Trattamento dell’iperuricemia nel paziente nefropatico: è giunto il momento di agire?

Numerosi studi epidemiologici condotti nella popolazione generale indicano che l\u2019iperuricemia si associa ad un incremento del rischio di sviluppare insufficienza renale. Inoltre, tra i soggetti che sono gi\ue0 affetti da una malattia renale cronica (MRC), l\u2019iperuricemia si associa sia ad una pi\uf9 rapida progressione di malattia sia ad un significativo incremento della mortalit\ue0 e degli eventi cardiovascolari. Tuttavia, ad oggi il ruolo causale dell\u2019iperuricemia nel determinare l\u2019insorgenza e la progressione del danno renale e cardiovascolare non \ue8 ancora completamente accertato, per cui le indicazioni al trattamento farmacologico dell\u2019iperuricemia asintomatica nei pazienti con MRC sono ancora affidate all\u2019orientamento personale del singolo medico. Al fine di stabilire se sia possibile esprimere un orientamento clinico basato sull\u2019evidenza abbiamo eseguito un\u2019analisi comparativa degli studi prospettici che hanno valutato l\u2019impatto della terapia ipouricemizzante con inibitori della xantino ossidasi (IXAO) rispetto all\u2019insorgenza e alla progressione del danno renale. Inoltre, dal momento che in passato nei soggetti con funzionalit\ue0 renale ridotta il trattamento con IXAO \ue8 stato associato ad un elevato rischio di tossicit\ue0, abbiamo analizzato la tossicit\ue0 di questi farmaci per vari gradi compromissione della funzione renale riassumendo indicazioni, controindicazioni e dosi consigliate nei pazienti affetti da MRC. In fine, a conclusione della nostra analisi abbiamo elaborato un algoritmo finalizzato ad orientare le decisioni cliniche in merito al trattamento dell\u2019iperuricemia nei soggetti affetti da MRC.Numerous epidemiological studies conducted in the general population indicate that hyperuricemia is associated with an increased risk of developing renal failure. Moreover, among those subjects who are already suffering from chronic kidney disease (CKD), hyperuricemia is associated with a more rapid progression of disease besides with an increased risk of mortality and cardiovascular events. However, to date, the causal role of hyperuricaemia in determining the onset and progression of cardiovascular and renal damage is not yet fully established. Therefore the indications for pharmacological treatment of hyperuricemia (and particulary of asymptomatic hyperuricemia) in patients with CKD are still assigned to the personal orientation of the physician. In order to produce an evidence-based clinical appraisal on this topic, we performed a comparative analysis that included all the prospective studies that have evaluated the impact of treatment with xanthine oxidase inhibithors (XOI) with respect to the onset and progression of CKD. Moreover, since in the past the treatment with XOI was associated with a high risk of toxicity in patients with impaired renal function, we analyzed the toxicity of these drugs for various degrees of renal function impairment summarizing indications, contraindications and recommended doses in patients affected by CKD. In the end, as conclusion of our analysis, we propose an algorithm aimed at guiding the clinical decisions about the treatment of hyperuricemia in patients with CKD

Native Hypovitaminosis D in CKD Patients : From Experimental Evidence to Clinical Practice

Native hypovitaminosis D (n-hVITD) is frequently found from the early stages of chronic kidney disease (CKD) and its prevalence increases with CKD progression. Even if the implications of n-hVITD in chronic kidney disease-mineral bone disorder (CKD-MBD) have been extensively characterized in the literature, there is a lot of debate nowadays about the so called "unconventional effects" of native vitamin D (25(OH)VitD) supplementation in CKD patients. In this review, highlights of the dimension of the problem of n-hVITD in CKD stages 2-5 ND patients will be presented. In addition, it will focus on the "unconventional effects" of 25(OH)VitD supplementation, the clinical impact of n-hVITD and the most significant interventional studies regarding 25(OH)VitD supplementation in CKD stages 2-5 ND

Gut microbiota composition and frailty in elderly patients with Chronic Kidney Disease

Background Frailty is common in older patients affected by chronic kidney disease (CKD). Since gut microbiota (gMB) may contribute to frailty, we explored possible associations between gMB and frailty in CKD. Methods We studied 64 CKD patients (stage 3b-4), categorized as frail (F, 38) and not frail (NF, 26) according to Fried criteria, and 15 controls (C), all older than 65 years. In CKD we assessed serum C-reactive protein, blood neutrophil/lymphocyte ratio, Malnutrition-inflammation Score (MIS); gMB was studied by denaturing gel gradient electrophoresis (DGGE), high-throughput sequencing (16S r-RNA gene), and quantitative real-time PCR (RT-PCR). Results No differences in alpha diversity between CKD and C and between F and NF patients emerged, but high-throughput sequencing showed significantly higher abundance of potentially noxious bacteria (Citrobacter, Coprobacillus, etc) and lower abundance of saccharolytic and butyrate-producing bacteria (Prevotella spp., Faecalibacterium prausnitzii, Roseburia spp.), in CKD respect to C. Mogibacteriaceae family and Oscillospira genus abundance was positively related to inflammatory indices in the whole CKD cohort, while that of Akkermansia, Ruminococcus and Eubacterium genera was negatively related. Compared with NF, in F there was a higher abundance of some bacteria (Mogibacteriacee, Coriobacteriacee, Eggerthella, etc), many of which have been described as more abundant in other diseases. Conclusions These results suggest that inflammation and frailty could be associated to gMB modifications in CKD

