Chronic rhinosinusitis is a common disease worldwide and can be categorized into chronic rhinosinusitis with nasal polyps and chronic rhinosinusitis without nasal polyps. Chronic rhinosinusitis with nasal polyps is common in patients with asthma and, particularly, severe asthma. Severe asthma is effectively treated with biologics and the coexistence of severe asthma with chronic rhinosinusitis with nasal polyps presents a phenotype that is more likely to respond to such treatment. In this review, we focus on the link between asthma and nasal polyps, and we review the treatment effect of various monoclonal antibodies in patients with severe asthma and nasal polyps as well as in patients with nasal polyps without asthma or with mild-to-moderate asthma. With the enhancement of our armamentarium with new monoclonal antibodies the right choice of biologic becomes an important target and one that is difficult to achieve due to the lack of comparative head-to-head studies. The prevalence of chronic rhinosinusitis is around 10% in the US and Europe . CRSwNP Current treatment options for patients with nasal polyposis (NP) are intranasal and, for severe cases, oral corticosteroids (OCS) and long-term antibiotics ,6. SurgePatients with CRSwNP have a Th2-predominant type of inflammation and present high levels of interleukin-5 (IL-5) and eosinophilic inflammation, an image that is often also seen in severe asthma, where the aforementioned mAbs are also used with great efficacy ,10. HoweThe association between asthma and CRSwNP is not just a simple coexistence. Core underlying pathophysiological mechanisms are shared between them, with T2 inflammation being the cornerstone of both airway disorders. Thus, taking into account that the extent of T2 inflammation strongly impacts the severity of both diseases, it can be expected that patients suffering from severe asthma will usually experience severe CRSwNP symptoms too, and vice versa . Around H2) CD4+ cells by antigen presentation. The second pathway revolves around the innate immune response since the type 2 innate lymphoid cells (ILC2) are triggered by alarmins such as thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and interleukin-33 (IL-33). These alarmins act exactly as their name suggests, by “raising the alarm” of innate immunity after the exposure of airway epithelium to environmental triggers such as allergens or viruses [T2-high inflammation results from two different molecular pathways, eventually leading to the production of cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), which in turn orchestrate the production, migration and tissue infiltration of eosinophils and mast cells. The first pathway revolves around the adaptive immune response through the stimulation of T-helper 2 , prostaglandin F2alpha (PGF2α) and cysteinyl leukotrienes such as LTE4 [A distinct phenotype of coexisting asthma and nasal polyposis is aspirin-exacerbated respiratory disease (AERD). It is marked by CRSwNP, difficult-to-control asthma and adverse respiratory reactions to medications such as aspirin or non-steroid anti-inflammatory drugs (NSAIDs) which inhibit cyclooxygenase-1 (COX-1) . Eosinop as LTE4 ,34.2 is an inflammatory mediator which can bind to the chemoattractant receptor-homologous molecule (CRTH2) found on the surface of TH2 cells, ILC2, eosinophils and basophils, activating and recruiting them to the airways. Additionally, it can bind to the DP1 receptor, also leading to chemotaxis of pro-inflammatory cells and causing nasal edema by inducing vasodilation [2α is another eicosanoid produced by eosinophils, mast cells and possibly epithelial cells of the respiratory tract. It also acts as an agonist for the CRTH2 receptor [2α can induce bronchoconstriction even in healthy individuals, but asthmatics are far more sensitive and respond with more severe flow impairment, implying that in patients with comorbid CRSwNP and bronchial asthma the excess production of PGF2α can worsen the symptoms of asthma [4 is another eicosanoid product which is produced mainly from eosinophils and mast cells. IL-5 plays a crucial role in regulating its production since inhibition of IL-5 signal through anti-IL-5 or anti-IL-5R biologics drastically reduces its levels. LTE4, in turn, can upregulate the production of PGD2 and PGF2α, therefore inhibition of IL-5 acts beneficially for two crucial inflammatory mediators [PGDdilation . PGF2α ireceptor . Furtherf asthma . Last buediators ,38.IL-5, as previously mentioned, is the most crucial cytokine in the pathogenesis of T2-high inflammation. Its effect is not limited to asthma since it can also induce the production of pro-inflammatory eicosanoids associated with AERD. In patients with AERD, the expression of IL-5R on the surface of eosinophils and mast cells is substantially increased, facilitating the T2 signaling process . AdditioIgE is the oldest target of biologic agents for asthma, with almost 20 years of experience with the anti-IgE mAb omalizumab. The role of IgE is also important in the coexistence of asthma and nasal polyps, especially in an allergic background, for instance, in patients with aeroallergen sensitization or other microbial antigens . It is aIt is clear that the link between these two respiratory disorders is strong, and in the era of personalized medicine, health experts should aim to optimize treatment for both asthma and CRSwNP. The shared molecular pathway of T2 inflammation is beneficial for targeted therapy with mAbs against pivotal cytokines, such as IL-4, IL-5 and IL-13 in both diseases. Initial results have shown remarkable success, and as our arsenal is growing, it is tempting to endotype asthma and CRSwNP when they coexist in order to choose the right biologic agent not for one, but for two health conditions, simultaneously. In the near future, we may even be in a position to target T2 inflammation in multiple steps with a combination of biologics, although, at the moment, no trials have been designed to test this hypothesis.In most RCTs regarding the efficacy of mepolizumab in severe eosinophilic asthma, NP was a comorbidity and patients were evaluated as a total population for the primary outcome, that being, the rate of exacerbations in the majority of them. In a large RCT—the DREAM study—62/616 patients (10%) had comorbid NP  . In the In the MUSCA study, 19% of patients presented with NP at baseline . The meaIn the meta-analysis of the MUSCA and MENSA studies, 166 out of 936 patients (18%) presented with NP at baseline. Mepolizumab reduced the annual exacerbation rate in patients with severe eosinophilic asthma versus placebo regardless of NP status, but to a greater degree in those with NP (80%) than without NP (49%). Of note, patients with NP had a higher baseline blood eosinophil count .The phase 3 study, SYNAPSE, was a 52-week, randomized, double-blind, parallel group study that assessed the efficacy and safety of mepolizumab compared to placebo in patients with recurrent severe bilateral NP. Such patients were defined as those with an average nasal obstruction visual analogue scale (VAS) symptom score >5 and an endoscopic score of at least 5 out of a maximum score of 8, with a minimum score of 2 in each nasal cavity despite treatment with standard of care. Patients also must have had a history of at least one prior surgery for NP in the previous 10 years. Mepolizumab demonstrated significant improvements in the total endoscopic nasal polyp score at week 52 and in nasal obstruction VAS score during weeks 49–52, compared to placebo. Moreover, the time to the first actual nasal surgery up to week 52—a key secondary endpoint—was also statistically significantly longer with mepolizumab vs. placebo showing a reduction of 57% [p = 0.0350) [In a real-life study from Italy, assessing the efficacy and safety of mepolizumab treatment after 1 year, 81/138 patients (59%) had NP, thus being the most frequent comorbidity of this population . In the  0.0350) . In a re 0.0350) . In anot 0.0350) . In the  0.0350) , while t 0.0350) .1 was also increased at 12 months and OCS intake and blood eosinophils were drastically reduced [An Italian real-word study recruited 44 severe asthmatics with eosinophilic asthma and CRSwNP who received mepolizumab and followed their course for 12 months. SNOT-22 and total endoscopic nasal polyp score (TENPS) were decreased by a statistically important margin already at 6 months and persisted until the end of the follow up period, while the ACT significantly increased over the same period. FEV reduced . Further reduced .Finally, the beneficial results of mepolizumab treatment have been demonstrated in a retrospective study including 32 patients, with half of them having concurrent severe asthma and bronchiectasis, which, as previously mentioned, often coexist along with CRSwNP. Treatment with mepolizumab managed to reduce the asthma exacerbation rate, the number of blood eosinophils and the OCS consumption, with better symptom control, nonetheless. The interesting point of this study is that asthma control was achieved regardless of the severity of bronchiectasis. This could possibly signal the effectiveness of mepolizumab treatment in patients with the “united airways diseases” phenotype .Among baseline characteristics in patients with severe eosinophilic asthma that could predict the response to treatment with benralizumab, NP was found to be one of the most important. In a study including patients from the SIROCCO and CALIMA phase III studies, it was shown that NP were associated with a greater reduction in the annual exacerbation rate and greater improvement in pre-bronchodilator FEV1 for those with >300 eosinophils/µL compared to those with severe asthma but without NP. Interestingly, NP could also predict a better response to benralizumab in reducing the exacerbation rate even in patients with <300 eosinophils/µL .n = 96) or placebo (n = 57) for 24 weeks. Treatment with benralizumab significantly improved symptoms of NP, as assessed by SNOT-22, compared to placebo for those with a high baseline SNOT-22 score (>30). The percentage of patients with clinically meaningful improvements in SNOT-22  from baseline to week 24 was greater for benralizumab compared with placebo (71.3% vs. 45.5%). This effect was even more obvious for those with a high baseline SNOT-22 score (79.7% vs. 48.8%). Moreover, a 69% reduction in the annualized exacerbation rate was observed compared to placebo as well as improvements in SGRQ, FEV1 and ACQ-6. The frequency of adverse events was similar in the two groups, and the most commonly  reported, at a higher frequency in benralizumab vs. placebo, included headache, sinusitis, pyrexia and influenza [A substudy of the ANDHI study included 153 patients with severe asthma and NP  that received benralizumab  presented with CRwNP. Patients with comorbid CRwNP presented with a significant improvement in SNOT-22 score, but significant improvements were also observed in ACT score, OCS dosage, FEV1 % and FEV1 (L), compared to patients without NP. Of note, the FeNO value was significantly higher in severe eosinophilic asthma with CRSwNP compared to severe eosinophilic asthma without NP . The study confirmed the greater benefit of benralizumab in asthma control and lung function when asthma and NP coexist. This is possibly explained by a higher degree of type 2 inflammation and eosinophilic infiltration observed in such patients .A retrospective review of 23 patients with severe eosinophilic asthma and CRSwNP revealed that treatment with benralizumab for 4 months was associated with significant improvements in ACT score, FEV1 and SNOT-22 score. Despite a non-significant improvement in endoscopic polyp score, a complete disappearance of NP was observed in 36% of the patients. It was noted that the improvement in ACT scores was associated