FGF23 as a Potential Pathophysiological Factor in Peripheral Arterial Disease Associated with Chronic Kidney Disease.

Fibroblast growth factor 23 (FGF23) levels are often elevated in chronic kidney disease (CKD). FGF23 and inflammation are common characteristics in CKD, and both are associated with worse disease progression and the occurrence of complications. The existence of an interaction between FGF23 and inflammation has been suggested, each of which influences the expression and activity of the other, leading to a vicious feedback loop with adverse outcomes, including cardiovascular disease and mortality. In this work, we determined circulating FGF23 levels in a group of patients with CKD stages 3 and 4 subjected to elective femoral endarterectomy due to established peripheral artery disease (PAD), a condition resulting from an athero-inflammatory process, and we studied its associations with different inflammatory markers and mediators. We evaluated its association with serum tumor necrosis factor (TNF)α, interleukin (IL) 6, and IL10, as well as with the gene expression levels of these parameters and A disintegrin and metalloproteinase domain-containing protein (ADAM) 17 in femoral vascular tissue and peripheral blood circulating cells (PBCCs). We also analyzed its association with serum concentrations of C-reactive protein (CRP), the systemic immune inflammation index (SII), and the neutrophil-to-lymphocyte ratio (NLR). Finally, we determined the vascular immunoreactivity of protein TNFα in a subgroup of patients. FGF23 concentrations were independently associated with circulating and PBCC mRNA levels of TNFα. Worst kidney function and diabetes were also found to be contributing to FGF23 levels. Patients with higher levels of FGF23 also had greater vascular immunoreactivity for TNFα.

Klotho expression in peripheral blood circulating cells is associated with vascular and systemic inflammation in atherosclerotic vascular disease.

Cardiovascular disease is the leading cause of death worldwide. New therapeutic strategies are aimed to modulate the athero-inflammatory process that partially orchestrates underlying vascular damage. Peripheral blood circulating cells include different immune cells with a central role in the development of the atherogenic inflammatory response. The anti-aging protein α-Klotho has been related to protective effects against CVD. KL is expressed in monocytes, macrophages, and lymphocytes where it exerts anti-inflammatory effects. In this work, we analyse the relationships of the levels of inflammatory markers with the expression of the KL gene in PBCCs and with the serum levels of soluble KL in atherosclerotic vascular disease. For this, we conducted a cross-sectional single-center case-control study including a study group of 76 CVD patients and a control group of 16 cadaveric organ donors without medical antecedent or study indicating CVD. Vascular artery fragments and whole blood and serum samples were obtained during elective or organ retrieval surgery. Serum levels of sKL, TNFα and IL10, and gene expression levels of KL, TNF, IL10, NFKB1, DNMT1, and DNMT3A in PBCCs were measured. In these cells, we also determined KL promoter methylation percentage. Histological and immunohistochemical analyses were employed to visualize atherosclerotic lesions and to measure IL10 and TNFα levels in vascular fragments. Patients with CVD presented higher values of proinflammatory markers both at systemic and in the vasculature and in the PBCCs, compared to the control group. In PBCCs, CVD patients also presented lower gene expression levels of KL gene (56.4% difference, P < 0.001), higher gene expression levels of DNMT1 and DNMT3A (P < 0.0001, for both) and a higher methylation status of in the promoter region of KL (34.1 ± 4.1% vs. 14.6 ± 3.4%, P < 0.01). In PBCCs and vasculature, KL gene expression correlated inversely with pro-inflammatory markers and directly with anti-inflammatory markers. sKL serum levels presented similar associations with the expression levels of pro- and anti-inflammatory markers in PBCCs. The differences in KL expression levels in PBCCs and in serum sKL levels with respect to control group was even greater in those CVD patients with macroscopically observable atheromatous plaques. We conclude that promoter methylation-mediated downregulation of KL gene expression in PBCCs is associated with the pro-inflammatory status in atherosclerotic vascular disease.

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort Study.

BACKGROUND: We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. METHODS: We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. RESULTS: During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619-0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352-0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449-0.804), p < 0.001] (interaction p = 0.094). CONCLUSIONS: These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. TRIAL REGISTRATION: European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415.

Cost-effectiveness of the hospital nutrition screening tool CIPA.

