Association of Autofluorescent Advanced Glycation End Products (AGEs) with Frailty Components in Chronic Kidney Disease (CKD): Data from a Single-Center Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) is characterized by an overproduction and accumulation of advanced glycation end products (AGEs). Because AGEs may play a role in the development of malnutrition and sarcopenia, two essential components of frailty, we evaluated whether they may also contribute to the onset of frailty in CKD patients. METHODS: We performed a cross-sectional analysis of 117 patients. AGEs were quantified using a fluorescence spectrophotometer and soluble receptor for AGE (sRAGE) isoforms by ELISA. We defined frailty according to the frailty phenotype (FP) proposed by Fried. RESULTS: The average age of patients was 80 ± 11 years, 70% were male, and the mean eGFR was 25 + 11 mL/min/1.73m2. Frailty was diagnosed in 51 patients, and 40 patients were classified as pre-frail. AGEs and RAGE isoforms seem not to correlate with overall frailty. Instead, AGEs were associated with specific frailty domains, inversely associated with BMI (R = -0.22, p = 0.016) and directly associated with gait test time (R = 0.17, p = 0.049). AGEs were also associated with involuntary weight loss (OR 1.84 p = 0.027), independent of age and sex. CONCLUSIONS: AGEs are associated with some pivotal components of the frailty phenotype, although they are not associated with frailty overall.

Association between Advanced Glycation End-Products and Sarcopenia in Patients with Chronic Kidney Disease.

BACKGROUND: In patients with chronic kidney disease (CKD), there is an overproduction and accumulation of advanced glycation end-products (AGEs). Since AGEs may have detrimental effects on muscular trophism and performance, we evaluated whether they may contribute to the onset of sarcopenia in CKD patients. METHODS: We enrolled 117 patients. The AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer and soluble receptor for AGE (sRAGE) isoforms by ELISA. As for the sarcopenia definition, we used the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. RESULTS: The average age was 80 ± 11 years, 70% were males, and the mean eGFR was 25 + 11 mL/min/1.73 m2. Sarcopenia was diagnosed in 26 patients (with a prevalence of 22%). The sarcopenic patients had higher levels of circulating AGEs (3405 ± 951 vs. 2912 ± 722 A.U., p = 0.005). AGEs were higher in subjects with a lower midarm muscle circumference (MAMC) (3322 ± 919 vs. 2883 ± 700 A.U., respectively; p = 0.005) and were directly correlated with the gait test time (r = 0.180, p = 0.049). The total sRAGE and its different isoforms (esRAGE and cRAGE) did not differ in patients with or without sarcopenia. CONCLUSIONS: In older CKD patients, AGEs, but not sRAGE, are associated with the presence of sarcopenia. Therefore, AGEs may contribute to the complex pathophysiology leading to the development of sarcopenia in CKD patients.

In Patients with Chronic Kidney Disease Advanced Glycation End-Products Receptors Isoforms (sRAGE and esRAGE) Are Associated with Malnutrition.

BACKGROUND: in patients with chronic kidney disease (CKD), the inflammatory and pro-oxidant milieu may contribute to malnutrition development. In this study, we investigated the relationship between inflammation, advanced glycation end-products (AGEs), and their receptors (RAGEs) with malnutrition in CKD patients. METHODS: we evaluated 117 patients. AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer, soluble RAGEs isoforms, and inflammatory interleukins by ELISA. Malnutrition was assessed by a malnutrition inflammation score. RESULTS: mean age was 80 ± +11 years, eGFR was 25 ± +11 mL/min/1.73 m2 and BMI was 28 ± 5 Kg/m2. Malnourished individuals were older, had lower estimated protein intake (nPCR 0.65 ± 0.2 vs. 0.8 ± 0.2 vs. 0.8 ± 0.3, p = 0.01), higher C reactive protein (CRP 0.6 ± 1 vs. 0.6 ± 0.7 vs. 0.17 ± 0.13, p = 0.02) and tumor necrosis factor α (TNF α 14.7 ± 8.7 vs. 15.6 ± 8 vs. 11.8 ± 5.8, p = 0.029). Malnourished patients had higher sRAGE (2813 ± 1477 vs. 2158 ± 1236 vs. 2314 ± 1115, p = 0.035) and esRAGE (648 [408-1049] vs. 476 [355-680] vs. 545 [380-730] p = 0.033). In the multivariate analysis, only sRAGE maintained its association with malnutrition (p = 0.02) independently of aging and inflammation. CONCLUSIONS: in CKD patients, RAGEs isoforms, but not AGEs, are associated with malnutrition, irrespective of systemic inflammation, aging, and renal function.

