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Frontiers in Medicine 2023Despite significant advances in therapeutic management of atypical hemolytic uremic syndrome (aHUS), guidelines are not timely updated and achieving a consensus on...
BACKGROUND
Despite significant advances in therapeutic management of atypical hemolytic uremic syndrome (aHUS), guidelines are not timely updated and achieving a consensus on management recommendations remains a topic of ongoing discussion.
METHODS
A Scientific Committee with five experts was set up. A literature review was conducted and publications addressing the classification of aHUS, patient profiles and therapeutic approach were selected. Recommendations were proposed at an initial meeting, evaluated through an online questionnaire and validated during a second meeting.
RESULTS
Patients with confirmed or clear suspicion of aHUS should be treated with C5 inhibitors within 24 h of the diagnosis or suspicion of aHUS. Treatment monitoring and the decision to interrupt treatment should be individualised according to the risk of relapse and each patient's evolution. aHUS with a genetic variant or associated with pregnancy should be treated for at least 6-12 months; aHUS associated with kidney transplant until renal function is recovered and genetic variants are ruled out; aHUS associated with malignant hypertension until genetic variants are ruled out; aHUS associated with non-kidney transplant, autoimmune diseases, infection-or drug-induced until the thrombotic microangiopathy is resolved. Patients with a high risk of relapse should be treated for longer than 6-12 months.
CONCLUSION
These recommendations provides physicians who are not familiar with the disease with recommendations for the management of aHUS in adults. The experts who participated advocate early treatment, maintenance for at least 6-12 months and treatment interruption guided by genetic background, trigger factors, risk of relapse and evolution.
PubMed: 38105887
DOI: 10.3389/fmed.2023.1264310 -
World Journal of Gastroenterology Mar 2024Liver disease accounts for approximately 2 million deaths per year worldwide. All chronic liver diseases (CLDs), whether of toxic, genetic, autoimmune, or infectious...
Liver disease accounts for approximately 2 million deaths per year worldwide. All chronic liver diseases (CLDs), whether of toxic, genetic, autoimmune, or infectious origin, undergo typical histological changes in the structure of the tissue. These changes may include the accumulation of extracellular matrix material, fats, triglycerides, or tissue scarring. Noninvasive methods for diagnosing CLD, such as conventional B-mode ultrasound (US), play a significant role in diagnosis. Doppler US, when coupled with B-mode US, can be helpful in evaluating the hemodynamics of hepatic vessels and detecting US findings associated with hepatic decompensation. US elastography can assess liver stiffness, serving as a surrogate marker for liver fibrosis. It is important to note that interpreting these values should not rely solely on a histological classification. Contrast-enhanced US (CEUS) provides valuable information on tissue perfusion and enables excellent differentiation between benign and malignant focal liver lesions. Clinical evaluation, the etiology of liver disease, and the patient current comorbidities all influence the interpretation of liver stiffness measurements. These measurements are most clinically relevant when interpreted as a probability of compensated advanced CLD. B-mode US offers a subjective estimation of fatty infiltration and has limited sensitivity for mild steatosis. The controlled attenuation parameter requires a dedicated device, and cutoff values are not clearly defined. Quan-titative US parameters for liver fat estimation include the attenuation coefficient, backscatter coefficient, and speed of sound. These parameters offer the advantage of providing fat quantification alongside B-mode evaluation and other US parameters. Multiparametric US (MPUS) of the liver introduces a new concept for complete noninvasive diagnosis. It encourages examiners to utilize the latest features of an US machine, including conventional B-mode, liver stiffness evaluation, fat quantification, dispersion imaging, Doppler US, and CEUS for focal liver lesion characterization. This comprehensive approach allows for diagnosis in a single examination, providing clinicians worldwide with a broader perspective and becoming a cornerstone in their diagnostic arsenal. MPUS, in the hands of skilled clinicians, becomes an invaluable predictive tool for diagnosing, staging, and monitoring CLD.
Topics: Humans; Liver Diseases; Ultrasonography; Liver Cirrhosis; Fatty Liver
PubMed: 38617743
DOI: 10.3748/wjg.v30.i12.1663 -
Current Vascular Pharmacology Dec 2023Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased...
