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Objective: In this study, we aimed to evaluate the kidney involvement assessed by estimated glomerular filtration rate (eGFR), the associations with specific clinical disease variables and laboratory findings, and the predictive role of eGFR on clinical outcomes of patients admitted with COVID-19 in Internal Medicine ward in the first wave., Patients and Methods: Clinical data of 162 consecutive patients hospitalized in the University Hospital Policlinico Umberto I in Rome, Italy, between December 2020 to May 2021 were collected and retrospectively analyzed., Results: The median eGFR was significantly lower in patients with worse outcomes than in patients with favorable outcomes [56.64 ml/min/1.73 m2 (IQR 32.27-89.73) vs. 83.39 ml/min/1.73 m2 (IQR 69.59-97.08), p<0.001]. Patients with eGFR < 60 ml/min/1.73 m2 (n=38) were significantly older compared to patients with normal eGFR [82 years (IQR 74-90) vs. 61 years (IQR 53-74), p<0.001] and they had fever less frequently [39.5% vs. 64.2%, p<0.01]. Kaplan-Meier curves demonstrated that overall survival was significantly shorter in patients with eGFR < 60 ml/min/1.73 m2 (p<0.001). In multivariate analysis, only eGFR < 60 ml/min/1.73 m2 [HR=2.915 (95% CI=1.110-7.659), p<0.05] and platelet to lymphocyte ratio [HR=1.004 (95% CI=1.002-1.007), p<0.01] showed a significant predictive value for death or transfer to intensive care unit (ICU)., Conclusions: Kidney involvement on admission was an independent predictor for death or transfer to ICU among hospitalized COVID-19 patients. The presence of chronic kidney disease could be regarded as a relevant factor in risk stratification for COVID-19.

Pulmonary embolism (PE) is a potentially life-threatening disorder. Beyond its usefulness in the prognostic stratification of heart failure, sST2 can represent a biomarker with high utility in several acute conditions. Our study was aimed to investigate whether sST2 can be used as a clinical marker of severity and prognostic outcome in acute PE. We enrolled 72 patients with documented PE and 38 healthy subjects; we measured the plasma concentrations of sST2 to evaluate the prognostic and severity performance of different levels of sST2 according to its association with the pulmonary embolism severity index (PESI) score and several parameters of respiratory function. PE patients had significantly higher levels of sST2 compared with healthy subjects (87.74 ± 17.1 vs. 17.1 ± 0.4 ng/mL, p < 0.001); we found higher PESI scores and serum lactate values in the group of patients with sST2 > 35 ng/mL compared with patients with sST2 < 35 ng/mL (138.7 ± 14.9 vs. 103.7 ± 15.1 and 2.43 ± 0.69 vs. 1.025 ± 0.05 mmol/L, respectively; p < 0.05). Patients with sST2 > 35 ng/mL showed higher radiological severity of PE compared with patients with sST2 < 35 ng/mL. Moreover, sST2 was the strongest parameter with a discriminative capacity for the development of acute respiratory failure and a PESI score >106 with respect to C reactive protein (CRP), creatinine, d-dimer, and serum lactate. We clearly demonstrated that sST2 significantly increased in PE and that its elevation was associated with disease severity. Therefore, sST2 may be used as a clinical marker in the evaluation of PE severity. However, further studies with larger patient populations are required to confirm these findings.

Objective: COVID-19 clinical presentation ranges from asymptomatic infection to an inflammatory cytokine storm with multi-organ failure and fatal outcomes. The identification of high-risk patients for severe disease is crucial to plan an early treatment and intensive follow-up. We aimed to investigate negative prognostic factors in a group of patients hospitalized for COVID-19., Patients and Methods: 181 patients (90 men and 91 women, mean age 66.56 ± 13.53 years) were enrolled. Each patient received a work-up including medical history, clinical examination, arterial blood gas analysis, laboratory blood tests, feasible ventilatory support required during hospital stay, intensive care setting required, duration of illness and length of hospital stay (>or<25 days). For the assessment of the severity of COVID-19, three main indicators were considered: 1) the intensive care unit (ICU) admission 2) the hospitalization length >25 days; 3) the need of non-invasive ventilation (NIV)., Results: The independent risk factor associated with the ICU admission were lactic dehydrogenase elevation (p=0.046), C reactive protein elevation (p=0.014) at hospital admission and direct oral anticoagulant home therapy (p=0.048); for hospital length >25 days: early corticosteroid therapy (p=0.035); for NIV treatment: ferritin elevation at hospital admission (p=0.006)., Conclusions: The presence of the above factors may be useful to identify patients at high risk of developing a severe COVID-19 that need an early treatment and intensive follow-up.

Background: Primary aldosteronism (PA) is characterized by several metabolic changes such as insulin resistance, metabolic syndrome, and adipose tissue (AT) inflammation. Mi(cro)RNAs (miRNAs) are a class of non-coding small RNA molecules known to be critical regulators in several cellular processes associated with AT dysfunction. The aim of this study was to evaluate the expression of some miRNAs in visceral and subcutaneous AT in patients undergoing adrenalectomy for aldosterone-secreting adrenal adenoma (APA) compared to the samples of AT obtained in patients undergoing adrenalectomy for non-functioning adrenal mass (NFA)., Methods: The quantitative expression of selected miRNA using real-time PCR was analyzed in surrounding adrenal neoplasia, peri-renal, and subcutaneous AT samples of 16 patients with adrenalectomy (11 patients with APA and 5 patients with NFA)., Results: Real-time PCR cycles for miRNA-132, miRNA-143, and miRNA-221 in fat surrounding adrenal neoplasia and in peri-adrenal AT were significantly higher in APA than in patients with NFA. Unlike patients with NFA, miRNA-132, miRNA-143, miRNA-221, and miRNA-26b were less expressed in surrounding adrenal neoplasia AT compared to subcutaneous AT in patients with APA., Conclusion: This study, conducted on tissue expression of miRNAs, highlights the possible pathophysiological role of some miRNAs in determining the metabolic alterations in patients with PA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Concistrè, Petramala, Circosta, Romagnoli, Soldini, Bucci, De Cesare, Cavallaro, De Toma, Cipollone and Letizia.)

Background: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing)., Methods: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants., Findings: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001)., Interpretation: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma., Funding: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino., Competing Interests: Declaration of interests IB has served as a consultant for Corcept Therapeutics, Sparrow Pharmaceutics, and Spruce Biosciences; was as a member of advisory or data safety monitoring boards for Adrenas Therapeutics, Recordati, and Strongbridge Biopharma (in all cases, institution fees were provided); and reports personal honoraria from Elsevier ClinicalKey. IC reports consulting fees and honoraria from HRA Pharma Rare Diseases and Recordati; was a member of advisory or data safety monitoring boards for HRA Pharma Rare Diseases and Recordati; and has participated in clinical studies from Corcept Therapeutics. ACh reports personal support for attending meetings or travel from Sanofi; personal honoraria from Ipsen; and was a member of advisory or data safety monitoring boards for Ipsen. TDe reports personal consulting fees for being a member of advisory or data safety monitoring boards for HRA Pharma Rare Diseases and Recordati; personal honoraria from Novartis; and has participated in clinical studies from Corcept Therapeutics and HRA Pharma Rare Diseases (for these, institution fees were provided). MF has participated in clinical studies from Corcept Therapeutics and HRA Pharma Rare Diseases (for these, institution fees were provided). LM was a member of the expert panel “Focus Area Adrenal and Cardiovascular Endocrinology” from the European Society of Endocrinology, and led the working group 5 of the project “CA20122—Harmonizing clinical care and research on adrenal tumours in European countries” from the European Cooperation in Science in Technology. JN-P reports grants from Diurnal Group; and has served as a consultant for and received honoraria from HRA Pharma Rare Diseases, Crinetics Pharmaceuticals, and Recordati (in all cases, institution fees were provided). CS reports consulting fees and honoraria from HRA Pharma Rare Diseases and Recordati; was a member of advisory or data safety monitoring boards for HRA Pharma Rare Diseases and Recordati; and has served as coordinator of the Pituitary Club of the Italian Society of Endocrinology. MT reports personal consulting fees (for being a member of advisory or data safety monitoring boards for Corcept Therapeutics and HRA Pharma Rare Diseases); and has participated in clinical studies from HRA Pharma Rare Diseases (for which institution fees were provided). ST reports personal support for attending meetings or travel from Ipsen, Pfizer, and Recordati; personal honoraria from Recordati; and has participated in clinical studies from Crinetics Pharmaceuticals, Novartis, and Strongbridge Biopharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intorduction: Aldosterone is known to play important role in developing cardiovascular, metabolic, renal damage in hypertensive patients., Aim: Aim of study was to evaluate parameters obtained by eco-color Doppler study, as non-invasive and easly performed method in asyntomatic patients with Essential Hypertension (EH) and Primary Aldosteronism (PA), without overt organ damage., Methods: From April 2019 to March 2020 we consecutively enrolled 73 hypertensive subjects (48 males, 25 women), distinguished in two groups: 30 EH patients (mean age 49.5 ± 18.7 years) and 43 PA patients (mean age 53.1 ± 11.6 years)] [23 with aldosterone-secreting adrenal adenoma (APA), 20 with idiopathic aldosteronism (IHA)]., Results: PA group showed higher renal filtration rate and 24-h urinary excretion of albumin respect to EH; moreover, in PA we found higher Pulsatility Index, altered percentage of Renale Resistance Index, Atrophy Index, and reducted parietal thickness than EH. The correlation study showed that plasma aldosterone were positively correlated with pulsatility index in PA group (right r = 0.35; p < 0.05; left r = 0.36; p < 0.05)., Conclusion: parameters obtained through the intra-renal eco-color Doppler examination, easly performed and non-invasive, can be useful in the early-stage identification of subclinical microvascular alterations, especially in PA, condition characterized by increased risk of cardio-vascular remodelling and metabolic alterations., (© 2021. Italian Society of Hypertension.)