The human papillomavirus type 18 E6 oncoprotein induces Vascular Endothelial Growth Factor 121 (VEGF121) transcription from the promoter through a p53-independent mechanism

Altered angiogenic response is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular Endothelial Growth Factor (VEGF) is one of the most potent inducers of angiogenesis and is up-regulated in carcinoma of the cervix. Infection by high-risk human papillomavirus and persistent expression of viral oncogene E6 are etiologically linked to the development of cervical cancer. E6 is able to immortalize cells and induce malignant transformation by inactivating p53. In cervical cancer, regulation of VEGF expression is poorly described. Thus, we investigated whether E6 oncoprotein could regulate VEGF expression in HPV18-positive cervical cancer-derived HeLa cells harboring a wild-type p53. The alternative splicing of vegf mRNA renders three major isoforms of 121, 165 and 189 amino-acids in humans. We have designed isoform specific real time QRT-PCR assays to quantitate vegf transcripts and VEGF121 was the predominant isoform. Silencing HPV18 E6 mRNA with specific siRNA reduced VEGF121 expression by at least 50% whereas silencing of p53 did not alter its expression. Treatment with cycloheximide did not inhibit E6-induced VEGF121 expression. Collectively, these results suggest that HPV18 E6 oncoprotein contributes to tumor angiogenesis by inducing VEGF transcription from the promoter in a p53-independent manner

Sarcopenia is Associated with Malnutrition but Not with Systemic Inflammation in Older Persons with Advanced CKD

Background: In patients with chronic kidney disease (CKD), sarcopenia can be determined by a wide spectrum of risk factors. We evaluated the association of sarcopenia with nutritional, behavioral and inflammatory patterns in older patients with advanced CKD. Methods: we cross-sectionally evaluated 113 patients with CKD stages 3b-5. Sarcopenia was defined according to the EWGSOP2 criteria. We assessed: anthropometry, bioelectrical impedance analysis, physical, and psychological performance. Nutritional status was assessed using the Malnutrition Inflammation Score (MIS) and by verifying the eventual presence Protein Energy Wasting syndrome (PEW). Systemic inflammation was assessed by dosing: CRP, IL6, TNF\u3b1, MCP1, IL10, IL17, fetuin, IL12. Results: 24% of patients were sarcopenic. Sarcopenic individuals had lower creatinine clearance (18 \ub1 11 vs. 23 \ub1 19 mL/min; p = 0.0087) as well as lower BMI (24.8 \ub1 3.0 vs. 28.4 \ub1 5.5 Kg/m2; p < 0.0001) and a lower FTI (11.6 \ub1 3.9 vs. 14.4 \ub1 5.1 kg/m2, p = 0.023). Sarcopenic persons had higher prevalence of PEW (52 vs. 20%, p < 0.0001) and a tendency to have higher MIS (6.6 \ub1 6.5 vs. 4.5 \ub1 4.0, p = 0.09); however, they did not show any difference in systemic inflammation compared to non-sarcopenic individuals. Conclusions: CKD sarcopenic patients were more malnourished than non-sarcopenic ones, but the two groups did not show any difference in systemic inflammation

Molecular dynamics simulations reveal the mechanisms of allosteric activation of Hsp90 by designed ligands

Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone's active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators

Anthropometric indices of sarcopenia in patients with Chronic Kidney Disease

The Chronic Kidney Disease (CKD) is a kidney dysfunction for which the estimated Glomerular Filtration Rate (eGFR) result

Southern Ocean deep convection as a driver of Antarctic warming events

Simulations with a free-running coupled climate model show that heat release associated with Southern Ocean deep convection variability can drive centennial-scale Antarctic temperature variations of up to 2.0 °C. The mechanism involves three steps: Preconditioning: heat accumulates at depth in the Southern Ocean; Convection onset: wind and/or sea-ice changes tip the buoyantly unstable system into the convective state; Antarctic warming: fast sea-ice–albedo feedbacks (on annual–decadal timescales) and slow Southern Ocean frontal and sea-surface temperature adjustments to convective heat release (on multidecadal–century timescales) drive an increase in atmospheric heat and moisture transport toward Antarctica. We discuss the potential of this mechanism to help drive and amplify climate variability as observed in Antarctic ice-core records

Mechanisms of Endothelial Dysfunction in Resistance Arteries from Patients with End-Stage Renal Disease

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern