[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.

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.

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.

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.

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.

[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.

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.

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.

Variáveis socioeconômicas e demográficas associadas a autorrelato de violência doméstica durante o "Fique em casa!": estudo transversal com amostra de uma comunidade universitária / Socioeconomic and Demographic Variables Associated with Self-Reported Domestic Violence During the "Stay At Home!" Mandate: a Cross-Sectional Study with a Sample of a University Community

Este estudo teve como objetivo estimar a frequência e identificar variáveis socioeconômicas e demográficas associadas ao autorrelato de violência doméstica durante as medidas de distanciamento social decorrentes da pandemia da COVID-19 em uma comunidade universitária. Trata-se de estudo transversal com amostra de conveniência online. Estudantes, técnicos administrativos e professores eram elegíveis ao estudo. A participação consistiu em responder a um questionário autoaplicável com questões sociodemográficas e da vivência da pandemia. Foram calculadas frequências absolutas e relativas e comparadas as proporções nas variáveis categóricas pelo teste Qui-Quadrado. Estimaram-se razões de chances via regressão logística para identificar os fatores associados ao autorrelato de violência doméstica durante o distanciamento social. De julho a agosto de 2020, 2.629 participantes responderam ao questionário. A maioria era do sexo feminino (57%), solteira (67%), branca (55%) e com até 29 anos de idade (62%). O autorrelato de violência doméstica esteve associado ao nível fundamental/médio (RCaj.: 2,80; IC95%: 1,60 ­ 5,50), ao nível de graduação (RCaj.: 2,20; IC95%: 1,20 ­ 4,40), ao sexo feminino (RCaj.: 1,60; IC95%: 1,20 ­ 2,20) e a ser solteiro (RCaj.: 1,60; IC95%: 1,10 ­ 2,40). O enfrentamento da violência, especialmente contra as mulheres, pessoas solteiras e com baixa escolaridade, deve ser construído a partir de uma base intersetorial e em rede, envolvendo ações emancipatórias, cuidado, proteção, assistência psicossocial e capacitação profissional.

This study aimed to estimate the frequency and identify socioeconomic and demographic variables associated with self-reporting of domestic violence during social distancing measures resulting from the COVID-19 pandemic in a university community. This is a cross-sectional study with an online convenience sample. Students, administrative assistants, and professors were eligible for the study. Participation consisted of answering a self-administered questionnaire with sociodemographic questions and experiences of the pandemic. Absolute and relative frequencies were calculated, and the proportions of categorical variables were compared using the chi-square test. Odds ratios were estimated via logistic regression to identify factors associated with self-reporting of domestic violence during social distancing. From July to August 2020, 2,629 participants responded to the questionnaire. Most were female (57%), single (67%), white (55%), and were up to 29 years of age (62%). Self-reported domestic violence was associated with elementary/high school education (AOR.: 2.80; 95% CI: 1.60 ­ 5.50), undergraduate level (AOR.: 2.20; 95% CI: 1.20 ­ 4 .40), female sex (AOR.: 1.60; 95% CI: 1.20 ­ 2.20), and single status (AOR.: 1.60; 95% CI: 1.10 ­ 2.40). Combating violence, especially against women, single and low educated people, must be constructed from intersectoral and networked basis, involving liberating actions, care, protection, psychosocial assistance, and professional training.

Growth Differentiation Factor 15 (GDF-15) Levels Associate with Lower Survival in Chronic Kidney Disease Patients with COVID-19.

A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized for COVID-19, and whether they differ in patients with eGFR higher and lower than 45 mL/min. The association between patients' characteristics, plasma biomarkers and mortality was conducted by univariate logistic regression models and independent predictors of mortality were then used to create a multivariate prediction model through Cox regression. Patients with lower eGFR had a significant increase of GDF-15, CD-25 and RAGE, with higher plasma levels in non-survivors and in patients who needed ventilation. At univariate analysis, low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk. Independent association between GDF-15 quartiles and mortality risk was confirmed in the Cox model and adjusted for eGFR, age, fever and dyspnea (HR 2.28, CI 1.53−3.39, p < 0.0001). The strength of the association between GDF-15 quartiles and mortality risk increased in patients with lower compared to higher eGFR (HR 2.53, CI 1.34−4.79 versus HR 1.99, CI 1.17−3.39). Our findings may suggest a further investigation of the effect of GDF-15 signaling pathway inhibition in CKD.

Cytokine and Chemokine Retention Profile in COVID-19 Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) patients are more susceptible to infections compared to the general population. SARS-CoV-2 virus pathology is characterized by a cytokine storm responsible for the systemic inflammation typical of the COVID-19 disease. Since CKD patients have a reduced renal clearance, we decided to investigate whether they accumulate harmful mediators during the COVID-19 disease. We conducted a retrospective study on 77 COVID-19 hospitalized subjects in the acute phase of the illness. Thirteen different cytokines were assessed in plasma collected upon hospitalization. The patients were divided into three groups according to their estimated glomerular filtration rate, eGFR &lt; 30 (n = 23), 30 &lt; eGFR &lt; 60 (n = 33), eGFR &gt; 60 mL/min (n = 21). We found that Tumor Necrosis Factor α and its receptors I and II, Interleukin-7, Leukemia Inhibitory Factor, FAS receptor, Chitinase 3-like I, and the Vascular Endothelial Growth Factor showed an increased accumulation that negatively correlate with eGFR. Moreover, non-survivor patients with an impaired kidney function have significantly more elevated levels of the same mediators. In conclusion, there is a tendency in COVID-19 ESRD patients to accumulate harmful cytokines. The accumulation seems to associate with mortality outcomes and may be due to reduced clearance but also to increased biosynthesis in most severe cases.