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased pulmonary vascular resistance, and right ventricular overload, ultimately leading to heart failure and death. A metabolic theory has been suggested to explain the pathophysiology of PAH whereby abnormalities in mitochondrial biogenesis can trigger a hyperproliferative and apoptosis-resistant phenotype in cardiopulmonary and malignant cells, leading to mitochondrial dysfunction, which in turn causes the Warburg effect. This can culminate in the mitophagy of pulmonary vessels and cardiomyocytes. The present narrative review focuses on the pathophysiology of PAH, the pharmacological agents currently available for its treatment, and promising and challenging areas of therapeutic investigation.
PubMed: 38115617
DOI: 10.2174/0115701611266576231211045731 -
British Journal of Pharmacology Oct 2023First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat)....
BACKGROUND AND PURPOSE
First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required.
EXPERIMENTAL APPROACH
We report the high-throughput screening (HTS)-based discovery of a second generation of sGC stimulators from a novel imidazo[1,2-a]pyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY-747). The pharmacokinetic profile of BAY-747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension.
KEY RESULTS
BAY-747 is a highly potent sGC stimulator in vitro. In addition, BAY-747 showed an excellent pharmacokinetic profile with long half-life and low peak-to-trough ratio. BAY-747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY-747 caused a dose-related and long-lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY-747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY-747 caused a dose-related and long-lasting (>6 h) MAP decrease.
CONCLUSION AND IMPLICATIONS
BAY-747 is a potent, orally available sGC stimulator. BAY-747 shows long-acting pharmacodynamic effects with a very low peak-to-trough ratio. BAY-747 could be a treatment alternative for patients with hypertension, especially those not responding to standard-of-care therapy.
Topics: Rats; Animals; Dogs; Soluble Guanylyl Cyclase; Hypertension; Hypertension, Pulmonary; Heart Failure; Vasodilator Agents
PubMed: 37170767
DOI: 10.1111/bph.16142 -
The Lancet. Oncology Nov 2023The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical...
BACKGROUND
The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
METHODS
In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
FINDINGS
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
INTERPRETATION
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.
FUNDING
Merck Sharp & Dohme.
Topics: Humans; Male; Female; Adolescent; Adult; Aged; Antineoplastic Agents, Immunological; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37844598
DOI: 10.1016/S1470-2045(23)00446-1 -
Cancer Reports (Hoboken, N.J.) Jan 2024Endometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium. EAC is the most common female malignancy following the menopause period. About 40% of patients... (Review)
Review
BACKGROUND
Endometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium. EAC is the most common female malignancy following the menopause period. About 40% of patients with EAC are linked with obesity and interrelated with hypertension, diabetes mellitus, and high circulating estrogen levels. Proprotein convertase (PC) furin was involved in the progression of EAC.
RECENT FINDINGS
Furin is a protease enzyme belonging to the subtilisin PC family called PC subtilisin/kexin type 3 that converts precursor proteins to biologically active forms and products. Aberrant activation of furin promotes abnormal cell proliferation and the development of cancer. Furin promotes angiogenesis, malignant cell proliferation, and tissue invasion by malignant cells through its pro-metastatic and oncogenic activities. Furin activity is correlated with the malignant proliferation of EAC. Higher expression of furin may increase the development of EAC through overexpression of pro-renin receptors and disintegrin and metalloprotease 17 (ADAM17). As well, inflammatory signaling in EAC promotes the expression of furin with further propagation of malignant transformation.
CONCLUSION
Furin is associated with the development and progression of EAC through the induction of proliferation, invasion, and metastasis of malignant cells of EAC. Furin induces ontogenesis in EAC through activation expression of ADAM17, pro-renin receptor, CD109, and TGF-β. As well, EAC-mediated inflammation promotes the expression of furin with further propagation of neoplastic growth and invasion.
Topics: Humans; Female; Furin; Proprotein Convertases; Subtilisins; Signal Transduction; Adenocarcinoma
PubMed: 38018319
DOI: 10.1002/cnr2.1920 -
Thrombosis Journal Nov 2023Thrombotic Microangiopathy (TMA) is a syndrome characterized by the presence of anemia, thrombocytopenia and organ damage and has multiple etiologies. The primary aim is...
BACKGROUND
Thrombotic Microangiopathy (TMA) is a syndrome characterized by the presence of anemia, thrombocytopenia and organ damage and has multiple etiologies. The primary aim is to develop an algorithm to classify TMA (TMA-INSIGHT score).