with a reduction in SNOT-22 scores and endoscopic polyp scores. Those patients who demonstrated a reduction in endoscopic polyp scores presented with higher baseline eosinophil numbers . SimilarAnother real-world study from Japan including 17 patients with severe eosinophilic asthma that were treated with benralizumab for 1 year showed that the presence of CRSwNP could predict a rapid response to treatment within 4 weeks for ACQ-5, AQLQ and FEV1. On the other hand, a lack of NP (CRSsNP) was associated with a longer time to respond to benralizumab. It should be noted that eosinophils rapidly decreased to zero in both severe asthma with CRSwNP and CRSsNP groups after 4 weeks of treatment. These findings indirectly suggest that the time period to assess the response to benralizumab might be longer in patients with severe eosinophilic asthma without NP .In a randomized double-blind study, 24 patients with severe NP defined by endoscopic grade >5 out of 8 and with a history of previous surgical or endoscopic polypectomy were allocated to receive benralizumab or placebo for 20 weeks. All but two of the patients had comorbid mild-to-moderate asthma. Benralizumab-treated patients showed a significant reduction in endoscopic NP score compared to baseline but a non-significant one compared to placebo. Moreover, benralizumab also improved CT score compared to baseline but not compared to placebo. All patients treated with benralizumab had an improved SNOT-22 score. Noteworthy, the ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction, thus being a good predictor of the response to benralizumab. Accordingly, patients with a blood eosinophil count greater than 700/μL and those with negative skin prick testing all improved with benralizumab [Two Phase 3 trials (POLYP-1 and POLYP-2) assessed the safety and efficacy of omalizumab in CRSwNP. In these studies, 138 and 127 adults with CRSwNP that presented with an inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Both studies met both the coprimary end points, i.e., change from baseline to week 24 in Nasal Polyp Score and Nasal Congestion Score. Moreover, secondary endpoints—SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip and runny nose—were also significantly improved for omalizumab versus placebo. Omalizumab was well-tolerated .In a subgroup analysis of the replicate POLYP 1 and POLYP 2 trials, omalizumab efficacy was favored over placebo in patients with a blood eosinophil count >300 and ≤300 cells/μL, with or without previous sinonasal surgery, concomitant asthma and aspirin sensitivity, indicating broad efficacy regardless of underlying patient characteristics .An open-label 52-week extension study evaluated the continued efficacy, safety and durability of the response to omalizumab in adults with CRSwNP who completed POLYP 1 or POLYP 2. Patients who continued omalizumab experienced further improvements, while patients who switched from placebo to omalizumab experienced favorable responses across end-points that were similar to POLYP 1 and POLYP 2. Discontinuation of omalizumab resulted in gradually worsened scores over the 24-week follow-up, but these still remained improved from pretreatment levels. No safety issues were raised .A systematic review and meta-analysis of four randomized controlled trials including 303 patients aimed to assess the efficacy and safety of omalizumab for CRSwNP. Omalizumab significantly improved nasal polyps score, nasal congestion, SNOT-22 and total nasal symptom score and reduced the need for surgery in adults with moderate-to-severe CRSwNP, and it was safe and well tolerated .A real-life study from Italy included 123 severe asthma patients of whom 17 (13.8%) had comorbid CRSwNP. There was no significant difference in ACQ, FEV1 and annual exacerbation rate between those with CRSwNP and those without NP. However, the proportion of patients who achieved an improvement in all three outcomes was numerically greater in the CRSwNP group (35.7% vs. 23.0%) . In anotLIBERTY SINUS-24 (24-week duration) and LIBERTY SINUS-52 (52-week duration) were two multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 included 276 patients, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. SINUS-52 included 448 patients, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. In both studies dupilumab significantly improved nasal polyp score, nasal congestion or obstruction score and Lund-Mackay CT score versus placebo .In a pooled analysis of the phase 3 SINUS-24 and SINUS-52 studies, 428 patients had CRSwNP and comorbid asthma. In this population, dupilumab vs. placebo improved the nasal polyp score, nasal congestion score, Lund-Mackay CT score, peak nasal inspiratory flow and SNOT-22 score. Moreover, dupilumab significantly improved FEV1 and ACQ-6 vs. placebo . A furthIn a large study including 724 patients with CRSwNP, the efficacy of dupilumab was evaluated according to the number of prior surgeries and the time since last surgery. Patients were randomized to placebo or dupilumab 300 mg every 2 weeks; 459/724 (63.4%) patients had ≥1 prior surgery. Compared to placebo, dupilumab significantly improved nasal polyp score, nasal congestion, Lund-Mackay CT score and SNOT-22 score in all subgroups defined by number of surgeries and by time since last surgery. However, nasal polyp score and Lund-Mackay CT score improved to a greater extent in those patients with <3 years since last surgery than patients with ≥5 years, indicating a stronger effect associated with a shorter duration from last surgery . In a raThere is no doubt that the era of biologics has dramatically changed the management of severe asthma, mainly by reducing the rate of exacerbations and OCS use but also by improving lung function, asthma control and quality of life. CRSwNP is a common comorbidity of asthma and, quite often, of the severe asthma. Most studies on biologics have demonstrated that severe asthma with nasal polyps is an asthma phenotype that is more likely to respond to the biologic treatment. This advanced response applies to exacerbation rate reduction, OCS reduction and lung function improvement.Patients with severe asthma and comorbid nasal polyps are eligible for biologic treatment, but recently, patients with nasal polyps and comorbid mild-to-moderate asthma also became eligible. In the case of severe asthma with comorbid nasal polyps, the precise definition of the asthmatic phenotype may guide the decision for the choice of biologic therapy. In the case of severe CRSwNP and mild-to-moderate asthma, the question is, which should be the choice of biologic therapy, or even better, which should be the first choice? Is it worth phenotyping mild-to-moderate asthma again to understand the underlying mechanism which is likely to be the same as that responsible for severe CRSwNP? Th2-predominant inflammation associated with high levels of IL-5 and eosinophils is evident in the majority of patients with severe asthma and nasal polyps but definitely not in all of them. Moreover, there are no randomized controlled studies comparing the effect of different mAbs in patients with severe asthma and comorbid CRSwNP, and accordingly, the main question remains, which mAb should be preferred in such a patient? Some systematic reviews have attempted to shed light on the answer to this question.A systematic review and network meta-analysis regarding the efficacy of biologics in CRSwNP included nine RCTs with 1190 patients comparing three different biologics  and placebo. In terms of nasal polyp score, SNOT-22, University of Pennsylvania Smell Identification Test (UPSIT) score and nasal congestion score, dupilumab had the best efficacy. Omalizumab ranked second in efficacy in terms of SNOT-22, UPSIT and nasal congestion score, while mepolizumab ranked second in efficacy in terms of nasal polyp score but had the highest risk of adverse events .A Cochrane database review assessed the effects of biologics on the treatment of chronic rhinosinusitis and included 10 RCTs with 1262 patients. Dupilumab improved SNOT-22 score compared to placebo and resulted in a reduction in disease severity measured by VAS and in the number of serious adverse events. Mepolizumab may improve SNOT-22 score but it is unknown if there was a difference in disease severity or the number of serious adverse events. Furthermore, omalizumab probably improved SNOT-22 score compared to placebo but it also is uncertain if there was a difference in the number of serious adverse events, while no evidence was presented regarding the effect of omalizumab on disease severity .A systematic review following the EAACI guidelines evaluated the efficacy and safety of biologicals for CRSwNP compared with standard care. Dupilumab reduced the need for surgery and OCS use (RR 0.28) and definitely improved smell  and quality of life  with fewer treatment-related adverse events. Omalizumab also reduced the need for surgery (RR 0.85), decreased OCS use (RR 0.38) and improved smell and SNOT-22, but increased treatment-related adverse events. It is unclear if mepolizumab actually reduced the need for surgery or improved QoL while it also demonstrated an increase in treatment-related adverse events. The evidence for reslizumab is also very uncertain . An indiDespite the appreciation that indirect comparisons are not safe to exclude definite conclusions it seems that changes in nasal polyp score are greater in absolute or percentage terms for dupilumab than for omalizumab and mepolizumab. This is possibly attributed to the mechanism of action. Dupilumab acts at a higher level of the type 2 inflammatory cascade by blocking signaling of IL-4 and IL-13. Real-life studies have shown similar trends. In a real-life setting, 28 patients with CRSwNP were treated with mAbs , and all but one had concomitant asthma (but not necessarily severe). Treatment with mepolizumab was associated with a better success rate (78.9%) followed by omalizumab (50%) and benralizumab (50%) but the latter was with few cases . HoweverFor severe asthma, the choice among mAbs is guided by the asthma phenotype, and the option of switching from one to another exists in the case of suboptimal a response. Comorbid CRSwNP represents a unique phenotype that enhances biological effectiveness.In the case of CRSwNP with or without asthma (not necessarily severe), there is neither clear evidence nor biomarkers that could guide the initial biologic choice.Additionally, there are no switching studies from one biologic to another and, as previously mentioned, only indirect comparisons exist among them, making the clinician‘s decision more difficult. A recent study evaluated the efficacy of benralizumab in patients with CRSwNP, where it managed to improve nasal polyp score and nasal blockage score, but this improvement was not demonstrated in patients with BMI >30, patients with fewer than 2 nasal polyp surgeries, patients without comorbid asthma and those with fewer than 560/μL blood eosinophils . This stCRSwNP is a chronic inflammatory disease of the nasal passage linings or sinuses often combined with severe asthma. This combination of severe asthma with CRSwNP presents a unique phenotype with a better response to biologic treatment which is evident in the reduction of asthma exacerbations, use of maintenance steroids and improvement in asthma control, lung function and asthma-related quality of life. CRSwNP without asthma or with mild-to-moderate asthma may be treated effectively with biologics, but the choice of which one is a matter of investigation. The phenotype of mild-to-moderate asthma may aid such decisions. Further studies involving nasal biopsies and a multidisciplinary approach, including the asthma and ENT specialist, may assist in defining clinical characteristics and/or biomarkers for the best choice of biologic treatment in CRSwNP.