Antibody responses to BNT162b2 mRNA vaccine: Infection-naïve individuals with abdominal obesity warrant attention.

OBJECTIVE: The excess of visceral adipose tissue might hinder and delay immune response. How people with abdominal obesity (AO) will respond to mRNA vaccines against SARS-CoV-2 is yet to be established. SARS-CoV-2-specific antibody responses were evaluated after the first and second dose of the BNT162b2 mRNA vaccine, comparing the response of individuals with AO with the response of those without, and discerning between individuals with or without prior infection. METHODS: Immunoglobulin G (IgG)-neutralizing antibodies against the Trimeric complex (IgG-TrimericS) were measured at four time points: at baseline, at day 21 after vaccine dose 1, and at 1 and 3 months after dose 2. Nucleocapsid antibodies were assessed to detect prior SARS-CoV-2 infection. Waist circumference was measured to determine AO. RESULTS: Between the first and third month after vaccine dose 2, the drop in IgG-TrimericS levels was more remarkable in individuals with AO compared with those without AO (2.44-fold [95% CI: 2.22-2.63] vs. 1.82-fold [95% CI: 1.69-1.92], respectively, p < 0.001). Multivariable linear regression confirmed this result after inclusion of assessed confounders (p < 0.001). CONCLUSIONS: The waning antibody levels in individuals with AO may further support recent recommendations to offer booster vaccines to adults with high-risk medical conditions, including obesity, and particularly to those with a more prevalent AO phenotype.

AGEs and sRAGE Variations at Different Timepoints in Patients with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are affected by enhanced oxidative stress and chronic inflammation, and these factors may contribute to increase advanced glycation end-products (AGEs). In this study we quantified AGEs and soluble receptors for AGE (sRAGE) isoforms and evaluated the association between their variations and eGFR at baseline and after 12 months. We evaluated 64 patients. AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer, and sRAGE by ELISA. Median age was 81 years, male patients accounted for 70%, 63% were diabetic, and eGFR was 27 ± 10 mL/min/1.73 m2. At follow up, sRAGE isoforms underwent a significant decrement (1679 [1393;2038] vs. 1442 [1117;2102], p < 0.0001), while AGEs/sRAGE ratios were increased (1.77 ± 0.92 vs. 2.24 ± 1.34, p = 0.004). Although AGEs and AGEs/sRAGE ratios were inversely related with eGFR, their basal values as well their variations did not show a significant association with eGFR changes. In a cohort of patients with a stable clinical condition at 1 year follow-up, AGEs/sRAGE was associated with renal function. The lack of association with eGFR suggests that other factors can influence its increase. In conclusion, AGEs/sRAGE can be an additional risk factor for CKD progression over a longer time, but its role as a prognostic tool needs further investigation.

Soluble Receptor for Advanced Glycation End Products and Its Forms in COVID-19 Patients with and without Diabetes Mellitus: A Pilot Study on Their Role as Disease Biomarkers.

The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.

Circulating Irisin and esRAGE as Early Biomarkers of Decline of Metabolic Health.

A decline in metabolic health may take place before observing any alteration in the levels of the traditional metabolic markers. New indicators of metabolic derangement are therefore compelling. Irisin is a myokine with important metabolic functions. The role of irisin as a metabolic biomarker in humans has not been fully established yet. We quantified plasma irisin and esRAGE in 106 apparently healthy individuals and we performed a cluster analysis to evaluate their associations with metabolic profile. Plasma levels of various traditional markers of metabolic risk (i.e., glucose and lipid levels) were all within the ranges of normality. We identified two clusters of individuals. Compared to cluster 2, individuals in cluster 1 had higher irisin levels, a metabolic profile shifted toward the limits of the reference ranges and lower esRAGE levels. The traditional metabolic blood tests seem not to be enough to identify a metabolic decline early. Irisin increase and esRAGE decrease may reflect a metabolic derangement at the beginning of its development. The role of these molecules as early biomarkers of decline of metabolic health seems an interesting topic to be further explored.

