GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective in improving glycaemic control either as monotherapy or in combination with other hypoglycaemic drugs, and have low incidence of side effects, such as hypoglycaemia, nausea and weight gain, thus increasing patients' adherence to therapy. Methods: In this review we report the most recent studies demonstrating the beneficial effects of GLP-1RAs on renal outcomes, and also discuss the direct and indirect mechanisms through which they confer kidney protection. Finally, we discuss the metabolic and anti-inflammatory effects of GLP-1RAs in diabetic patients with COVID-19 disease. Results: GLP-1RAs have a nephroprotective action, which is expressed through both indirect (improvement of blood pressure and glycaemic control, weight loss) and direct (restoration of normal intrarenal haemodynamics, prevention of ischaemic and oxidative damage) effects. They have shown also metabolic and anti-inflammation beneficial effects in patients with COVID-19 disease. Conclusions: GLP-1RAs prevent albuminuria and slow the decline of renal function towards end stage renal disease in patients with diabetic kidney disease. They might be an opportunity to break the typical inflammation processes of COVID-19 disease.

SGLT2 Inhibitors: A Broad Impact Therapeutic Option for the Nephrologist.

Since their introduction as antidiabetic drugs, SGLT2 inhibitors (SGLT2i) have come a long way, proving to be beneficial on cardiovascular and renal outcomes independently of diabetes status. The benefits go far beyond glycemic control, and both the cardio- and nephroprotection are underpinned by diverse mechanisms. From the activation of tubule glomerular feedback and the consequent reduction in hyperfiltration to the improvement of hypoxia and oxidative stress in the renal cortex, SGLT2i have also been shown to inhibit hepcidin and limit podocyte damage. Likewise, they improve cardiac metabolism and bioenergetics, and reduce necrosis and cardiac fibrosis and the production of adipokines, cytokines, and epicardial adipose tissue mass. In terms of outcomes, the efficacy has been demonstrated on blood pressure control, BMI, albuminuria, stroke, heart disease, and mortality rate due to cardiovascular events. Patients with chronic kidney disease and proteinuria, with or without diabetes, treated with some SGLT2i have a reduced risk of progression. The analysis of subgroups of individuals with specific diseases such as IgA nephropathy has confirmed this solid effect on renal outcomes. Given these overarching activities on such a broad pathophysiological background and the favorable safety profile that goes with the use of SGLT2i, it is now certain that they are changing our approach to clinical interventions for important outcomes with an impressive impact.

[GLP-1 receptor agonists in the treatment of diabetes mellitus type 2: cardioprotection, and more!]

Optimal glycemic control in diabetic patients remains a difficult goal to achieve. Hypoglycemia, nausea and weight gain can compromise the patients' adherence to antidiabetic therapy over time. GLP-1 receptor agonists have been shown to improve glycemic control and reduce the incidence of side effects both when used in monotherapy and in combination with other hypoglycemic drugs. The growing interest of nephrologists in GLP-1 receptor agonists derives from numerous studies showing that not only they positively affect traditional cardiovascular risk factors, but also exert a protective effect on renal function regardless of their hypoglycemic effects, thus delaying the development and progression of diabetic nephropathy. The aim of this paper is to review the latest evidence on pharmacokinetics and pharmacodynamics and the direct and indirect mechanisms through which GLP-1 receptor agonists confer nephroprotection, improving the renal outcomes of diabetic patients.

Plasma Levels of Inflammatory Biomarkers in Peripheral Arterial Disease: Results of a Cohort Study.

Previous research analyzed the level of plasma inflammatory markers in patients with coronary disease, but very few studies have evaluated these markers in patients with peripheral arterial disease (PAD). The objective of this study was to investigate the plasma levels of inflammatory markers in patients with PAD and in healthy controls. The following plasma levels of biomarkers were measured in 80 patients with PAD (mean age 68 ± 5 years) and in 72 healthy participants (mean age 67 ± 6 years): interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), L-selectin (LS), neopterin (N), P-selectin (PS), E-selectin (ES), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and matrix metalloproteinase 2 (MMP-2), and 9 (MMP-9). Significantly higher levels of IL-6 (P < .001), TNF-α (P < .0001), ES (P < .0001), LS (P < .0001), PS (P < .0001), ICAM-1 (P < .001), VCAM-1 (P < .001), N (P < .001), MMP-2 (P < .001), and MMP-9 (P < .005) were found in the patients with PAD. Patients with PAD show a inflammation marker profile different from that of control participants. Reducing the high plasma levels of inflammatory markers could be a new therapeutic approach both for the prevention and the treatment of PAD.