Blood pressure regulation is an automatic, moment-by-moment buffering of the blood pressure in response to physiological changes such as orthostasis, exercise and haemorrhage. This finely orchestrated reflex is called the baroreflex. It is a regulated arc of afferent, central and efferent arms. Multiple physiological changes occur with ageing that can disrupt this reflex, making blood pressure regulation less effective. In addition, multiple changes can occur with ageing-related diseases such as neurodegeneration, atherosclerosis, deconditioning and polypharmacy. These changes commonly result in orthostatic hypotension, hypertension or both, and are consistently associated with multiple adverse outcomes. In this article, we discuss the healthy baroreflex, and physiological and pathophysiological reasons for impaired baroreflex function in older people. We discuss why the common clinical manifestations of orthostatic hypotension and concomitant supine hypertension occur, and strategies for balancing these conflicting priorities. Finally, we discuss strategies for treating them, outlining our practice alongside consensus and expert guidance. The healthy baroreflex regulates moment-by-moment buffering of blood pressure, responding to physiological changes.Multiple physiological and pathophysiological changes occur with ageing that impair the sensitivity of the baroreflex.An impaired baroreflex means impaired blood pressure regulation—often resulting in orthostatic hypotension and hypertension.Orthostatic hypotension is consistently associated with adverse cardiovascular outcomes.Concomitant orthostatic hypotension and supine hypertension commonly co-occur and require careful managementImpaired blood pressure (BP) regulation and its consequences are common in older patients. Orthostatic hypotension (OH) in particular is responsible for almost a quarter of Emergency Department attendances with syncope . DefinedUnderstanding the underlying pathophysiology of impaired BP regulation is essential for managing it. In this article, we describe healthy BP regulation, ageing-related physiological and pathological changes and the principles behind diagnosis and management.BP is regulated by the baroreflex—an automatic, autonomic-mediated reflex responsible for buffering acute changes in BP which may be induced by postural change, exercise, haemorrhage or other physiological stress. The body’s response to orthostasis illustrates this well. When a healthy person stands up, 500–700 ml blood pools into abdominal, pelvic and lower limb blood vasculature. The consequent reduction in venous return to the heart is sensed by stretch-sensitive baroreceptors in the carotid artery and aortic arch, and mechanoreceptors in the heart and lungs. Neural impulses are transmitted to the brainstem (the Nucleus Tractus Solitarius in the pons) via afferent neurons and are integrated and processed in the Central Autonomic Network in the brain—interconnected areas between the brainstem and forebrain responsible for controlling autonomic impulses. Sympathetic nervous system (SNS) outflow is then increased via efferent post-ganglionic autonomic neurons which release noradrenaline. Noradrenaline acts on α- and β-adrenoceptors in the blood vessels (causing vasoconstriction) and heart (increasing heart rate and contractility). In addition, adrenaline is released from the adrenal medulla, and augments β-adrenoceptor activation in the heart, contributing to the increased heart rate and contractility. Finally, the increased sympathetic output also stimulates the hypothalamus to produce anti-diuretic hormone, thus increasing plasma volume and stimulating the renin-angiotensin system .These changes occur within seconds, and may manifest as a transient increase in heart rate, a small decrease in systolic BP and rise in diastolic BP . UsuallyConversely, when BP rises, baroreceptors and mechanoceptors sense increased stretch and inhibit sympathetic activity. Simultaneously parasympathetic tone is activated via the parasympathetic nervous system’s (PNS) main effector, the vagus nerve. Acetylcholine is released from cardiac ganglia, acting on muscarinic receptors and lowering heart rate, contractility and BP , 8, 9.The two arms of the autonomic nervous system (the SNS and PNS) work together in finely tuned harmony, regulating the BP on a moment-by-moment basis. A healthy system is flexible and responsive, and is capable of reacting to sudden bursts of activity and stress, (mediated by the SNS) and periods of rest and recovery (via the PNS). The reflex arc can be disrupted at multiple points. For example, impairment may occur at the sensing stretch receptors, in the afferent nerves to the brainstem, in the brain and central autonomic network, the efferent pre- and post-ganglionic neurons to the effector organs, the ganglia themselves, or neurotransmitter production and transmission.The baroreflex—this automatic ability to buffer acute changes in BP by altering autonomic outputs—becomes less sensitive with ageing . This inSimilarly, increasing age is associated with decreased muscarinic receptor density and synaptic density in the PNS .BP variability (another independent cardiac risk factor ) increasThere is also a sustained, predictable and linear reduction in the heart’s intrinsic pacemaker rate throughout life . This maCardiovascular autonomic failure occurs when there is sympathetic denervation in the heart. This may occur in neurodegeneration or peripheral nerve or ganglionic disorders. Any lesion in the afferent, central or efferent arms of the baroreflex, at adrenoceptors, or interfering with neurotransmitter transmission can be implicated.‘Cardiac autonomic neuropathy’ is a common end-organ complication of diabetes, with rates as high as 65% in long-standing diabetes . It is aSynucleinopathies encompass a spectrum of neurodegenerative disorders involving abnormal protein inclusions of α-synuclein in the brain and autonomic nervous system. The distribution and nature of these inclusions is predictable and stereotyped, and determines the clinical syndrome; for example Parkinson’s disease and Dementia with Lewy Bodies are characterised by Lewy Body inclusions in the basal ganglia and cortex respectively. Multi-System Atrophy involves oligodendroglial cytoplasmic inclusions in pre-ganglionic sympathetic neurons and Pure Autonomic Failure is caused by inclusions in post-ganglionic neurons. These conditions are strongly associated with OH and associated supine hypertension depending on which anatomical correlate of the baroreflex is affected , 23. NeuMedications are the commonest cause of OH-related hospital admission, with multiple medications associated with higher OH risk . A recenProlonged bedrest results in significant cardiovascular, neural and baroreflex changes. Physiological effects of head down bed rest have been studied extensively as a model for weightlessness in astronauts. Prolonged immobility is associated with reduction in total plasma volume, reduced cardiac filling and stroke volume, and cardiac atrophy . There iOH is an adverse prognostic sign for poor outcome across a wide range of conditions: most immediately it is associated with increased risk of falls, syncope and injury , 6, 34. Commonly accompanying orthostatic hypotension is neurogenic supine hypertension. This occurs commonly in neurodegenerative conditions affecting the autonomic nervous system. This is defined as supine BP greater than or equal to 140/90 after 3 min . It initIn addition to neurogenic supine hypertension, essential hypertension is another common comorbidity. OH is present in 14–17% of cohorts with hypertension . ArteriaManaging OH and concomitant hypertension requires a careful individualised management plan taking into account the immediate challenges of injurious syncope, wellbeing and quality of life (QoL), and longer term cardiovascular and end-organ risks of associated hypertension. There is little evidence in this area, particularly for frail individuals already at high risk of falls and injury, leading to heterogeneity in clinical approach.It is important to distinguish whether the patient has essential hypertension with OH (from impaired baroreflex), overtreated hypertension or neurogenic OH and supine hypertension from autonomic nervous system disease. If the former, and the patient is otherwise fit, then more intensive BP goals (aiming for systolic BP <120mmHg) may be preferred. More intensive goals are consistently associated with improved cardiovascular outcomes and all-cause mortality without worsening OH , 50–52. Identifying non-neurogenic causes—for example deconditioning, medications and volume depletion—are critical. Clinicians should understand the distinction in physiology underlying these from neurogenic OH to be able to fully inform their patients. Physical function, risk of injury, emergency department attendance, fear of falling, QoL and time able to stand and walk to an acceptable level should be considered. For patients with advanced neurodegenerative conditions, supportive care to maximise imminent safety and QoL may be of higher priority than longer term cardiovascular goals. Our approach to treatment, incorporating expert consensus guidelines and opinions , 55, 56,Evaluate trends. Home monitoring BP recordings over a range of times and activities can determine trends. A possible schedule could be supine, sitting, and standing BPs early in the morning (before/on getting out of bed), after lunch, at bedtime and when symptomatic. These trends could be taken for a defined period prior to clinic visits or after intervention or medication changes. Twenty-four-hour ambulatory BP monitoring can elucidate this further, and the patient should keep details of meals, alcohol, activity, time getting up and going to bed, and rest periods. It should be emphasised that this is now a ubiquitous and relatively inexpensive investigation. In clinic, an active stand  for 5 min, then standing BP at 1 and 3 min may confirm OH. If the diagnosis of OH is suspected but not confirmed in clinic, a formal active stand test with BP monitoring beat-to-beat or tilt table testing could be considered.Identify and optimise non-neurogenic causes of OH. Culprit medications should be reviewed, especially α- and β-blockers, diuretics, nitrates, anticholinergic and psychoactive medications. Night-time anti-hypertensive administration can improve cardiovascular outcomes, with attention to dosage, time of administration and half-life of the chosen medication, which may mitigate effects of supine hypertension and pressure natriuresis [riuresis . Fluid bAvoid the supine position completely. This should be emphasised to the patient (and carers) explaining the underlying physiology—that this position induces supine hypertension, which leads to pressure natriuresis, dehydration and worsening OH. Similarly, BP augmenting agents must not be taken when supine as they will increase the risk of supine hypertension without manifesting benefits. Patients should be advised to sleep with the head of the bed raised to 12 degrees at least, or higher if tolerated, to avoid this. Steps must be taken to avoid slipping off the bed during the night.Avoid bed-rest. Hospitalised patients in particular may be considered at risk of falls and unsafe to get up, which will worsen deconditioning effects. Ensuring that the bed is tilted and gradually increasing sitting duration  should occur as soon as the problem is identified and guided by physiotherapy.Ensure fluid repletion, aiming for 2–2.5 L of fluid per day [ per day . Drinkin per day . Compres per day . ButtockPatients should be reminded to be cautious on standing up, especially after prolonged resting. Those who are able to should be taught to employ counter-pressure manoeuvres such as squatting, leg crossing and lower body tensing to improve cardiac venous return [s return . CarryinAttention should be paid to size and frequency of meals, emphasising avoiding large carbohydrate rich meals and concomitant alcohol, which can cause post-prandial hypotension. If post-prandial hypotension is an issue, it could be used to customise BP control . Patients should also be advised to be cautious about triggers such as hot, warm environments.Medications. Non-pharmacological management should form the mainstay of treatment, but occasionally pharmacotherapy is indicated.• Midodrine is a α-agonist, resulting in splanchnic vasoconstriction and increasing BP and it improves BP and QoL in patients with OH and syncope . Advanta• Fludrocortisone is a fluid expander which is relatively contraindicated in individuals with supine hypertension as this is a significant risk. It can be effective in OH , 66, but• Medications which are not yet endorsed in guidelines but which show promise are droxidopa , 69, pyrAvoiding pressure natriuresis by avoiding the supine position is the mainstay of non-pharmacological treatment. In addition, inducing post-prandial hypotension by eating a night-time snack may help avoid pressure natriuresis at night. Short-acting nocturnal agents can be considered, with one consensus guideline suggesting treatment when systolic BP reaches 160–180 mmHg . Short aImpaired blood regulation is common in older people, whether due to physiological changes in the baroreflex, age-related diseases or states, or autonomic neuropathies. The consequences—OH and associated hypertension—are debilitating conditions and herald poor prognosis. Identifying the underlying cause, understanding the associated pathophysiology and mitigating exacerbating factors through predominantly lifestyle measures are essential. Future work should focus on identifying optimal BP targets for these individuals, particularly the frailest patients at highest risk of falls and injury.