Usefulness of glycated albumin as a biomarker for glucose control and prognostic factor in chronic kidney disease patients on dialysis (CKD-G5D).

In chronic kidney disease patients on dialysis (CKD-G5D) accurate assessment of glycemic control is vital to improve their outcome and survival. The best glycemic marker for glucose control in these patients is still debated because several clinical and pharmacological factors may affect the ability of the available biomarkers to reflect the patient's glycemic status properly. This review discusses the role of glycated albumin (GA) both as a biomarker for glucose control and as a prognostic factor in CKD-G5D; it also looks at the pros and cons of GA in comparison to the other markers and its usefulness in hemodialysis and peritoneal dialysis.

Neutrophil gelatinase-associated lipocalin and acute kidney injury in endovascular aneurysm repair or open aortic repair: a pilot study.

INTRODUCTION: Acute kidney injury (AKI) occurs frequently after abdominal aortic surgery and there is currently no effective marker able to detect early onset. The aim of this study is to evaluate the ability of neutrophil gelatinase-associated lipocalin (NGAL) to early identify the development of acute renal damage in patients undergoing endovascular aneurysm repair (EVAR) or open aortic repair (OAR). MATERIALS AND METHODS: Serial samples of blood and urine were obtained from 25 patients undergoing both EVAR and OAR. Seven male subjects with AKI and 18 subjects with no-AKI (17 males, 1 female) were included in the study. We determined concentrations of serum creatinine (sCr) and urinary, serum and whole blood NGAL (uNGAL, sNGAL, bNGAL) collected at baseline, and after 4 and 18 hours. AKI was defined according to the RIFLE criteria (risk, injury, failure, loss of kidney function, and end-stage kidney disease): increase by 50% in sCr or reduction of at least 25% of estimated glomerular filtration rate (eGFR) from baseline. RESULTS: Seven patients developed AKI in the stage Risk. There was no significant difference in sNGAL concentrations in the AKI group as compared to no-AKI group. However, the uNGAL/uCreatinine ratio and bNGAL concentrations were significantly higher after 18 hours in the AKI group (no-AKI 1.69 (0.91 - 2.47) vs AKI 3.2 (2.08 - 5.92) ng/mg for uNGAL/uCreatinine ratio, P = 0.036; and no-AKI 83 (59 - 131) vs AKI 164 (126 - 263) ng/mL for bNGAL, P = 0.029). CONCLUSIONS: Our results suggest that uNGAL, sNGAL and bNGAL, after abdominal aortic surgery, are not suitable as early biomarkers of AKI.

Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide.

BACKGROUND AND AIMS: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominant inherited muscular dystrophies with multiple systemic involvement, often producing cardiac injury. This study sought to determine the clinical significance of elevated high sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI), and N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in this population. METHODS: Sixty DM patients (35 men and 25 women; mean age: 45.1 years, range: 12-73 years) underwent clinical cardiac investigations and measurements of serum hs-cTnT, hs-cTnI, creatine kinase (CK), and NT-proBNP. Left ventricular (LV) ejection fraction (EF) was assessed by echocardiography. RESULTS: Genetic analysis revealed that 46 of the 60 patients were DM1, and 14 DM2. Blood measurements showed persistent elevation of hs-cTnT and CK in 55/60 DM patients (91.73%). In contrast, hs-cTnI values were persistently normal throughout the study. Only 2 patients showed an EF <50%, being the overall range of this population between 40% and 79%. We found ECG abnormalities in 19 patients. Of these patients, 13 showed first or second-degree atrio ventricular (AV) blocks (PR interval ≥ 200 ms), 4 showed a left bundle branch block (LBBB) prolonged (QRS duration ≥120 ms), and 2 had an incomplete bundle branch block (QRS duration between 110 and 119 ms). After excluding patients with EF <50%, NT-pro-BNP measurement > 125 pg/mL was an independent predictor of ECG abnormalities. CONCLUSIONS: NT-pro-BNP levels may be considered to be used clinically to identify DM patients at increased risk of developing myocardial conduction abnormalities.

Anti-TNF-Mediated Modulation of Prohepcidin Improves Iron Availability in Inflammatory Bowel Disease, in an IL-6-Mediated Fashion.