INTRODUCTION: Hospital malnutrition is very common and worsens the clinical course of patients while increasing costs. Lacking clinical-economic studies on the implementation of nutrition screening encouraged the evaluation of the CIPA (Control of Food Intake, Protein, Anthropometry) tool. MATERIAL AND METHODS: An open, non-randomized, controlled clinical trial was conducted on patients admitted to internal medicine and general and digestive surgery wards, who were either assigned to a control (standard hospital clinical care) or to an intervention, CIPA-performing ward (412 and 411, respectively; n = 823). Length of stay, mortality, readmission, in-hospital complications, and quality of life were evaluated. Cost-effectiveness was analysed in terms of cost per quality-adjusted life years (QALYs). RESULTS: The mean length of stay was higher in the CIPA group, though not significantly (+ 0.95 days; p = 0.230). On the surgical ward, more patients from the control group moved to critical care units (p = 0.014); the other clinical variables did not vary. Quality of life at discharge was similar (p = 0.53), although slightly higher in the CIPA group at 3 months (p = 0.089). Patients under CIPA screening had a higher mean cost of € 691.6 and a mean QALY gain over a 3-month period of 0.0042. While the cost per QALY for the internal medicine patients was € 642 282, the results for surgical patients suggest that the screening tool is both less costly and more effective. CONCLUSIONS: The CIPA nutrition screening tool is likely to be cost-effective in surgical but not in internal medicine patients.

Inflammatory Targets in Diabetic Nephropathy.

One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation.

Association between serum levels of Klotho and inflammatory cytokines in cardiovascular disease: a case-control study.

Decrease in soluble anti-aging Klotho protein levels is associated to cardiovascular disease (CVD). Diverse studies have shown a bidirectional relationship between Klotho and inflammation, a risk factor for the development of CVD. In this work we aimed to evaluate the association between Klotho and inflammatory cytokines levels in the context of human CVD.The study included 110 patients with established CVD and preserved renal function, and a control group of 22 individuals without previous history of cardiovascular events. Serum Klotho and IL10 levels were significantly lower in the CVD group. Inflammatory status, marked by the TNFα/IL10 ratio and the C-reactive protein (CRP) levels, was significantly increased in the group of patients with established CVD. Soluble Klotho levels were directly correlated with eGFR (r=0.217) and IL10 (r=0.209) and inversely correlated with age (r=-0.261), CRP (r=-0.203), and TNFα/IL10 (r=-0.219). This association with TNFα/IL10 remained significant in age-matched subgroups. Multiple logistic regression analysis showed that age, smoking and the neutrophil-to-lymphocyte ratio (NLR) constituted risk factors for the presence of CVD, while Klotho was a protective factor.In conclusion, in patients with established CVD, the reduction in soluble Klotho is associated with a pro-inflammatory status marked by lower IL10 concentrations and higher TNFα/IL10 ratio and CRP levels.

Fibroblast growth factor 23 expression in human calcified vascular tissues.

Vascular calcification is a major risk for cardiovascular disease and implies the transformation of smooth muscle cells to an osteoblastic phenotype as a consequence of dysregulation of calcium and phosphate metabolism. Fibroblast growth factor (FGF) 23 is the most potent phosphate regulator. Observational studies suggest that high levels of FGF23 are related to cardiovascular morbidity and mortality. In this work, we determined the levels of both the intact and the carboxi-terminal fragments of circulating FGF23 in 133 patients with established cardiovascular disease, the expression of FGF23, its receptors 1 and 3, and its co-receptor Klotho in vascular fragments of aorta, carotid and femoral in 43 out of this group of patients, and in a control group of 20 organ donors. Patients with atherosclerosis and vascular calcification presented increased levels of FGF23 respect to the control group. Vascular immunoreactivity for FGF23 was also significantly increased in patients with vascular calcification as compared to patients without calcification and to controls. Finally, gene expression of FGF23 and RUNX2 were also higher and directly related in vascular samples with calcification. Conversely, expression of Klotho was reduced in patients with cardiovascular disease when comparing to controls. In conclusion, our findings link the calcification of the vascular tissue with the expression of FGF23 in the vessels and with the elevation of circulating levels this hormone.

FGF23 and Klotho Levels are Independently Associated with Diabetic Foot Syndrome in Type 2 Diabetes Mellitus.

BACKGROUND: Diabetic foot syndrome (DFS) is a prevalent complication in the diabetic population and a major cause of hospitalizations. Diverse clinical studies have related alterations in the system formed by fibroblast growth factor (FGF)-23 and Klotho (KL) with vascular damage. In this proof-of-concept study, we hypothesize that the levels of FGF23 and Klotho are altered in DFS patients. METHODS: Twenty patients with limb amputation due to DFS, 37 diabetic patients without DFS, and 12 non-diabetic cadaveric organ donors were included in the study. Serum FGF23/Klotho and inflammatory markers were measured by enzyme-linked immunosorbent assay (ELISA). Protein and gene expression levels in the vascular samples were determined by immunohistochemistry and quantitative real-time PCR, respectively. RESULTS: Serum Klotho is significantly reduced and FGF23 is significantly increased in patients with DFS (p < 0.01). Vascular immunoreactivity and gene expression levels for Klotho were decreased in patients with DFS (p < 0.01). Soluble Klotho was inversely related to serum C-reactive protein (r = -0.30, p < 0.05). Vascular immunoreactivities for Klotho and IL6 showed an inverse association (r = -0.29, p < 0.04). Similarly, vascular gene expression of KL and IL6 were inversely associated (r = -0.31, p < 0.05). Logistic regression analysis showed that higher Klotho serum concentrations and vascular gene expression levels were related to a lower risk of DFS, while higher serum FGF23 was associated with a higher risk for this complication. CONCLUSION: FGF23/Klotho system is associated with DFS, pointing to a new pathophysiological pathway involved in the development and progression of this complication.

Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons.

Diabetic kidney disease is one of the most relevant complications in diabetes mellitus patients, which constitutes the main cause of end-stage renal disease in the western world. Delaying the progression of this pathology requires new strategies that, in addition to the control of traditional risk factors (glycemia and blood pressure), specifically target the primary pathogenic mechanisms. Nowadays, inflammation is recognized as a critical novel pathogenic factor in the development and progression of renal injury in diabetes mellitus. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic properties clinically used for more than 30 years in the treatment of peripheral vascular disease. In addition, this compound also exerts anti-inflammatory actions. In the context of diabetic kidney disease, pentoxifylline has shown significant antiproteinuric effects and a delay in the loss of estimated glomerular filtration rate, although at the present time there is no definitive evidence regarding renal outcomes. Moreover, recent studies have reported that this drug can be associated with a positive impact on new factors related to kidney health, such as Klotho. The use of pentoxifylline as renoprotective therapy for patients with diabetic kidney disease represents a new example of drug repositioning.

Preventing future fractures: effectiveness of an orthogeriatric fracture liaison service compared to an outpatient fracture liaison service and the standard management in patients with hip fracture.

An observational study was carried out in two hospitals in patients > 65 years admitted for hip fracture. At 6 months, 15% of patients in the hospital with orthogeriatric standard care and 75% in the hospital with fracture liaison service were receiving bisphosphonates. PURPOSE: Many patients with fractures are discharged without preventive therapy against further fractures. We sought to compare the effectiveness of an orthogeriatric fracture liaison service (FLS), outpatient FLS, and the standard care after hip fractures in prevention of future fractures. METHODS: An observational study was carried out in two hospitals in patients > 65 years of age, admitted between March and July 2016 for fractures. The Candelaria hospital (HUNSC) has no specific protocol for secondary prevention, while at the Negrin Hospital (HUGCDN), an FLS nurse visits the inpatients, gathers metabolic history, instructs regarding the diet, exercises, and fall prevention, and completes a discharge report regarding osteoporosis treatment. The prescription rate of osteoporosis treatment was analyzed at admission, discharge, and 6 months after discharge. We also analyzed the data of patients with hip fractures who attended the outpatient FLS before March 2016. RESULTS: We included a total of 185 inpatients with a mean age of 82 years and 73% were women. At admission, 8% of the patients in HUNSC and 10% in HUGCDN were receiving bisphosphonates. At discharge, the percentages were 8 and 96%, while at 6 months they were 15 and 75%, respectively (p < 0.001). The outpatient FLS recorded 206 hip fractures (27% of discharges for fractures), with 77% adherence to treatment at 6 months. CONCLUSIONS: Compared with the conventional management, the FLS model for inpatients with hip fractures achieved a fivefold increase in the adherence to treatment at 6 months, similar to the rates of outpatient FLS.

Perfil antiinflamatorio del paricalcitol en el receptor de trasplante renal / Anti-inflammatory profile of paricalcitol in kidney transplant recipients

Antecedentes y objetivos: El paricalcitol, un activador selectivo del receptor de la vitamina D, se utiliza en el tratamiento del hiperparatiroidismo secundario en el receptor de trasplante renal. Estudios tanto clínicos como experimentales realizados en pacientes renales no trasplantados muestran propiedades antiinflamatorias para esta molécula. En este estudio exploratorio, hemos evaluado el perfil antiinflamatorio del paricalcitol en receptores de trasplante renal. Métodos: Treinta y un pacientes trasplantados con hiperparatiroidismo secundario completaron 3 meses de terapia con paricalcitol oral (1μg/día). Se determinaron las concentraciones séricas y los niveles de expresión génica de citocinas inflamatorias en células mononucleares de sangre periférica al inicio y al final del estudio. Resultados: El paricalcitol provocó una disminución significativa en los niveles de hormona paratiroidea, sin cambios en los de calcio y fósforo. Además, indujo una reducción en las concentraciones séricas de la interleucina (IL)-6 y del factor de necrosis tumoral alfa (TNF-α), con reducciones porcentuales respecto al estado basal de un 29% (p<0,05) y de un 9,5% (p<0,05), respectivamente. Los niveles de expresión génica de la IL-6 y del TNF-α en células mononucleares de sangre periférica experimentaron un descenso de un 14,1% (p<0,001) y de un 34,1% (p<0,001), respectivamente. La proporción entre las citocinas proinflamatorias (TNF-α e IL-6) y la antiinflamatoria IL-10, tanto para los niveles séricos como para los de expresión génica, también disminuyó significativamente. Conclusiones: La administración del paricalcitol a receptores de trasplante renal se asocia con efectos beneficiosos sobre su estado inflamatorio, lo que podría asociarse a un potencial beneficio clínico (AU)

Background and objectives: Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. Methods: Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1μg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. Results: Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. Conclusions: Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits (AU)

Soluble levels and endogenous vascular gene expression of KLOTHO are related to inflammation in human atherosclerotic disease.