Ultrasound, biochemical, and biopsy examinations were performed on the same day. Radiomics signatures were extracted from the SWE images. Results: In total, 187 patients were included and followed up for 24.57 ± 5.52 months. The median SWE value of the left kidney cortex (L_C_median) is an independent risk factor for kidney prognosis for stage 3 or over (HR 0.890 (0.796–0.994), p < 0.05). The inclusion of 9 out of 2511 extracted radiomics signatures improved the prognostic performance of the Cox regression models containing the SWE and the traditional index . The traditional Cox regression model had a c-index of 0.9051 (0.8460–0.9196), which was no worse than the machine learning models, Support Vector Machine (SVM), SurvivalTree, Random survival forest (RSF), Coxboost, and Deepsurv. Conclusions: SWE can predict kidney injury progression with an improved performance by radiomics and Cox regression modeling.Background: Shear wave elastography ultrasound (SWE) is an emerging non-invasive candidate for assessing kidney stiffness. However, its prognostic value regarding kidney injury is unclear. Methods: A prospective cohort was created from kidney biopsy patients in our hospital from May 2019 to June 2020. The primary outcome was the initiation of renal replacement therapy or death, while the secondary outcome was eGFR < 60 mL/min/1.73 m Chronic kidney disease (CKD) has become a global health burden, with an incidence of around 10% . HoweverUltrasound remains the preferred non-invasive radiographic method for diagnosing CKD due to its economic and portable properties . Two-dimRecent advances in the radiomics analysis of ultrasound images of fibrosis ,14 and aHence, we observed the predictive value of SWE for CKD progression in our kidney biopsy cohort. We used the clinical index and pathological changes as references. We also applied a PyRadiomics analysis of SWE ultrasound images, traditional Cox regression models, and machine learning models in our study. We hypothesized that SWE would predict CKD progression with or without the help of radiomics and machine learning.The study featured a prospective cohort of kidney biopsy patients in our hospital from May 2019 to June 2020. The inclusion criteria were patients aged 18–70 with unexplained abnormal kidney function, proteinuria over 1 g/day, rapidly progressive glomerulonephritis, or persistent hematuria with proteinuria. The exclusion criteria were patients who could not cooperate with breath-holding for SWE, contraindication for kidney biopsy , pregnancy, comorbidities of cysts, urological stones or tumors, unilateral kidney atrophy, or pathological diagnosis of acute kidney injury. B-mode, SWE, and collection of serum and urinary samples from patients were performed on the day of the kidney biopsy. The included patients were then re-examined every three months for the first year and every six months thereafter. The primary outcome was the initiation of renal replacement therapy or death. The secondary outcome was CKD stage over 3. CKD stage was evaluated based on eGFR (MDRD) as CKD 1, ≥90; CKD 2, 60–89; CKD 3, 30–59; CKD 4, 15–29; and CKD 5, <15 at the time of inclusion and follow-up . CKD proSerum creatinine (Scr) and urinary creatinine (UCr) were measured by the sarcosine oxidase method. Urinary albumin was measured by the immunoturbidimetric method. The urinary albumin–creatinine ratio (ACR) was subsequently calculated. The eGFR was calculated using the MDRD equation .B-mode and SWE ultrasound examinations were conducted by one ultrasound radiologist who had received specialized training in kidney ultrasound and SWE for more than five years. The radiologist was blind to patients’ clinical information. B-mode was performed before SWE as a reference for kidney imaging . SWE wasA kidney biopsy was performed under the guidance of B-mode ultrasound at the inferior pole of the left kidney. Biopsy specimens were formalin-fixed before routine hematoxylin and eosin, periodic acid–Schiff, periodic Schiff–methenamine silver, and immunofluorescence staining, or fixed with 4% PFA and 2.5% glutaraldehyde before observation under electron microscopy. Pathological changes were divided into 13 categories, scored, and diagnosed by two renal pathologists with over 20 years of experience. Grades of chronic changes were then determined according to total renal chronicity score as minimal, 0–1; mild, 2–4; moderate, 5–7; and severe, ≥8, by referring ,29.Considering the heterogeneity of kidney histological changes during CKD and the purpose of adding values to SWE, ROIs for radiomics analysis were manually drawn using 3DSlicer based on the ROIs of the SWE ultrasound images . Radiomip < 0.1 in univariate Cox regression entered further multivariate Cox regression using the stepwise-backward method. The hypothesis of proportional hazard was verified by the chi-square test before Cox regression modeling. The likelihood test was also used in the comparison of Cox regression models. Nomogram was built based on the results of multivariate Cox regression. Machine learning models SVM, RSF, SurvivalTree, Coxboost, and deep learning model DeepSurv were built using the same features as the Cox regression model by the scikit-survival package (v0.17.1) of Python (v3.7.0). The dataset was split randomly at an 8:2 ratio, 80% for training and 20% for testing to prevent overfitting of the machine learning or deep learning models. Hyperparameters were optimized through grid search and 10-fold cross-validation. Models were evaluated by the concordance index (C-index). C-index >0.9 means a model with high accuracy; 0.7–0.9 means medium accuracy; 0.5–0.7 means poor accuracy. Ninety-five percent confidence intervals were calculated by Bootstrap 1000 times.Lasso regression and Cox regression were conducted using glmnt (v4.1–3) and survival (v3.2–10) in R (v4.0.5) and SPSS (v26). Features with likelihood test t-test for normally distributed and Mann–Whitney U test for non-normally distributed data. The chi-square test was used for the comparison of categorical variables. A paired t-test was applied for within-group comparisons. Log-rank test was applied for comparison between Kaplan–Meier curves. p < 0.05 was considered statistically significant.Statistical analysis was performed by SPSS (v26) and R (v4.1.0). Normality distribution was tested by the Kolmogorov–Smirnov method before the Students’ In total, 187 patients were recruited. The average time of follow-up was 24.57 ± 5.52 months. At the time of inclusion, 59 out of 187 (31.55%) were at CKD stage 1, 61 (32.62%) at CKD2, 46 (24.60%) at CKD 3, 16 (8.56%) at CKD 4, and 5 (2.67%) at CKD 5. For the pathological diagnoses, 69 out of 187 (36.90%) were diagnosed with IgA nephropathy, 35 (18.72%) with membranous nephropathy, 20 (10.70%) with diabetic nephropathy, 16 (8.56%) with a minimal-change disease, 7 (3.74%) with a tubulointerstitial disease, 7 (3.74%) with hypertensive renal disease, 17 (9.09%) with focal segmental glomerulosclerosis, and 29 (15.51%) with other diseases . Some of the patients had combined pathological diagnoses, resulting in a sum of pathological diagnoses of over 187.During the follow-up, three patients died. One of these deaths was due to multi-organ failure (at CKD stage 3 at the time of inclusion), while the causes of the other two were unknown (at CKD stage 2 at the time of inclusion). Six patients initiated renal replacement therapy, of whom two were at CKD stage 5 at the time of inclusion, two were at CKD 4, and two were at CKD 3. Of the remaining patients who did not die or initiate renal replacement therapy, 18 out of 187 (9.63%) had a sustained decrease  of eGFR over 25% from baseline, accompanied by a drop in CKD stage. Furthermore, 48 out of 187 (25.67%) had a sustained increase  in eGFR over 25% from baseline, which could be considered as a regression of CKD . The totIn total, 973 features, including clinical index, pathological changes, ultrasound parameters, and radiomics signature, were entered into the lasso regression analysis. The 26 significant features selected were Scr, eGFR, 24-h urinary protein at baseline, glomerular global sclerosis rate, glomerular focal segmental sclerosis rate, interstitial inflammation, and 20 radiomics signatures. Details of the features and their coefficients are shown in Univariate and multivariate Cox regression analyses were performed next, using both statistical and clinically significant parameters from the results of the differential comparison  and lassp < 0.1 in the univariate Cox regression analysis were further calculated as cutoff values for the secondary outcome based on Kaplan–Meier method  . Furthermore, the Cox regression model containing them performed better than the Model-Clin + Patho and Model-Clin + SWE (In addition, we also found nine radiomics signatures that were independent risk factors for CKD progression (in + SWE . These rThe limitations of this study are of its short follow-up time and use of a single center, which may have caused selection bias. External validation and a 5-year or 10-year follow-up will be needed in our feature studies.In conclusion, the median SWE value of the left kidney cortex can independently predict a 2.5-year CKD prognosis of CKD stage 3 or over. Radiomics can improve the predictive performance of SWE for CKD progression. Traditional Cox regression modeling is no worse than machine learning.