ICAM-1 and SRD5A1 gene polymorphisms in symptomatic peripheral artery disease.

The genotype distribution of two gene polymorphisms, previously associated with peripheral artery disease (PAD), has been evaluated in a population of diabetic (DPAD) and non-diabetic (NDPAD) patients affected by symptomatic PAD (stages II-IV). A decreased frequency of the AA genotype of rs5498 (ICAM-1) was observed in the PAD subjects compared to controls but this result did not reach statistical significance (p=0.06 by chi-squared test). On the contrary, a significant increase in the frequency of the GG homozygous genotype of rs248793 (SRD5A1) was observed in the PAD patient group in comparison to controls (p=0.01). These data confirm that the GG genotype of rs248793 in the SRD5A1 gene is significantly associated with symptomatic PAD and show a trend towards a stronger association with the non-diabetic status.

Thrombophilia in Patients With Lower Limb Deep Veins Thrombosis (LDVT) Results of a Monocentric Survey on 103 Consecutive Outpatients.

A debate concerns the utility of large screening for acquired or inherited thrombophilia. The study concerns relationship between inherited thrombophilic status and lower limb deep vein thrombosis (LDVT) and highlights the possible use of extensive thrombophilia screening to determine an emerging risk of LDVT. From January 2010 to January 2012, 103 consecutive patients with LDVT were considered. In all, 57 (55.3%) patients with LDVT showed inherited thrombophilia. The most frequent trombophilic alterations were deficiency of protein S (33 patients, 32.0%), methylentethrafolate reductase (MTHFR) gene C677T variant (22 patients, 21.4%), protrombin gene G20210A alteration (50, 14.6%), and deficiency of protein C (12, 11.6%). Age and MTHFR variant were found related to LDVT and thrombophilia was related to distal LDVT. A high frequency of thrombophylic factor was found in patients with LDVT, but we believe that a generic genetic screening should not be suggested for these patients.

Neopterin: a potential marker in chronic peripheral arterial disease.

Neopterin is a marker of macrophage activation that has exhibited high plasma levels in atherosclerotic diseases including coronary heart disease and critical limb ischemia. The role of neopterin in chronic peripheral arterial disease (PAD) has yet to be elucidated. In the present study, neopterin (Ν) serum concentrations were analyzed in asymptomatic (AsP) and symptomatic (SyP) patients with PAD as well as controls (C). In total 120 subjects, 40 AsP [ankle brachial index (ABI) ≤0.90], 40 SyP (ABI ≤0.90 plus pain in legs) and 40 controls (ABI >0.9) were enrolled. The results of the present study showed that neopterin plasma levels were statistically different among the groups. These findings demonstrated that activation of N­mediated monocyte­macrophage, was also observed in chronic PAD.

Patients with unrecognized peripheral arterial disease (PAD) assessed by ankle-brachial index (ABI) present a defined profile of proinflammatory markers compared to healthy subjects.

BACKGROUND: Many studies have postulated that atherosclerosis should be considered as an inflammatory disease. In addition, some studies have focused on the relationship between inflammation and peripheral arterial disease (PAD). OBJECTIVE: Define the plasma levels of soluble markers, including the proinflammatory cytokine interleukin-6 (IL-6), the anti-inflammatory cytokine transforming growth factor-ß1 (TGF-ß1), the endothelial-specific adhesion factor (E-selectin) and two proteinases involved in extracellular matrix degradation (matrix metalloproteinases-2 and -9, MMP-2, and MMP-9) in previously unrecognized patients with peripheral artery disease (PAD) and non-PAD controls. RESULTS: Significantly higher levels of IL-6, E-selectin and MMP-2/MMP-9 and significantly reduced levels of TGF-ß1 were found in PAD patients (ankle-brachial index, ABI⩽0.9) compared to non-PAD control subjects (1.4>ABI>0.9). CONCLUSION: The results demonstrated the subjects with unrecognized PAD (ABI⩽0.9) show a characteristic phlogistic pattern differently from healthy subjects and it strongly supports the pivotal role played by inflammatory and immunological mechanisms in the initiation and progression of the atherosclerotic process in peripheral arteries. These biomarkers could be helpful to screen the susceptibility for the diseases in peripheral arteries.