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46-15.71) in males and 13.21 (95% CI 7.52-21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15-5.44, p = 0.021 for 50-59 vs. <50-year category; HR 3.46, 95% CI 1.67-7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10-0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.

Systemic capillary leak syndrome (SCLS) is a very rare and lethal disease characterized by hemoconcentration and hypoalbuminemia caused by reversible plasma extravasation. The underlying cause for SCLS remains largely unknown and acute treatment has remained mainly supportive. Prophylaxis with intravenous immunoglobulin (IVIG) has been shown to successfully prevent further episodes in affected patients. We reported a case of SCLS in a patient who presented to our hospital with COVID-19 and developed profound shock.

The aim of our cross-sectional study was to evaluate skin microvascular alterations in patients with hypertension secondary to primary aldosteronism (PA) and in subjects with essential hypertension (EH). Skin microcirculation was detected by nailfold videocapillaroscopy (NVC) and laser Doppler perfusion imaging (LDPI), both noninvasive techniques for the evaluation of digital capillaroscopic damage and hand skin blood perfusion. From September 2018 to April 2019, we consecutively enrolled 80 patients, of whom 42 had PA and 38 had EH. A morphological and structural study of cutaneous microcirculation was carried out through NVC, while functional evaluation of the peripheral microcirculation was carried out with LDPI. Using LDPI indices, dermal perfusion gradients were calculated in various regions of interest at the level of the back of the hand (ROI1 and ROI2). No differences between the two groups in NVC parameters were found. In contrast, LDPI showed worse skin perfusion parameters in patients with PA compared with patients with EH (ROI1: 143.9 ± 29.9 pU vs 163.3 ± 35.2 pU, p = 0.01; perfusion gradient ROI1-ROI2: 62.4 ± 28.8 pU vs 79.3 ± 33.5 pU, p = 0.019). Furthermore, the ROI1-ROI2 (proximal-distal) perfusion gradient was negatively correlated with aldosterone plasma levels (r -0.269; p = 0.017). Multivariate analysis showed that aldosterone was significantly associated with the ROI1-ROI2 perfusion gradient (b -0.220; p = 0.044). Patients with PA showed altered skin perfusion and greater microvascular dysfunction compared with the EH group. Our results are consistent with the hypothesis that aldosterone may have a pathophysiological role in microvascular remodeling in patients with PA, with predominant functional dysfunction.