We welcome the initiative by Jordan et al.  on distiWe have, though, some comments regarding the timeframe proposed for the assessments of the upright systolic blood pressure (SBP) measurements. The authors mentioned that SBP while standing should be measured after 1, 3, and 5 min to confirm the persistent character of the blood pressure change. However, they do not provide references to support the time intervals that they propose. While time intervals that are too short may likely not provide reliable results, time intervals that are too long may increase the total time burden of patients or study participants, as well as of study personnel. Although at first sight small differences may seem negligible, when performed daily on a routine basis, this may also increase the financial burden in clinical practice as well as in research settings. Ultimately, these factors may have a negative impact on the acceptability of the measurement, both on the side of the patient (or study participant) as well as on the side of the clinician (or researcher) –4. ThereIn addition, the authors recommended that measurements should be conducted in a quiet surrounding to limit confounding of orthostatic changes by external stimuli and that repeated tested should be conducted on a different day. We would like to add the importance of taking into consideration body, room, and external temperature when assessing the blood pressure parameters, given that they provide important insights on hemodynamic changes in blood pressure . Finally


At one-year follow-up, median proteinuria was 0.9 g/24 h (IQR 2.4). At the end of the follow-up, mean eGFR was 72.1 ± 43.3 mL/min/1.73 m2. Proteinuria (p = 0.435) and the eGFR (p = 0.880) at the time of diagnosis did not correlate with long-term decline in the eGFR. Proteinuria < 1 g/24 h (HR 0.45 (95% CI 0.25–0.83) p = 0.011) after the first year was protective against long-term decline in the eGFR. It maintained this association with the long-term eGFR decline, independently of the duration of the follow-up (HR 0.30 (95% CI 0.17–0.52) p < 0.001). Conclusions: Proteinuria reduction to lower than 1 g/24 h, during the first year after diagnosis, was a protective factor for the long-term decline of kidney function, having a more important role than proteinuria or the GFR at the time of the diagnosis.Background: In glomerular disease, the degree of proteinuria is closely related to the progression of chronic kidney disease, and its reduction is associated with a slower decline in the glomerular filtration rate (eGFR) and consequent improvement in the renal prognosis. The aim of this study was to evaluate the impact of proteinuria reduction on the decline of the eGFR in patients with glomerular disease, during the first year after the diagnosis. Methods: This was a retrospective analysis of patients with primary glomerular disease, followed at the Nephrology Department of Centro Hospitalar Universitário Lisboa Norte, during 2019. We analyzed demographic, clinical and laboratorial characteristics . The outcome assessed was the decline in renal function, defined as a reduction in the GFR ≥ 25%, during the follow-up period. Results: We analyzed 197 patients with glomerular disease, with a mean age of 41.7 ± 19.7 years and follow-up time of 6.5 ± 5.3 years. At the time of the diagnosis, the eGFR was 81.5 ± 49.8 mL/min/1.73 m Chronic kidney disease (CKD) is a common disease, with an estimated prevalence of 8 to 16% worldwide ,3. In thMembranous nephropathy, focal segmental glomerulosclerosis and IgA nephropathy are the primary glomerular diseases associated with greater decline in renal function .The decline in renal function is intimately related to the degree of proteinuria, the presence of arterial hypertension and the glomerular filtration rate (GFR) at the time of the diagnosis. The proteins that are filtrated by the glomerular capillaries exert direct toxic damage to the tubulointerstitial structures, by activating several genes responsible for codifying vasoactive and proinflammatory molecules, which, associated with other risk factors such as hypertension, accelerate the decline of the kidney function .Therefore, proteinuria is a major risk factor for an accelerated decline of the GFR. Ruggenenti et al. studied 352 patients with nondiabetic renal disease and concluded that patients with proteinuria superior to 3.9 g/24 h at the time of the diagnosis had an association with a greater decline of the GFR, compared with patients with proteinuria lower than 1.9 g/24 h, and more frequently reached end-stage kidney disease (ESKD) . AnotherThe aim of this single center study was to evaluate the impact of proteinuria reduction on the decline of the GFR in patients with glomerular disease, during the first year after the diagnosis.This was a retrospective analysis that included adult patients with glomerular diseases, followed at the Nephrology and Renal Transplantation Department of Centro Hospitalar Universitário Lisboa Norte (CHULN) during 2019. The study included patients that were diagnosed from 2005 to 2017. This study was approved by the Ethical Committee in agreement with institutional guidelines. Due to the retrospective and noninterventional nature of the study, informed consent was waived by the Ethical Committee.Eligible patients were selected as adult patients (≥18 years of age) with a diagnosis of primary glomerular disease, confirmed by kidney biopsy, with at least 2 years of follow-up.The included glomerular diseases were minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy and membranoproliferative glomerulonephritis.2 at the time of clinical presentation and patients lost in the follow-up. We excluded patients with pauci-immune glomerulonephritis, neoplasia and other secondary causes of glomerulonephritis.Exclusion criteria comprised patients with an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 mPatient variables were collected from individual clinical records. We analyzed several clinical variables including patient demographic characteristics , laboratory values at the time of the diagnosis (serum creatinine (SCr), 24 h proteinuria measurement or urinary protein to creatine ratio in first morning urine), the histopathology result of the kidney biopsy and immunosuppressive regiment used.The glomerular filtration rate was estimated based on the CKD-EPI formula . We evalComplete remission was defined as proteinuria < 0.3 g/24 h, normal SCr and serum albumin > 3.5 g/dL. Partial remission was defined as proteinuria between 0.3 g/24 h and 3.5 g/24 h, with a decline of at least 50% from the highest measurement, and stable SCr (variation < 25%).2, persistent for at least 3 months [CKD was defined as an eGFR < 60 mL/min/1.73 m3 months .The primary outcome was the decline of kidney function, defined as a reduction in the eGFR ≥ 25% during the follow-up. We also analyzed the reduction in the eGFR ≥ 50%, the variation of the eGFR during the follow-up and the annual decline of the eGFR.t-test and categorical variables were compared with a chi-square test. Variables that did not follow a normal distribution were compared using the Mann-Whitney test and described as the median and interquartile range (IQR). To calculate the probability of the decline of the eGFR dependent on proteinuria reduction, we used a Kaplan–Meier analysis as a log-rank.Normal distribution of the variables was evaluated with a Kolmogorov–Smirnov test. Categorical variables were described as the total number and percentage for each category, whereas continuous variables were described as the mean ± standard deviation. Continuous variables were compared with the Student’s p-value < 0.05. Statistical analysis was performed with the statistical software package, SPSS for Windows .We used the Cox logistic regression method to determine the variables with a significant statistical difference for the decline of the eGFR. Data were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was defined as a We identified 197 patients with glomerular disease. One hundred and nine (55.3%) were male, with a mean age of 41.7 ± 19.7 years . Nearly 2, with 41.6% (n = 82) of patients having an eGFR < 60 mL/min/1.73 m2. Median proteinuria was 3.5 g/g or g/24 h (IQR 5.8), with 21.3% (n = 42) having proteinuria < 1 g/24 h, 24.4% (n = 54) with proteinuria of 1–3 g/24 h, 19.3% (n = 38) with 3–5 g/24 h and 35.0% (n = 69) having proteinuria ≥ 5 g/24 h (2) and patients with MN had higher baseline proteinuria (6.1 g/g or g/24 h (IQR 4.5)) ) . At the QR 4.5)) .At a one-year follow-up, median proteinuria was 0.9 g/g or g/24 h (IQR 2.4). The majority of patients  had a proteinuria reduction ≥ 25%, and 49.7% (n = 98) had a reduction ≥ 50%. Concerning the level of proteinuria, most patients had proteinuria lower than 1 g/24 h , 27.4% (n = 54) had 1–3 g/24 h, 9.1% (n = 18) had 3–5 g/24 h and 11.2% (n = 22) had proteinuria ≥ 5 g/24 h. Accordingly, at a one-year follow-up, 27.4% of patients (n = 54) were in complete remission and 48.2% (n = 95) were in partial remission . There w2, which corresponds to a variation of 9.3 mL/min/1.73 m2 (IQR 26.6). The annual decline of the eGFR was 1.4 mL/min/1.73 m2 (IQR 5.2). Almost one third of patients had at least a 25% decline in the eGFR , and 13.2% (n = 26) had a decline ≥ 50%. At the end of the follow-up, 42.6% (n = 84) had an eGFR < 60 mL/min/1.73 m2, as shown in The mean time of observation was 6.5 ± 5.3 years. The eGFR at the end of the follow-up was 72.1 ± 43.3 mL/min/1.73 mIn this study, 32.5% of patients (n = 64) presented an eGFR reduction ≥ 25% during follow-up. There was no significant difference in age, gender, the presence of hematuria, baseline eGFR or proteinuria .There were no significant differences in eGFR decline between patients with different glomerular diseases .p = 0.076) and less frequently presented a complete remission of proteinuria  during the first year of follow-up, nearly reaching statistical significance. Concerning the amount of proteinuria, they less frequently had proteinuria < 1 g/24 h  at the first-year follow-up  and more frequently had an eGFR < 60 mL/min/1.73 m2 . These patients had a longer follow-up time , and the annual decline of the eGFR was significantly higher (5.1 mL/min/1.73 m2 (IQR 5.1) vs. 0.4 mL/min/1.73 m2 (IQR 3.3), p < 0.001)  .The reduction in proteinuria to values of < 1 g/24 h, during the first year of diagnosis, was associated with a lesser eGFR decline in the long-term follow-up (log-rank 0.003) .p = 0.077). Proteinuria < 1 g/24 h (HR 0.45 (95% CI 0.25–0.83) p = 0.011) at the first-year follow-up was a predictor of long-term decline of the eGFR , the eGFR .p < 0.001).A subanalysis was performed to analyze the impact of proteinuria on eGFR decline, independently of the duration of follow-up, and proteinuria < 1 g/24 h maintained a significant association as protective against eGFR decline in the long term (HR 0.30 (95% CI 0.17–0.52) In this study, we demonstrated that proteinuria reduction during the first-year follow-up was protective against the long-term decline in renal function. A reduction in proteinuria ≥ 50% was associated with a slower decline in renal function. A reduction to levels lower than 1 g/24 h, or reaching complete remission in the first year, was protective against the long-term decline of the GFR.Several studies showed an association between the degree of proteinuria and a decline in renal function. Berhane et al. studied a population of 2420 diabetic patients and concluded that patients with microalbuminuria at the time of the diagnosis had a risk 2.1 times greater for developing ESKD, and patients with macroalbuminuria were 9.1 times more likely to develop ESKD, when compared with patients without proteinuria . 