Background. Anaemia is common in inflammatory bowel disease (IBD), frequently resulting from a combination of iron deficiency and of anaemia of chronic disease (ACD). ACD is characterized by macrophage iron retention induced by proinflammatory cytokines. Hepcidin is the master inducer of iron accumulation during ACD, and its production is mainly regulated by IL-6 and the novel erythroid hormone erythroferrone (ERFE). This study evaluates whether anti-TNF monoclonal antibodies therapy modurates hepcidin production and the levels of its main regulators, leading to a restoration of iron homeostasis. Methods. Sera were collected from 21 IBD patients, before each anti-TNF administration, for the first 6 weeks of therapy. Prohepcidin, erythropoietin, erythroferrone, C reactive protein, interleukin-6, iron markers, and haemoglobin levels were measured and clinical activity indexes were evaluated. Results. Serum prohepcidin, IL-6, CRP, and ferritin were significantly reduced after 6-week treatment; an increase in serum iron and total transferrin was observed. No changes in the EPO-ERFE axis were found. Remarkably, haemoglobin was significantly increased. Conclusions. Anti-TNF therapy improves iron metabolism and, subsequently, anaemia in IBD. This effect appears to be related to the modulation of the cytokine network and specifically IL-6 leading to a relevant decrease of hepcidin, a master regulator of ACD.

Effect of an isocaloric diet containing fiber-enriched flour on anthropometric and biochemical parameters in healthy non-obese non-diabetic subjects.

We studied the effect of soluble fiber-enriched products on anthropometric and biochemical variables in 30 healthy non-obese, non-diabetic subjects. This was a randomized, controlled crossover, single-blind, dietary intervention study performed for 8 weeks. Subjects received an isocaloric diet with fiber-enriched products for the first 4 weeks and with regular flour products for the following 4 weeks, or vice versa. Weight, height, measures of fat distribution (waist, hip circumference), glucose, insulin and triglycerides were measured at baseline, after 4 and 8 weeks of intervention. BMI and insulin sensitivity indices were calculated. Weight and BMI decreased in the first period of isocaloric diet in both groups, regardless of the type of flour consumed (weight p<0.01, p<0.001 respectively; BMI p = 0.01, p<0.001 respectively). At the end of the 8 weeks, weight and BMI further decreased in the group consuming the fiber-enriched diet (p<0.01). Insulin resistance, estimated with the Homeostasis Model Assessment index and the Lipid Accumulation Product index, improved in all subjects after the fiber-enriched flour diet (p = 0.03, p = 0.02, respectively). In conclusion, an isocaloric diet supplemented with fiber-enriched products may improve measures of fatness and insulin sensitivity in healthy non-obese non-diabetic subjects. We might hypothesize a similar effect also in subjects with metabolic abnormalities.

MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients.

MicroRNAs (miRNAs) are noncoding RNAs that act as negative regulators of gene expression. Interestingly, specific alterations of miRNA expression have been found in failing hearts of different etiologies. The aim of this study was to identify the miRNA expression pattern of peripheral blood mononuclear cells (PBMCs) derived from chronic heart failure (CHF) patients affected by ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. The expression profile of 257 miRNAs was assessed in 7 NIDCM patients, 8 ICM patients, and 9 control subjects by quantitative real-time PCR. Significantly modulated miRNAs were validated by using an independent set of 34 CHF patients (NIDCM = 19, ICM = 15) and 19 control subjects. Three miRNAs (miR-107, -139, and -142-5p) were downmodulated in both NIDCM and ICM patients versus control subjects. Other miRNAs were deregulated in only one of the CHF classes analyzed compared with control subjects: miR-142-3p and -29b were increased in NIDCM patients, while miR-125b and -497 were decreased in ICM patients. Bioinformatic analysis of miRNA predicted targets and of gene expression modifications associated with CHF in PBMCs indicated a significant impact of the miRNA signature on the transcriptome. Furthermore, miRNAs of both the NIDCM and the ICM signature shared predicted targets among CHF-modulated genes, suggesting potential additive or synergistic effects. The present study identified miRNAs specifically modulated in the PBMCs of NIDCM and ICM patients. Intriguingly, most of these miRNAs were previously reported as deregulated in human and/or mouse failing hearts. The identified miRNAs might have a potential diagnostic and/or prognostic use in CHF.