Inflammation in peripheral arterial disease (PAD).

Peripheral arterial disease (PAD) affects a large number of individuals over the age of 55 years old, and data from studies has shown a relationship between inflammation, and PAD. Many researchers have not only focused on the role played by inflammatory biomarkers and the progression of PAD, but also on the efficiency of biomarkers in monitoring medical, surgical and interventional strategies in PAD patients. In this review, Authors aim to demonstrate that biomarkers play a key role in the pathophysiology of PAD, and consequently they could be screened to highlight individuals showing these crucial pathophysiological signs. Based on a large debate about phlogosis, it is now considered to be a relevant objective in reducing the prevalence and consequences of atherosclerotic diseases such as PAD. Finally, efforts must be made towards addressing this very important objective, and consequently a greater number of studies need to be made in combatting phlogosis, especially among PAD patients.

Phase II study of the antiretroviral activity and safety of the glucocorticoid receptor antagonist mifepristone in HIV-1-infected patients.

Preclinical studies have shown that the anti-glucocorticoid drug mifepristone effectively inhibits HIV replication both in vitro and in vivo. However, the drug did not demonstrate anti-HIV activity in a previous phase I/II study when administered at the daily dose of 75-225 mg. The aim of this study was to assess whether mifepristone may exert antiretroviral activity or influence immunological parameters when administered orally at daily doses of 150 or 300 mg in highly active antiretroviral therapy (HAART)-naïve HIV-infected patients. We performed an open label non-randomized phase II study that included 26 patients who underwent 28 days of once daily oral administration of 150 (12 subjects) or 300 mg (14 subjects) of mifepristone. A total of 3 patients dropped out of the study, respectively 1 in the 150 mg dose group and 2 in the 300 mg dose group. The main hemato-chemical alterations reported were hypokalemia and increase in the blood levels of cortisol, especially in those patients that received mifepristone at the dose of 300 mg/day. Although we observed a trend of reduced viral load along the study in both groups, statistical significance was not achieved for either the primary nor the secondary endpoints. In summary, mifepristone treatment was well-tolerated but it failed to significantly influence viro-immunological parameters in HAART-naïve HIV-infected patients.

Prevalence of high ankle-brachial index (ABI) in general population of Southern Italy, risk factor profiles and systemic cardiovascular co-morbidity: an epidemiological study.

Many studies have been carried out to assess the prevalence, risk factors and co-morbidities of peripheral artery disease (PAD). By contrast, to date there is a lack of data on patients with high-ABI. This study aimed at estimating the prevalence of increased ABI (ABI>1.4) and to evaluate the involvement of traditional cardiovascular (CV) risk factors and the atherosclerotic burden (peripheral and carotid arteries) of these patients in a population of Southern Italy. We invited 9647 subjects, age ranging from 30 to 80, by letters to undergo an ABI measurement. Consequently, in patients with ABI>1.4, an ultrasound evaluation of the peripheral and carotid arteries was performed. An ABI>1.4 was found in 260 of 3412 subjects (7.6%). Statistically significant differences were reported in age, diabetes and hypertension, body mass index (BMI) and waist circumference (WC). No differences in sex distribution, dyslipidemia and smoke prevalence were observed. Moreover, 67.9% of ABI>1.4 patients showed a peripheral intima-media thickness (IMT)>0.9 mm; at linear regression it was correlated with ABI values; 25% of patients showed peripheral plaques. A carotid IMT>0.9 mm was reported in 78.6% of high-ABI patients and 32.1% were affected by atherosclerotic plaques. The observed increased-ABI prevalence of 7.6% was higher than previously reported. This was more prevalent in an older population with diabetes, hypertension and obesity. Moreover, these patients are characterized by an extended atherosclerotic involvement. Further studies are needed to clarify this evidence, a longitudinal observation of this clinical outcome, as we are performing, could provide a number of interesting elements.

