect in counteracting post-transplant proteinuria. New insights are mandatory to establish if the improvement of surrogate outcomes will translate into better patient and graft outcome.

[Palliative and Supportive Dialysis: Current Practices and Recommendations for Best Clinical Practice].

"Palliative dialysis" is defined as the renal replacement therapy directed to patients living the most critical phases of illness and the end-of-life stage. Offering targeted dialysis prescriptions becomes imperative when health conditions, along with comorbidities, unfavorable prognosis and complications, do not allow standard dialysis to be started or continued. Management should also integrate adequate supportive care measures in both incident and prevalent patients. This document summarizes nephrological recommendations and scientifical evidence regarding the palliative approach to dialysis, and proposes operative tools for a good clinical practice. After planning and sharing the route of care ("shared-decision-making"), which includes multidimensional evaluation of the patient, a pathway of treatment should be started, focusing on combining the therapeutical available options, adequacy and proportionality of care and patients' preferences. We propose a framework of indications that could help the nephrologist in practicing appropriate measures of treatment in patients' frailest conditions, with the aim of reducing the burden of dialysis, improving quality of life, providing a better control of symptoms, decreasing the hospitalization rates in the end-of-life stage and promoting a home-centered form of care. Such a decisional pathway is nowadays increasingly needed in nephrology practice, but not standardized yet.

Paricalcitol and cardiorenal outcome: from the IMPACT study to clinical practice.

Chronic kidney disease mineral bone disorders (CKD-MBD) encompass laboratory, vascular and bone abnormalities that might portend a poor prognosis in CKD. In spite of a great effort in elucidating the CKD-MBD natural history and pathogenesis, the underlying mechanisms are still largely unknown. However, a deficit in vitamin D is commonly reported as one of the first steps in CKD-MBD, and numerous epidemiological studies have associated serum vitamin D levels with different markers of cardiovascular disease and the risk of death in different populations. We herein summarize current evidence that links vitamin D deficiency to an adverse outcome and the results of the most recent clinical trials that have investigated the impact of paricalcitol supplementation on hard outcome in CKD patients.

The open system of FGF-23 at the crossroad between additional P-lowering therapy, anemia and inflammation: how to deal with the intact and the C-terminal assays?

Fibroblast growth factor 23 (FGF-23) has been associated with increased cardiovascular risk and poor survival in dialysis patients. It is well established that FGF-23 synthesis is directly induced by positive phosphate (P) balance. On the other hand, P-lowering treatments such as nutritional P restriction, P binders and dialysis are capable of reducing FGF-23 levels. However, there are many uncertainties regarding the possibility of adopting FGF-23 to guide the clinical decision-making process in the context of chronic kidney disease-mineral bone disorder (CKD-MBD). Furthermore, the best assay to adopt for measurement of FGF-23 levels (namely the intact vs the C-terminal one) remains to be determined, especially in conditions capable of altering the synthesis as well as the cleavage of the intact and biologically active molecule, as occurs in the presence of CKD and its complications. This Editorial discusses the main insights provided by the post hoc analysis of the NOPHOS trial, with particular attention given to evidence-based peculiarities of the intact and the C-terminal assays available for measuring FGF-23 levels, especially in patients receiving additive P-lowering therapy in the presence of inflammation, anemia and iron deficiency.

[Extended release calcifediol and paricalcitol in the treatment of secondary hyperparathyroidism: a network meta-analysis of indirect comparison].

Introduction: Secondary hyperparathyroidism (SHPT) is a common and major complication of chronic kidney disease (CKD) among patients on dialysis and in patients with CKD stage G3 to G5. SHPT in CKD is caused by disturbances in metabolic parameters. Paricalcitol (PCT), other active vitamin D analogous (doxercalciferol and alfacalcidol), and active vitamin D (calcitriol) have been commonly used to treat SHPT in non-dialysis CKD (ND-CKD) for several years. However, recent studies indicate that these therapies adversely increase serum calcium, phosphate, and fibroblast growth factor 23 (FGF-23) levels. Extended release calcifediol (ERC) has been developed as an alternative treatment for SHPT in ND-CKD. The present meta-analysis compares the effect of ERC against PCT in the control of PTH and calcium levels. Methods: A systematic literature review was conducted, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to identify studies for inclusion in the Network Meta-Analysis (NMA). Results: 18 publications were eligible for inclusion in the network meta-analysis and 9 articles were included in the final NMA. The estimated PTH reduction from PCT (-59.5 pg/ml) was larger than the PTH reduction from ERC (-45.3 pg/ml), but the difference in treatment effects did not show statistical significance. Treatment with PCT caused statistically significant increases in calcium vs. placebo (increase: 0.31 mg/dl), while the marginal increase in calcium from treatment with ERC (increase: 0.10 mg/dl) did not reach statistical significance. Conclusions: The evidence suggests that both PCT and ERC are effective in reducing levels of PTH, whereas calcium levels tended to increase from treatment with PCT. Therefore, ERC may be an equally effective, but more tolerable treatment alternative to PCT.