2/year) had proteinuria > 50 g/mol more frequently at the time of the diagnosis  [A similar association between proteinuria and decline of the kidney function was demonstrated in patients with nondiabetic kidney disease. Ali et al. studied a population of 336 patients with CKD and concluded that patients with a faster decline in the GFR (Δ eTFG ≤ −4 mL/min/1.73 m< 0.001) . In fact2/month vs. −0.030 ± 0.46 mL/min/1.73 m2/month). All patients that reached proteinuria < 1 g/24 h during the follow-up, regardless of the proteinuria concentration at the diagnosis, presented a similar decline in the GFR [Reich et al. analyzed 542 patients with primary IgA nephropathy and found that those with sustained proteinuria > 3 g/24 h, during the six-and-a-half-year follow-up, presented a decline in the kidney function 25 times faster than patients with proteinuria < 1 g/24 h  and a 23% reduction in the rate of decline of the kidney function [Apart from immunosuppressive therapy used for the treatment of glomerular diseases, there are several antiproteinuric therapies that must be used in order to prevent the decline of the renal function. Renin–angiotensin–aldosterone system (RAAS) inhibitors are the most studied and simultaneously the most effective drugs used for the reduction in proteinuria. By inducing vasodilatation of the efferent arteriola, they reduce intraglomerular pressure, which results in lower proteinuria . In addifunction . Accordifunction .Mineralocorticoid receptor antagonists have also been demonstrated to be effective in reducing proteinuria, reducing the inflammatory and profibrotic effect of proteinuria. However, their use is limited by the risk of hypercalemia. A recent meta-analysis that included 1646 patients with CKD showed that adding a mineralocorticoid receptor antagonist to the classic RAAS blockade produced an additional reduction in proteinuria of 38.7%; however patients were three times more likely to develop hypercalemia .mellitus, and have been associated with a proteinuria reduction of 30–50% [More recently, sodium-glucose transport protein 2 (SGLT2) inhibitors have been studied as antiproteinuric drugs. These drugs are currently the first line for the treatment of type 2 diabetes f 30–50% ,35,36. Tf 30–50% .In our study, 63% of the patients were submitted to immunosuppressive therapy, and 54% presented a proteinuria reduction > 50% at the first-year follow-up. Although not all antiproteinuric drugs were evaluated, all the patients were using RAAS inhibitors, highlighting the importance of these drugs in the treatment of patients with glomerular disease. This study has some limitations. First, it is a retrospective study, with a relatively small number of patients, which may affect the extrapolation to the general population. The limited number of patients may also affect the statistical significance of some variables, which may have reached significance with a larger population. Secondly, the method for the quantification of proteinuria was not uniform among the different patients, with some patients having a quantification of proteinuria in a 24 h urine sample and others having a proteinuria to creatinuria ratio based on the first morning urine. We also did not consider the characteristics of kidney biopsies, such as the degree of interstitial fibrosis and tubular atrophy, which may influence the prognosis; instead, we focused on clinical characteristics. However, the analysis of these patients as a whole allowed us to demonstrate the importance of the degree of proteinuria and renal prognosis, regardless of the cause of the glomerular disease. Finally, we did not analyze the immunosuppression used, which may have influenced the rate of reduction in proteinuria and the long-term reduction in the renal function. Overall, our study was the first to demonstrate the impact of proteinuria reduction during the first year after diagnosis on the long-term decline of the eGFR, in patients with glomerular disease, regardless of the degree of proteinuria at the time of the diagnosis.In this retrospective study of patients with glomerular disease, a proteinuria reduction to lower than 1 g/24 h, during the first year after diagnosis, was a protective factor against the long-term decline of kidney function. Therefore, the first year after the diagnosis of glomerular disease is of utmost importance for the renal prognosis. It is vital to invest in therapeutical strategies to reduce proteinuria in order to delay the decline of the renal function.


The use of cricoid compression to prevent insufflation remains controversial, and its use in children is limited. This study aimed to examine the effect of real-time ultrasound-guided esophageal compression on the prevention of gastric insufflation.2O to determine the pressure at which gastric insufflation occurred. The primary outcome was the incidence of gastric insufflation during anesthetic induction with variable peak inspiratory pressure after real-time ultrasound-guided esophageal compression was applied.This prospective observational study was conducted with fifty children aged < 2 years undergoing general anesthesia. Patients were excluded if they were at an increased risk for gastric regurgitation or pulmonary aspiration. Following anesthetic induction under spontaneous breathing, ultrasound-guided esophageal compression was performed during pressure-controlled face-mask ventilation using a gradual increase in peak inspiratory pressure from 10 to 24 cm HP = 0.220).Data from a total of 42 patients were analyzed. Gastric insufflation was observed in 2 (4.7%) patients. All patients except one had their esophagus on the left side of the trachea. Applying ultrasound-guided esophageal compression did not affect the percentage of glottic opening scores (The use of real-time ultrasound-guided esophageal compression pressure can aid preventing gastric insufflation during face-mask ventilation in children less than 2 years old.Clinicaltrials.gov identifier: NCT04645043.The online version contains supplementary material available at 10.1186/s12871-022-01803-5. Face-mask ventilation is a method of supplying oxygen before achieving a confirmed and secured airway by intubation during anesthetic induction. However, this method can cause gastric insufflation through the esophagus along with ventilation through the airway. Furthermore, ventilation difficulty can result from an increase in extrapleural pressure following gastric distension due to gastric insufflation –3.Cricoid pressure is one of the methods that help prevent this adverse reaction through the compression of the esophagus with pressure on the cricoid cartilage, which prevents aspiration and gastric regurgitation , 5. CricWith real time ultrasound, we can easily check the location of esophagus and compressed esophageal lumen. Several case reports regarding the use of this method in adults have been conducted previously , 10. TheThe Institutional Review Board of Seoul National University Hospital approved this study . This study was registered at clinicaltrials.gov . The first participant was enrolled on 30/11/2020 and the last participant was followed up on 18/03/2021. This was conducted in accordance with the tenets of the Declaration of Helsinki. This prospective observational study was conducted at Seoul National University Children’s Hospital.This study included patients aged < 2 years who underwent general anesthesia. Patients were excluded if they were at an increased risk for regurgitation or pulmonary aspiration due to factors such as hypertrophic pyloric stenosis, delayed gastric emptying time, or esophageal stricture; difficult visualization of the stomach via ultrasound was expected due to factors such as paralytic ileus, bowel perforation, hepatomegaly, splenomegaly; or there were air artefacts in the stomach at baseline gastric ultrasound examination. One investigator explained the study protocol the day before the surgery and obtained informed consent from the guardians of the pediatric patients.2O to 24 cm H2O) were used while ultrasound guided esophageal compression was performed. Gastric insufflation was detected by real time ultrasound examination of the antrum (acoustic shadow phenomenon and/or a comet-tail artifacts) [The primary outcome was the incidence of gastric insufflation during positive pressure ventilation by mask after induction of anesthesia. Varying peak inspiratory pressure (increasing from 10 cm Htifacts) . The sec−1) and thiopental (5 mg.kg−1) along with oxygen through a face mask while the patient was monitored using electrocardiography, pulse oxygen saturation, and non-invasive blood pressure monitoring. Sevoflurane (3–5 vol%) was administered via spontaneous ventilation. After loss of consciousness, the baseline gastric ultrasound examination was conducted and the gastric antral area (GAA) was measured with the linear-shaped L3-12 T ultrasound transducer, E-CUBE i7  using the following formula: GAA = π × D1 × D2 × 4–1 [−1) was administered, and positive pressure ventilation was started with a two-handed technique and jaw thrust on the tight sealing of the face mask with 100% oxygen flow at 2 l.min−1. Ventilation was controlled using a pressure-controlled mode, which maintained the esophageal pressure. The first inspiratory pressure was 10 cm H2O, which was sequentially increased to a maximum of 24 cm H2O. At least three ventilations were applied to the patient at each inspiratory pressure level. If any evidence of gastric insufflation during the increase in inspiratory pressure was observed, the investigation was halted and the pressure that achieved gastric insufflation and the GAA just before that time was recorded. If no gastric insufflation was observed at any inspiratory pressure, the investigation was stopped, and the GAA at the maximum inspiratory pressure was recorded. The study was also stopped if the peak inspiratory pressure applied resulted in a tidal volume was > 20 ml.kg−1. After finishing the investigation via an increase in the inspiratory pressure, the POGO score was recorded using the videolaryngoscope (McGRATH™ MAC Video Laryngoscope) under esophageal compression, and intubation proceeded  with an HSL25xp 13–6 MHz linear probe. The investigator measured the depth from the skin to the esophagus and the esophageal width and height before and after applying ultrasound-guided compression. The presence of esophageal and tracheal air insufflation was monitored during positive pressure ventilation , during positive pressure ventilation. The gastric antrum was identified between the left lobe of the liver and the pancreas in the sagittal plane to the right parasagittal plane at the level between the