Study on unrecognized peripheral arterial disease (PAD) by ankle/brachial index and arterial comorbidity in Catania, Sicily, Italy.

Peripheral arterial disease (PAD) is under diagnosed and early diagnosis decreases consequences. We screened unrecognized PAD focusing on arterial co-morbidities. In the 3412 subjects, screened from 10 general practices in the city of Catania (Sicily, Italy), ankle brachial index (ABI) measurements were performed. An ABI < or =0.9 was considered as valid in diagnosing PAD. ABI value < or =0.9 was found in 2.3%, and a significant rate of carotid stenosis was also found Echocardiographic markers left ventricular diameter (LVD) >55 mm, interventricular septum (IVS) >11 mm, left ventricular diastolic volume (LVDV) was found > 100 ml), and ejection fraction (EF) was <50% were found with high frequency in those with ABI < or =0.9. Unrecognized PAD is lower compared with other findings but our prevalence resulted higher than other prevalence previously found by other study performed in Italy. Unrecognized PAD shows significant arterial co-morbidities and the ABI is a useful method to screen asymptomatic PAD.

Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer's disease and vascular dementia.

Inflammation has been involved in the development of dementia in cerebrovascular diseases. To investigate the cellular activation of the peripheral immune system in patients with Alzheimer's disease (AD) and vascular dementia (VaD), we determined the presence of IL-18 and TGF-beta1 in the plasma by using ELISA. The levels of IL-18 and TGF-beta1 were significantly elevated in patients with AD and VaD compared to non-demented, age-matched subjects. We found an inverse correlation between the levels of IL-18 and TGF-beta1 in AD patients. In VaD patients, the correlation between IL-18 and TGF-beta1 reached a borderline positive value. Whereas, in the non-demented, age-matched subjects, a positive correlation between IL-18 and TGF-beta1 levels was observed. These findings indicate that IL-18 and TGF-beta1 elevation is associated with AD and VaD patients, confirming that the immune system might exert a remarkable role in the development and progression of neurodegenerative disorders. Moreover, as different modifications were detected in the patients affected by AD and VaD, we propose that IL-18 and TGF-beta1 plasma levels might represent possible differential biomarkers.

Propionyl-L-carnitine therapy: effects on endothelin-1 and homocysteine levels in patients with peripheral arterial disease and end-stage renal disease.

BACKGROUND/AIMS: Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy. DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months. RESULTS: In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group. CONCLUSIONS: Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.

Analysis of interleukin (IL)-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and IL-1 accessory protein in HCV-associated lymphoproliferative disorders.

Hepatitis C virus (HCV) causes hepatitis, liver cirrhosis and hepatocellular carcinoma, and may also induce type II mixed cryoglobulinemia syndrome (MC), a disease characterized by clonal B-cell lymphoproliferations that can evolve into non-Hodgkin's lymphoma (NHL). Interleukin-1 (IL-1) is a cytokine that plays an important role in initiating the cascade of events of immunoinflammatory responses through costimulation of T lymphocytes, B-cell proliferation, induction of adhesion molecules and stimulation of the production of other inflammatory cytokines. The role of IL-1 in immunoinflammatory responses is highlighted by the presence of endogenous regulators (IL-1 receptor antagonist, soluble receptors type 1 and II, human IL-1 accessory protein) that, when secreted into the blood stream may serve as endogenous regulators of IL-1 action. The aim of this study was to evaluate whether abnormalities in the blood levels of IL-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and human IL-1 accessory protein in HCV+ patients are associated with development of MC and/or NHL. Relative to healthy controls, we observed: i) an increase in the circulating levels of IL-1beta in HCV+ patients simultaneously affected by NHL; ii) increased levels of IL-1 accessory protein in patients singly infected by HCV; iii) increase of IL-1 receptor antagonist in HCV+ patients and in those affected also by NHL with or without MC; iv) a homogeneous increase of sIL-1R type II in all the subgroup of patients. These data indicate that an attempt to increased circulating levels of IL-1 inhibitors occurs at different extent in the course of HCV infection as well as in its progression to NHL and/or MC.