Purpose: Adrenal incidentalomas (AI) are discovered after work-up unrelated to adrenal gland diseases; up to 30% of AI show subclinical endogenous cortisol excess (SH), frequently associated to hypertension, obesity, metabolic disorders and increased incidence of cardiovascular events (CVEs)., Methods: We analysed 628 AI patients divided into two groups: 471 non-functional adrenal adenoma (NFA) and 157 SH. All patients underwent complete examinations, 24-h ambulatory blood pressure monitoring, biohumoral parameters and vascular damage markers, such as c-IMT and ankle brachial index. After long-term follow-up, we registered newly onset of CVEs such as myocardial infarction (MI), percutaneous stenting and surgical bypass (PTA/CABG), stroke, overall/cardiovascular mortality. Moreover, SH patients underwent to surgical (SSH) or pharmacological treatment (MSH)., Results: SH patients showed higher prevalence of metabolic syndrome, diabetes mellitus, and previous CVEs respect NFA at baseline. After follow-up MSH group showed higher recurrence of major CV events compared with NFA and SSH (RR 2.27 MSH vs NFA for MI; RR 2.30 MSH vs NFA for PTA/CABG; RR 2.41 MSH vs NFA for stroke). In SSH there was a significant reduction of the number of antihypertensive medications needed to reach target blood pressure levels (2.3 ± 1.0 to 1.5 ± 0.4 drugs). None differences were found in SH patients, distinguished in relation to cortisol plasma levels after dexamethasone suppression test (1.8-5 µg/dL, above 5 µg/dL)., Conclusions: SH is linked to relevant cardiovascular and metabolic alterations, leading to worsen clinical outcomes. In eligible patients, adrenalectomy is valid and safe option to treat SH, reducing cardiometabolic abnormalities.

Background and Aim: Considering the amount of novel knowledge generated in the last five years, a team of experienced hypertensionlogists was assembled to furnish updated clinical practice guidelines for the management of primary aldosteronism., Methods: To identify the most relevant studies, the authors utilized a systematic literature review in international databases by applying the PICO strategy, and then they were required to make use of only those meeting predefined quality criteria. For studies of diagnostic tests, only those that fulfilled the Standards for Reporting of Diagnostic Accuracy recommendations were considered., Results: Each section was jointly prepared by at least two co-authors, who provided Class of Recommendation and Level of Evidence following the American Heart Association methodology. The guidelines were sponsored by the Italian Society of Arterial Hypertension and underwent two rounds of revision, eventually reexamined by an External Committee. They were presented and thoroughly discussed in two face-to-face meetings with all co-authors and then presented on occasion of the 36th Italian Society of Arterial Hypertension meeting in order to gather further feedbacks by all members. The text amended according to these feedbacks was subjected to a further peer review., Conclusions: After this process, substantial updated information was generated, which could simplify the diagnosis of primary aldosteronism and assist practicing physicians in optimizing treatment and follow-up of patients with one of the most common curable causes of arterial hypertension., Competing Interests: None., (© 2020 The Authors.)

Background and Aims: The adrenal mineralocorticoid system plays a key role in cardiovascular, metabolic and renal damage. This study aimed to assess the relationship between plasma aldosterone concentration (PAC) and some surrogate markers of subclinical atherosclerosis, such as carotid intima-media thickness (cIMT), ankle-brachial index (ABI) and biochemical parameters in patients with essential hypertension., Methods and Results: From January 2014 to December 2017, we consecutively enrolled 804 essential hypertensive patients (407 men and 397 women, mean age 50 ± 14 years) without cardiovascular complications, distinguishing patients in quartiles according to PAC. Compared with the first quartile, the highest PAC quartile was associated with the highest levels of serum uric acid (SUA) (5.3 ± 1.3 vs. 5.0 ± 1.0 mg/dl; P = 0.01), triglycerides (117.5 ± 15.7 vs. 106.8 ± 10.5 mg/dl; P < 0.05), 24-h urinary albumin excretion (UAE) (38.8 ±  vs. 7.6 ± mg/24 h; P < 0.05), cIMT (0.87 ± 0.22 vs. 0.80 ± 0.21 mm; P = 0.001) and increased prevalence of carotid plaques (26 vs. 16%; P < 0.005). Moreover, we found that in patients with PAC more than 150 pg/ml, the ABI was significantly lower than those with PAC < 150 pg/ml (1.01 ± 0.09 vs. 1.10 ± 0.09; P < 0.022). PAC was also found to be an independent predictor of the presence of carotid plaques and pathological ABI (<0.9) in essential hypertensive individuals., Conclusion: Our results revealed that higher PAC values are strongly associated with some metabolic variables, as triglycerides, UAE, cIMT, worse ABI and major prevalence of carotid plaques that, together with elevated blood pressure values, are strictly correlated with higher risk of atherosclerosis and cardiovascular complications.