SGLT2 Inhibitors in Diabetic and Non-Diabetic Chronic Kidney Disease.

Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin-angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection.

Extracorporeal veno-venous ultrafiltration in congestive heart failure: What's the state of the art? A mini-review.

Hospitalizations for heart failure exceed 1 million per year in both the United States and Europe and more than 90% are due to symptoms and signs of fluid overload. Rates of rehospitalizations or emergency department visit at 60 days are remarkable regardless of whether loop diuretics were administered at low vs high doses or by bolus injection vs continuous infusion. Ultrafiltration (UF) has been considered a promising alternative to stepped diuretic therapy and it consists in the mechanical, adjustable removal of iso-tonic plasma water across a semipermeable membrane with the application of hydrostatic pressure gradient generated by a pump. Fluid removal with ultrafiltration presents several advantages such as elimination of higher amount of sodium with less neurohormonal activation. However, the conflicting results from UF studies highlight that patient selection and fluid removal targets are not completely understood. The best way to assess fluid status and therefore establish the fluid removal target is also still a matter of debate. Herein, we provide an up-to-date systematic review about the role of ultrafiltration among patients with fluid overload and its gaps in daily practice.

The pathophysiology and management of vascular calcification in chronic kidney disease patients.

INTRODUCTION: Vascular calcification (VC) which is the pathological mineral deposition in the vascular system, predominantly at the intimal and medial layer of the vessel wall, is an important comorbidity in patients with chronic kidney disease (CKD) leading to significant morbidity and mortality while necessitating appropriate treatment. Our review aims to provide an in-depth analysis of the current understanding of VC. AREAS COVERED: In this review, we first discuss the pathophysiology of VC in CKD patients, then we explain the methods to predict and assess VC. Afterwards, we provide the currently available as well as the potential therapeutic approaches of VC. We finally discuss our understanding regarding the current situation surrounding VC in our expert opinion section. EXPERT OPINION: Predicting, assessing and treating VC is crucial and the future advances in the field of research surrounding VC will potentially occur in one or more of these three areas of clinical management. There is a current lack of evidence and consensus regarding specific therapeutic options for alleviating VC and this situation may not necessitate VC to be determined, detected, and documented before the available options are implemented. Regardless, the prediction and assessment of VC is still important and requires further improvement together with the developments in therapeutic alternatives. The future has the potential to bring better research which would guide and improve the management of this patient group. A more specialized approach consisting of targeted therapies and more tailored management plans for patients with CKD and VC is on the horizon.

Early aging and premature vascular aging in chronic kidney disease.

Aging is the progressive decline of body functions and a number of chronic conditions can lead to premature aging characterized by frailty, a diseased vasculature, osteoporosis, and muscle wasting. One of the major conditions associated with premature and accelerated aging is chronic kidney disease (CKD), which can also result in early vascular aging and the stiffening of the arteries. Premature vascular aging in CKD patients has been considered as a marker of prognosis of mortality and cardiovascular morbidity and therefore requires further attention. Oxidative stress, inflammation, advanced glycation end products, fructose, and an aberrant gut microbiota can contribute to the development of early aging in CKD patients. There are several key molecular pathways and molecules which play a role in aging and vascular aging including nuclear factor erythroid 2-related factor 2 (Nrf-2), AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and klotho. Potential therapeutic strategies can target these pathways. Future studies are needed to better understand the importance of premature aging and early vascular aging and to develop therapeutic alternatives for these conditions.

Future treatment of vascular calcification in chronic kidney disease.

INTRODUCTION: Cardiovascular disease (CVD) is one of the global leading causes of morbidity and mortality in chronic kidney disease (CKD) patients. Vascular calcification (VC) is a major cause of CVD in this population and is the consequence of complex interactions between inhibitor and promoter factors leading to pathological deposition of calcium and phosphate in soft tissues. Different pathological landscapes are associated with the development of VC, such as endothelial dysfunction, oxidative stress, chronic inflammation, loss of mineralization inhibitors, release of calcifying extracellular vesicles (cEVs) and circulating calcifying cells. AREAS COVERED: In this review, we examined the literature and summarized the pathophysiology, biomarkers and focused on the treatments of VC. EXPERT OPINION: Even though there is no consensus regarding specific treatment options, we provide the currently available treatment strategies that focus on phosphate balance, correction of vitamin D and vitamin K deficiencies, avoidance of both extremes of bone turnover, normalizing calcium levels and reduction of inflammatory response and the potential and promising therapeutic approaches liketargeting cellular mechanisms of calcification (e.g. SNF472, TNAP inhibitors).Creating novel scores to detect in advance VC and implementing targeted therapies is crucial to treat them and improve the future management of these patients.