Atherosclerosis is a chronic inflammatory disorder affecting the artery wall. Klotho, an anti-aging factor expressed in the vessel walls that participates in the maintenance of vascular homeostasis, can be down-regulated by inflammation. In this proof-of-concept work we seek to characterize the arterial KLOTHO expression in the vascular wall, as well as the serum concentration of this protein, in a group of patients with clinical atherosclerotic disease. In addition, we aim to analyze the relationship between Klotho and inflammation. Vascular samples were obtained from 27 patients with atherosclerotic disease under an elective vascular surgery procedure, and from 11 control subjects (cadaveric organ donation programme). qRT-PCR was performed to analyze the gene expression of KLOTHO, TNF-α, IL-6, and IL-10 Serum levels of soluble KLOTHO were measured by ELISA. As compared with control subjects, serum concentrations and vascular expression of Klotho were lower in patients with atherosclerotic vascular disease, whereas inflammatory status was significantly higher. There was a negative and significant correlation between inflammatory parameters and Klotho. After controlling for the effect of other variables, partial correlation showed a direct relationship between vascular KLOTHO gene expression and IL-10 mRNA levels, whereas there was a negative association with serum LDL concentrations and vascular TNF-α expression. Our study indicates an inverse interrelationship between inflammation and Klotho in atherosclerosis. Further studies are necessary to elucidate whether the inflammatory state causes Klotho deficiency or, on the contrary, reduction of Klotho could be responsible for greater inflammation, and finally, to investigate the potential clinical relevance of this association.

Anti-inflammatory profile of paricalcitol in kidney transplant recipients. / Perfil antiinflamatorio del paricalcitol en el receptor de trasplante renal.

BACKGROUND AND OBJECTIVES: Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. METHODS: Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1µg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. RESULTS: Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. CONCLUSIONS: Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits.

Pericarditis purulenta por Estafilococo Panton-Valentine secundaria a implantes de cabello / Purulent pericarditis by Staphylococcus Panton-Valentine secondary to hair implants

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Clinical and cost-effectiveness analysis of early detection of patients at nutrition risk during their hospital stay through the new screening method CIPA: a study protocol.

BACKGROUND: Malnutrition is highly prevalent in hospitalized patients and results in a worsened clinical course as well as an increased length of stay, mortality, and costs. Therefore, simple nutrition screening systems, such as CIPA (control of food intake, protein, anthropometry), may be implemented to facilitate the patient's recovery process. The aim of this study is to evaluate the effectiveness and cost-effectiveness of implementing such screening tool in a tertiary hospital, consistent with the lack of similar, published studies on any hospital nutrition screening system. METHODS: The present study is carried out as an open, controlled, randomized study on patients that were admitted to the Internal Medicine and the General and Digestive Surgery ward; the patients were randomized to either a control or an intervention group (n = 824, thereof 412 patients in each of the two study arms). The control group underwent usual inpatient clinical care, while the intervention group was evaluated with the CIPA screening tool for early detection of malnutrition and treated accordingly. CIPA nutrition screening was performed upon hospital admission and classified positive when at least one of the following parameters was met: 72 h food intake control < 50%, serum albumin < 3 g/dL, body mass index < 18.5 kg/m2 (or mid-upper arm circumference ≤ 22.5 cm). In this case, the doctor decided on whether or not providing nutrition support. The following variables will be evaluated: hospital length of stay (primary endpoint), mortality, 3-month readmission, and in-hospital complications. Likewise, the quality of life questionnaires EQ-5D-5 L are being collected for all patients at hospital admission, discharge, and 3 months post-discharge. Analysis of cost-effectiveness will be performed by measuring effectiveness in terms of quality-adjusted life years (QALYs). The cost per patient will be established by identifying health care resource utilization; cost-effectiveness will be determined through the incremental cost-effectiveness ratio (ICER). We will calculate the incremental cost per QALY gained with respect to the intervention. DISCUSSION: This ongoing trial aims to evaluate the cost-effectiveness of implementing the malnutrition screening tool CIPA in a tertiary hospital. TRIAL REGISTRATION: Clinical Trial.gov ( NCT02721706 ). First receivevd: March 1, 2016 Last updated: April 8, 2017 Last verified: April 2017.