aorta and the superior mesenteric artery or the inferior vena cava, after which the transducer was tilted and rotated to the long axis of the antrum .To our knowledge, no previous studies have evaluated the effect of ultrasound-guided esophageal compression on the incidence of gastric insufflation. Considering the exploratory nature of this study, we assumed that 50 pediatric patients were sufficient to demonstrate the effect of ultrasound-guided esophageal compression.P < 0.05.All continuous variables are presented as mean ± standard deviation (SD) or median with interquartile range (IQR), depending on whether the variable was parametric. The normal distribution assumption was verified using the Kolmogorov–Smirnov test. The esophageal depth from the skin and esophageal width, height, and POGO score before and after ultrasound-guided esophageal compression application were assessed using a paired t-test. Statistical analyses were performed using SPSS version 18 software . Differences were considered statistically significant at Fifty pediatric patients were enrolled in this study. After eight patients showing gastric insufflation in the baseline examination were excluded, data from 42 patients were included in the final analysis.2O.The patients’ characteristics are presented in Table 2O in two patients who had gastric insufflation despite of ultrasound-guided esophageal compression, respectively. Esophageal ultrasound detected esophageal insufflation in one of these patients. Esophageal air insufflation was observed in four patients at peak inspiratory pressures of 14, 16, 16, and 22 cm H2O, respectively. Among them, three did not experience gastric insufflation despite the occurrence of esophageal insufflation.Table P = 0.220; 95% CI, -1.33–5.62).The esophagus of every patient except one was located left to the trachea, while that of the other was located posterior to the trachea. The POGO score did not differ before and after ultrasound-guided esophageal compression application (This study is the first prospective study to confirm that real-time ultrasound-guided esophageal compression can be safely applied to prevent gastric insufflation in infants and children. The location of the esophagus relative to the trachea was also laterally displaced in 97.6% of the patients in the present study.Cricoid pressure, first found in the literature in 1774 and contributed by Sellick in 1961, may help to prevent gastric insufflation during positive ventilation; however, controversy regarding its use remains. In particular, routine use of this method on patients aged < 1 years by pediatric anesthesiologists occurs in less than half of their practices, and the risk of trauma associated with the compression of the surrounding structures and trachea is still a concern . In addi2O, which was higher than the 12 and 18 cm H2O observed during previous studies on children [2O reported in adults with and without the use of cricoid pressure, respectively [As a result, the incidence of gastric insufflation in the present study was 4.7%, suggesting that this approach may be effective as compared to various studies confirming gastric insufflation , 13–15. Meanwhile, tracheal insufflation was confirmed in all patients in the present study (Additional File The posterior tracheal ring is expected to compress the esophagus by compressing the trachea at the cricoid cartilage level during the application of conventional cricoid pressure . HoweverThis study has some limitations. First, this study was conducted as an observational study to determine the usefulness of real-time ultrasound-guided esophageal pressure and sample size could not be estimated before conducting this study; therefore, biases related to observational studies, such as confounders and selection bias, could not be assessed. However, the results obtained in this study may be comparable with other studies that did not use ultrasound-guided esophageal compression even though this study was not performed as a randomized controlled trial. Second, we excluded patients with hypertrophic pyloric stenosis or delayed gastric emptying time, both of which increase the risk of aspiration; therefore, further research regarding this matter is needed. Also, gastric insufflation may be affected by obtrsuctive airway states. Gastric insufflation in this study was confirmed in a state with no observed airway obstruction, and there is a limit to applying it in the presence of airway obstruction. Third, a neuromuscular blocking agent was used during this study; however, positive ventilation was performed in the absence of self-ventilation instead of a train of four monitors, possibly affecting insufflation. Lastly, even though measurements performed in the left lateral decubitus position via gastric ultrasonography are more accurate for detecting gastric insufflation, the supine position was used in the present study, which may have affected the findings. Therefore, we may not have detected the small quantities of air that would not have reached the antrum in the supine position.In conclusion, applying real-time ultrasound-guided esophageal compression can help prevent gastric insufflation without causing ventilation difficulty during mask ventilation in small children.Additional file 1.


Chronic kidney disease (CKD) is a global health burden with a continuously increasing prevalence associated with an increasing incidence of diabetes and hypertension in aging populations. CKD is characterized by low glomerular filtration rate (GFR) and other renal impairments including proteinuria, thus implying that multiple factors may contribute to the etiology this disease. While there are indications of ethnic differences, it is hard to disentangle these from confounding social factors. Usually, CKD is detected in later stages of the disease when irreversible renal damage has already occurred, thus suggesting a need for early non-invasive diagnostic markers. In this study, we explored the urine secretome of a CKD patient cohort from Ghana with 40 gender-matched patients and 40 gender-matched healthy controls employing a kidney injury and a more general cytokine assay. We identified panels of kidney-specific cytokine markers, which were also gender-specific, and a panel of gender-independent cytokine markers. The gender-specific markers are IL10 and MME for male and CLU, RETN, AGER, EGFR and VEGFA for female. The gender-independent cytokine markers were APOA1, ANGPT2, C5, CFD, GH1, ICAM1, IGFBP2, IL8, KLK4, MMP9 and SPP1 (up-regulated) and FLT3LG, CSF1, PDGFA, RETN and VEGFA (down-regulated). APOA1—the major component of HDL particles—was up-regulated in Ghanaian CKD patients and its co-occurrence with APOL1 in a subpopulation of HDL particles may point to specific CKD-predisposing APOL1 haplotypes in patients of African descent—this, however, needs further investigation. The identified panels, though preliminary, lay down the foundation for the development of robust CKD-diagnostic assays. Chronic kidney disease (CKD) is defined by a glomerular filtration rate (GFR) < 60 mL/min per 1.73 m² or the presence of kidney damage predominantly manifested by proteinuria for 3 months or more .Protein in urine as an indicator of kidney damage is often measured by the urine albumin-to-creatinine ratio (UACR). Proteinuria and decreased GFR directly reflect physical properties of the filter between blood and urine constituted by an endothelial layer, the glomerular basement membrane (GMB) and podocytes. This filter is coarse at the endothelial side and fine at the podocytes and works in the dimension of nanometers in addition to a negative polarity. Thus, bigger and negatively charged molecules, such as most proteins under physiological conditions, cannot traverse this barrier. In proteinuria, larger proteins, such as albumin, immunoglobulins G and M and α1-microglobulin, β2-microglobulin, correlating with the severity of histologic lesions , can traThe increasing prevalence of CKD is largely influenced by the increase of diabetes and hypertension among the aging population ,5. AlthoEthnic differences have been reported for diabetic nephropathy, particularly in Pima Indians , and forBiomarkers for the early diagnosis of CKD are urgently needed and studies aiming at their identification have been performed using serum  as well In this study, aimed at gender-neutral and -specific CKD biomarker identification, we investigated proteins secreted into the urine of a cohort of CKD patients and healthy controls from Ghana using a general (Human XL) assay and a kidney injury-specific cytokine assay.2 (creatinine based chronic kidney disease epidemiology [CKD-EPI] collaboration equation without race adjustment) [2 and albumin/creatinine ratio < 3.0 mg/mmol (<30 mg/g). Random urine samples were collected from cases and controls and aliquots of 10 mLs were taken into cryovials. All participants of this study are from African ancestry. We were anticipating that ancestry might lead to some differences due to higher prevalences of genetic variants, such as the known APOL1 risk haplotype [Participants in the present study were recruited from two academic medical centers in urban regions of Ghana between 2012–2017. Persons with kidney disease were individuals aged 1–74 years with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 maplotype ,21, whicEthics approval was obtained locally at each clinical site. The approval number for the Case-Control study is: GHSERC: 07/03/2013. Written informed consent was obtained from all participants. Participants unable or unwilling to give consent or who were institutionalized were excluded.The urine samples were analyzed using the Human Kidney Biomarker Array (ARY019) as well as the Human XL Cytokine Array kit (ARY022B) from Research And Diagnostic Systems, Inc. , according to the manufacturer’s protocols. For the experiment series 1, the urine samples (control and CDK) were pooled prior to analysis. In the experiment series 2, we analyzed another pool of urine samples (control and CDK).In the experiment series 3, urine from one individual male control sample was compared to the pooled male and female CKD samples. For each membrane, 1 mL of urine was incubated overnight at 4 °C on the respective membranes. Detection was carried out using a streptavidin-HRP and the ECL Prime WesternfBlot-Detectionreagent  detection reagents. The obtained signal was analyzed using FIJI/ImageJ software .https://www.optinav.info/MicroArray_Profile.htm, accessed on 21 December 2022), which was employed to quantify the integrated densities of the spots. Grid positions were annotated with the cytokine identifiers provided in the manuals of the manufacturer .Scanned images of the cytokine assays were read into the FIJI/ImageJ software . The semp < 0.05) over the background spots, which were determined as spots with the minimum density plus 0.05 (max_density–min_density). Differential expression was assessed via the moderated t-test from the Bioconductor limma package [p-values were adjusted for the false discovery rate (FDR) by the method described by Benjamini and Hochberg [p-value < 0.05 in at least one condition, ratio < 0.667 (down-regulated), ratio > 1.5 (up-regulated), limma-p-value < 0.05, FDR < 0.25. Heatmaps were generated with the function heatmap.2 from the gplots package [barplot. Dendrograms were produced via the R package dendextend [Integrated densities of the spots quantified by the FIJI Microarray plugin were imported into the R/Bioconductor  environm package . Limma pHochberg . Cytokin package  using Pendextend  using PeUrine samples from CKD patients aged 6–71 years and control urine samples from probands with no history of CKD aged 11–68 were used . The uriAfter identification of CKD biomarkers on the Human Kidney Biomarker Array we set out to identify CKD-associated cytokines which include both pro-and anti-inflammatory molecules. Leukostasis and Artery Disease . The proteins associated with the regulation of kidney development  are highlighted in the network in Based on the identified differentially regulated cytokines, we set out to identify and characterize a protein interaction network involved in the inflammatory pathophysiology of CKD.  