METHODS
This was a single-center retrospective cohort study including hospitalized patients with TMA at a single center. We included all consecutive patients diagnosed with TMA between 2012 and 2021. TMA was defined based on the presence of anemia (hemoglobin level < 10 g/dL) and thrombocytopenia (platelet count < 150,000/µL), signs of hemolysis, and organ damage. We classified patients in eight categories: infections; Malignant Hypertension; Transplant; Malignancy; Pregnancy; Thrombotic Thrombocytopenic Purpura (TTP); Shiga toxin-mediated hemolytic uremic syndrome (STEC-SHU) and Complement Mediated TMA (aHUS). We fitted a model to classify patients using clinical characteristics, biochemical exams, and mean arterial pressure at presentation.
RESULTS
We retrospectively retrieved TMA phenotypes using automatic strategies in electronic health records in almost 10 years (n = 2407). Secondary TMA was found in 97.5% of the patients. Primary TMA was found in 2.47% of the patients (TTP and aHUS). The best model was LightGBM with accuracy of 0.979, and multiclass ROC-AUC of 0.966. The predictions had higher accuracy in most TMA classes, although the confidence was lower in aHUS and STEC-HUS cases.
CONCLUSION
Secondary conditions were the most common etiologies of TMA. We retrieved comorbidities, associated conditions, and mean arterial pressure to fit a model to predict TMA and define TMA phenotypic characteristics. This is the first multiclass model to predict TMA including primary and secondary conditions.
PubMed: 37993892
DOI: 10.1186/s12959-023-00564-6 -
Cardiovascular Diabetology Nov 2023Uric acid (UA) is an independent prognostic factor for cardiovascular events, but there are no data demonstrating a different risk profile between women and men. Thus,...
BACKGROUND
Uric acid (UA) is an independent prognostic factor for cardiovascular events, but there are no data demonstrating a different risk profile between women and men. Thus, we tested whether UA is associated with a possible sex-related difference in fatal and non-fatal cardiovascular events.
METHODS
In this prospective population-based study we enrolled 1,650 never-treated Caucasian hypertensive outpatients referred to Catanzaro University Hospital (Italy). Inclusion criteria were newly diagnosed hypertensive patients, aged 20 years or more. Exclusion criteria were secondary form of hypertension, previous cardiovascular events, rheumatic and non-rheumatic valvular heart disease, prosthetic valves, cardiomyopathies, type-2 diabetes, chronic kidney disease, malignant diseases, gout arthritis and secondary forms of hyperuricemia, liver diseases, peripheral vascular diseases, and heart failure. Anthropometric, clinical, and biochemical parameters were measured. UA prognostic role was investigated by Cox regression analyses. Receiver-operating characteristic curve analyses and area under the curve were used to determine the predictive validity and the optimal cut-off point of UA. We investigated following endpoints: coronary events (fatal and nonfatal myocardial infarction, unstable angina, coronary revascularization procedures, coronary death); fatal and nonfatal stroke; all-cause mortality and major adverse cardiovascular events (MACE).
RESULTS
We enrolled 830 males and 820 females aged 52.2 ± 11.3 years. During 9.5 ± 3.1 years follow-up, there were 424 new clinical events (2.71%): 250 coronary (1.59%), 118 (0.75%) cerebrovascular, and 56 (0.40%) deaths. Comparison between groups demonstrated a higher and significant difference in incidence rate in females for MACE (3.08 vs 2.33%, P = 0.001), coronary (1.82 vs 1.36%, P = 0.014) and cerebrovascular events (0.93 vs 0.57%, P = 0.006). UA at multiple Cox regression analysis resulted a strong and significant predictor of coronary events (HR = 1.493;95% CI 1.375-1.621), cerebrovascular events (HR = 1.256;95% CI 1.109-1.423), MACE (HR = 1.415;95% CI 1.328- 53 1.508), and all-cause mortality (HR = 1.469;95% CI 1.237-1.745) in the whole population and in both groups with a HR higher in females. The best estimated cut-off values of uric acid for males and females predicted these endpoints equally well, but it was always lower in females than males.
CONCLUSIONS
We demonstrate, that UA operates with a sex-related impact and best cut-off value in predicting cardiovascular outcomes and all-cause mortality, reflecting a possible sex difference in disease pathophysiology.
Topics: Humans; Male; Female; Prospective Studies; Uric Acid; Risk Factors; Sex Characteristics; Essential Hypertension; Hypertension
PubMed: 37915077
DOI: 10.1186/s12933-023-02006-z -
JAMA Network Open May 2024People with kidney failure receiving maintenance dialysis visit the emergency department (ED) 3 times per year on average, which is 3- to 8-fold more often than the...