Efficacy and Safety of COVID-19 Vaccine in Patients on Renal Replacement Therapy.

Patients with CKD on RRT are at high risk for severe disease and mortality in COVID-19 disease. We decided to conduct an observational prospective study to evaluate antibody response after vaccination for COVID-19 in a cohort of 210 adult patients on RRT (148 on HD; 20 on PD; and 42 kidney transplant recipients). Blood samples were taken before and 4 weeks after vaccination. Antibody levels were evaluated with CLIA immunoassay testing for IgG anti-trimeric spike protein of SARS-CoV-2. A positive antibody titer was present in 89.9% of HD patients, 90% of PD patients, and 52.4% of kidney transplant recipients. Non-responders were more frequent among patients on immunosuppressive therapy. Mycophenolate use in kidney transplant patients was associated with lower antibody response. The median antibody titer was 626 (228-1480) BAU/mL; higher in younger patients and those previously exposed to the virus and lower in HD patients with neoplasms and/or on immunosuppressive therapy. Only two patients developed COVID-19 in the observation period: they both had mild disease and antibody titers lower than 1000 BAU/mL. Our data show a valid response to COVID-19 mRNA vaccination in HD and PD patients and a reduced response in kidney transplant recipients. Mycophenolate was the most relevant factor associated with low response.

Argument mining as rapid screening tool of COVID-19 literature quality: Preliminary evidence.

Background: The COVID-19 pandemic prompted the scientific community to share timely evidence, also in the form of pre-printed papers, not peer reviewed yet. Purpose: To develop an artificial intelligence system for the analysis of the scientific literature by leveraging on recent developments in the field of Argument Mining. Methodology: Scientific quality criteria were borrowed from two selected Cochrane systematic reviews. Four independent reviewers gave a blind evaluation on a 1-5 scale to 40 papers for each review. These scores were matched with the automatic analysis performed by an AM system named MARGOT, which detected claims and supporting evidence for the cited papers. Outcomes were evaluated with inter-rater indices (Cohen's Kappa, Krippendorff's Alpha, s* statistics). Results: MARGOT performs differently on the two selected Cochrane reviews: the inter-rater indices show a fair-to-moderate agreement of the most relevant MARGOT metrics both with Cochrane and the skilled interval scores, with larger values for one of the two reviews. Discussion and conclusions: The noted discrepancy could rely on a limitation of the MARGOT system that can be improved; yet, the level of agreement between human reviewers also suggests a different complexity between the two reviews in debating controversial arguments. These preliminary results encourage to expand and deepen the investigation to other topics and a larger number of highly specialized reviewers, to reduce uncertainty in the evaluation process, thus supporting the retraining of AM systems.

A roadmap to parathyroidectomy for kidney transplant candidates.

Chronic kidney disease mineral and bone disorder may persist after successful kidney transplantation. Persistent hyperparathyroidism has been identified in up to 80% of patients throughout the first year after kidney transplantation. International guidelines lack strict recommendations about the management of persistent hyperparathyroidism. However, it is associated with adverse graft and patient outcomes, including higher fracture risk and an increased risk of all-cause mortality and allograft loss. Secondary hyperparathyroidism may be treated medically (vitamin D, phosphate binders and calcimimetics) or surgically (parathyroidectomy). Guideline recommendations suggest medical therapy first but do not clarify optimal parathyroid hormone targets or indications and timing of parathyroidectomy. There are no clear guidelines or long-term studies about the impact of hyperparathyroidism therapy. Parathyroidectomy is more effective than medical treatment, although it is associated with increased short-term risks. Ideally parathyroidectomy should be performed before kidney transplantation to prevent persistent hyperparathyroidism and improve graft outcomes. We now propose a roadmap for the management of secondary hyperparathyroidism in patients eligible for kidney transplantation that includes the indications and timing (pre- or post-kidney transplantation) of parathyroidectomy, the evaluation of parathyroid gland size and the integration of parathyroid gland size in the decision-making process by a multidisciplinary team of nephrologists, radiologists and surgeons.

Erratum to: A roadmap to parathyroidectomy for kidney transplant candidates.

[This corrects the article DOI: 10.1093/ckj/sfac050.].

Calciphylaxis after kidney transplantation: a rare but life-threatening disorder.

Calciphylaxis is a rare disorder characterized by vascular calcification and thrombosis of the subcutaneous microcirculation, leading to painful necrotic skin lesions and bearing a dreadfully high mortality rate. This syndrome is frequently also termed uraemic calcific arteriolopathy, since most cases are observed in patients with kidney failure. However, it is increasingly clear that calciphylaxis may also affect patients with normal or only slightly impaired renal function, including kidney transplant recipients. A precise definition of the characteristics and risk factors of calciphylaxis developing after kidney transplantation has been hindered by the extreme rarity of this condition, which also hampered the development of effective therapeutic strategies. In the present issue of CKJ, Guillén and colleagues report the largest case series of calciphylaxis in kidney transplant recipients to date, outlining several features that are apparently specific to this population. In this editorial, we briefly present the epidemiology and pathogenesis of calciphylaxis in different patient populations and discuss recent findings for its therapeutic management.