Disease C were deIn this two-phase analysis of cytokines in the urine of CKD patients and healthy individuals from Ghana, we identified urine-based cytokine biomarkers for CKD. In the first phase, which was performed on a Human Kidney Biomarker Array, we found variability between males and females and also between the two experimental series, which consisted of pooled urine samples from distinct individuals. This variability is a reflection of heterogeneity within biomarkers associated with CKD, which comprises a broad spectrum of distinct diseases, such as diabetic nephropathy and focal segmental glomerulosclerosis. Furthermore, there is much diversity in the genetic background of CKD and recent findings on biomarkers associated with hitherto neglected areas, such as telomeres, CNVs, mtDNA variants and sex chromosomes , which mFor the sake of robustness, only biomarkers regulated in the same direction in both experiment series are listed. The CKD biomarkers in male are: IL10  and MME . Sinuani et al. reported that IL10, through increased proliferation of mesangial cells and mediated by several other cytokines, induces progression of renal failure . DedicatIn the second phase, we used a more general cytokine (human XL) assay and found a high percentage of cytokine biomarkers overlapping between both genders. The CKD biomarkers regulated in the same direction between male and female are: APOA1, ANGPT2, C5, CFD, GH1, ICAM1, IGFBP2, IL8, KLK4, MMP9 and SPP1 (up-regulated) and FLT3LG, CSF1, PDGFA, RETN and VEGFA (down-regulated).Interestingly, APOA1 is connected to APOL1, which has been associated with FSGS in haplotypes carried by patients of African descent. APOL1 is bound to HDL particles, of which APOA1 is the major protein component, but only 10% of APOA1-containing HDL particles have APOL1 . We stilCytokines detected as differentially regulated on the Human XL cytokine assay as well as the Human Kidney Biomarker Array were RETN , MMP9  and VEGFA (down-regulated on the Human XL cytokine assay). VEGFA was regulated in the same direction on the Human Kidney Biomarker Array (down), while MMP9 was up-regulated in males in series 2 and females in series 1 and down-regulated in males in series 1 and females in series 2; however, RETN, in contrast to the XL assay, was up-regulated. As mentioned above for RETN, there are reports on elevated levels in CKD . MMP9 isp-value, nevertheless pointed in the same direction [We compared our detected biomarkers with association loci from GWAS and found that VEGFA, which we detected as a biomarker, had been identified in GWAS for an association with eGFR  and alsoirection . Furtherirection .We anticipate that our detected biomarkers may foster the mechanistic understanding of the development of CKD and further help to enable an earlier detection of the disease and in cases not detected by the conventional markers. CKD diagnosis mainly relies on GFR estimation indicating kidney dysfunction or albuminuria indicating kidney damage . GFR estWe conclude that our two-phase cytokine analysis of urine samples from CKD patients and healthy controls from Ghana has revealed panels of kidney-specific cytokine biomarkers which are also gender-specific and a panel of gender-independent cytokine markers. The gender-specific markers are IL10 and MME for males and CLU, RETN, AGER, EGFR and VEGFA for females. The gender-independent cytokine markers were APOA1, ANGPT2, C5, CFD, GH1, ICAM1, IGFBP2, IL8, KLK4, MMP9 and SPP1 (up-regulated) and FLT3LG, CSF1, PDGFA, RETN and VEGFA (down-regulated).


Background and Objectives: Although previous studies showed that an activity of xanthine oxidoreductase (XOR), a rate-limiting enzyme in purine metabolism, beyond the serum uric acid level, was associated with the development of coronary artery disease (CAD), the underlying mechanisms are unclear. Because endothelial dysfunction and a greater blood pressure (BP) variability may play a role, we investigated the relations among the endothelial function, XOR, and BP variability. Materials and Methods: This was a post-hoc study using pooled data of patients with a stable CAD from two prospective investigations, in which the systemic endothelial function was assessed with the reactive hyperemia index (RHI) and the XOR activity was measured. The BP variability was evaluated using BP measurements during the three- and four-day hospitalization. Results: A total of 106 patients with a stable CAD undergoing a percutaneous coronary intervention were included. Of the 106 patients, 46 (43.4%) had a systemic endothelial dysfunction (RHI < 1.67). The multivariable analysis identified a higher body mass index (BMI), female gender, and diabetes as factors associated with an endothelial dysfunction. A higher BMI was also related to an elevated XOR activity, in addition to current smoking. No significant correlation was observed between the RHI and XOR activity. Similarly, the in-hospital BP variability was associated with neither the endothelial function nor XOR. Conclusions: Among patients with a stable CAD, several factors were identified as being associated with a systemic endothelial dysfunction or an elevated XOR activity. However, no direct relations between the endothelial function, XOR, and BP variability were found. Endothelial dysfunction is the earliest stage of a coronary artery disease (CAD), leading to the plaque progression and cardiovascular events . The accThis study was a post-hoc analysis using patient-level pooled data of two prospective studies conducted at Chiba University Hospital ,11. A stSystemic endothelial function was non-invasively evaluated with the reactive hyperemic index (RHI) using the EndoPAT 2000 device , which is validated as being reproducible and operator-independent . The RHIBlood samples were obtained from an arterial sheath during the PCI and coronary angiography before the injection of unfractionated heparin in the fasting state. The plasma XOR activity was evaluated using a highly sensitive assay using a stable isotope-labeled xanthine and a combination of liquid chromatography and triple quadruple mass spectrometry  . The levThe BP variability during the hospitalization was investigated, as was accomplished in the present studies ,18. DuriThe primary interest of this study was the relation between the endothelial function assessed with the RHI and the XOR activity in patients with a stable CAD. We further investigated the factors associated with a systemic endothelial dysfunction and the XOR activity. As an exploratory analysis, the in-hospital BP variability was also evaluated.p < 0.10) were included into the multivariable analysis. The log-transformed XOR and RHI were included into the multivariable models irrespective of the p value in the univariable analysis. A p value < 0.05 was considered statistically significant.A statistical analysis was performed using SAS software version 9.3 . All data are expressed as mean ± SD, median [interquartile range], or frequency (%), as appropriate. The continuous variables were compared with a Student t-test, and the categorical variables were assessed with Fisher’s exact test. The plasma XOR activity was log-transformed because of the skewed distribution. The relation between the variables were analyzed using Pearson’s correlation coefficient. A multivariable analysis using a logistic regression analysis and a multiple linear regression analysis were performed to identify the factors associated with the RHI < 1.67 and XOR activity. The age, sex, and factors associated with the variables in a univariable analysis (p = 0.36). The multivariable analysis identified the female gender, a higher BMI, and the presence of diabetes, as predictors of a systemic endothelial dysfunction  had a systemic endothelial dysfunction (RHI < 1.67). function . A highefunction . With refunction .The present study demonstrated that among patients with a stable CAD undergoing a PCI, an endothelial dysfunction was observed in more than 40%. A higher BMI, the female gender, and diabetes were identified as factors associated with an impaired endothelial function, while XOR was related to a higher BMI and current smoking. There was no direct relationship between the systemic endothelial function and XOR. In addition, neither the endothelial function nor XOR was associated with the in-hospital BP variability.The dysfunction of the regenerated endothelial cells is recognized as the first step toward coronary atherosclerosis . NumerouIn the present study, a higher BMI, the female gender, and diabetes were indicated as predictors of a systemic endothelial dysfunction. Among women with no obstructive CAD, the iPOWER study showed that a higher BMI, diabetes, current smoking, and a lower high-density lipoprotein cholesterol level were associated with a lower RHI , which iThe BP variability was also evaluated in this study as a possible mechanism of coronary atherosclerosis and worse cardiovascular outcomes in patients with hyperuricemia. The in-hospital BP variability is a recently emerged index of the BP fluctuation, and we and others reported that it was associated with cardiovascular outcomes in patients with a CAD, a peripheral artery disease, and stroke ,18,23. BThere are several limitations to our study. This was a single-center, cross-sectional study with a relatively small sample size. Although the data were obtained in a prospective fashion, the present analysis was performed in a post-hoc manner. Although overall similar, the baseline characteristics of two studies were slightly different . In the Among the patients with a stable CAD undergoing a PCI, a systemic endothelial dysfunction was frequently observed and was associated with a higher BMI, the female gender, and diabetes. While a higher BMI was also identified as a factor related to the elevated activity of XOR, in addition to current smoking, no direct relationship between the endothelial function and XOR was found. Additionally, the in-hospital BP variability was not correlated with the endothelial function and the XOR activity. Future investigations are needed to clarify the underlying mechanisms in the development of cardiovascular disease in patients with an elevated SUA and XOR.