IMPORTANCE
People with kidney failure receiving maintenance dialysis visit the emergency department (ED) 3 times per year on average, which is 3- to 8-fold more often than the general population. Little is known about the factors that contribute to potentially preventable ED use in this population.
OBJECTIVE
To identify the clinical and sociodemographic factors associated with potentially preventable ED use among patients receiving maintenance dialysis.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used linked administrative health data within the Alberta Kidney Disease Network to identify adults aged 18 years or older receiving maintenance dialysis (ie, hemodialysis or peritoneal dialysis) between April 1, 2010, and March 31, 2019. Patients who had been receiving dialysis for more than 90 days were followed up from cohort entry (defined as dialysis start date plus 90 days) until death, outmigration from the province, receipt of a kidney transplant, or end of study follow-up. The Andersen behavioral model of health services was used as a conceptual framework to identify variables related to health care need, predisposing factors, and enabling factors. Data were analyzed in March 2024.
MAIN OUTCOMES AND MEASURES
Rates of all-cause ED encounters and potentially preventable ED use associated with 4 kidney disease-specific ambulatory care-sensitive conditions (hyperkalemia, heart failure, volume overload, and malignant hypertension) were calculated. Multivariable negative binomial regression models were used to examine the association between clinical and sociodemographic factors and rates of potentially preventable ED use.
RESULTS
The cohort included 4925 adults (mean [SD] age, 60.8 [15.5] years; 3071 males [62.4%]) with kidney failure receiving maintenance hemodialysis (3183 patients) or peritoneal dialysis (1742 patients) who were followed up for a mean (SD) of 2.5 (2.0) years. In all, 3877 patients had 34 029 all-cause ED encounters (3100 [95% CI, 2996-3206] encounters per 1000 person-years). Of these, 755 patients (19.5%) had 1351 potentially preventable ED encounters (114 [95% CI, 105-124] encounters per 1000 person-years). Compared with patients with a nonpreventable ED encounter, patients with a potentially preventable ED encounter were more likely to be in the lowest income quintile (38.8% vs 30.9%; P < .001); to experience heart failure (46.8% vs 39.9%; P = .001), depression (36.6% vs 32.5%; P = .03), and chronic pain (60.1% vs 54.9%; P = .01); and to have a longer duration of dialysis (3.6 vs 2.6 years; P < .001). In multivariable regression analyses, potentially preventable ED use was higher for younger adults (incidence rate ratio [IRR], 1.69 [95% CI, 1.33-2.15] for those aged 18 to 44 years) and patients with chronic pain (IRR, 1.35 [95% CI, 1.14-1.61]), greater material deprivation (IRR, 1.57 [95% CI, 1.16-2.12]), a history of hyperkalemia (IRR, 1.31 [95% CI, 1.09-1.58]), and historically high ED use (ie, ≥3 ED encounters in the prior year; IRR, 1.46 [95% CI, 1.23-1.73).
CONCLUSIONS AND RELEVANCE
In this study of adults receiving maintenance dialysis in Alberta, Canada, among those with ED use, 1 in 5 had a potentially preventable ED encounter; reasons for such encounters were associated with both psychosocial and medical factors. The findings underscore the need for strategies that address social determinants of health to avert potentially preventable ED use in this population.
Topics: Humans; Male; Female; Emergency Service, Hospital; Middle Aged; Renal Dialysis; Aged; Alberta; Adult; Cohort Studies; Kidney Failure, Chronic
PubMed: 38809552
DOI: 10.1001/jamanetworkopen.2024.13754 -
The Journal of Clinical Endocrinology... Mar 2024Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality.
CONTEXT
Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality.
OBJECTIVE
We aimed to determine the impact of adrenal disorders on the inflammation marker GlycA, total branched-chain amino acids (BCAA), ketone bodies and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine.
METHODS
We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFA), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGL), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n=802). Referent subjects included participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) study (n=5241). GlycA, BCAA, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus and statin therapy.
RESULTS
In age-and sex-adjusted comparison to referent subjects, increased GlycA was noted in all patient categories, increased BCAA in NFA, MACS, CS, PA and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of subjects with diabetes and cardiovascular disease.
CONCLUSION
Patients with functioning and non-functioning adrenal masses demonstrated increased GlycA and BCAA, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.
PubMed: 38546526
DOI: 10.1210/clinem/dgae204