As a known phenomenon, crossover between sinus node dysfunction and common atrial tachyarrhythmias—most notably, atrial fibrillation and atrial flutter—in older individuals has previously been seen. Here, we present one of the first case series demonstrating a similar relationship between sinus node dysfunction and much rarer etiologies of tachyarrhythmia—that is, postural tachycardia syndrome and inappropriate sinus tachycardia. The exact pathological mechanisms behind these arrhythmias as well as the observation of concurrent nodal dysfunction are poorly understood. Here, we propose both potential mechanistic pathways as well as an initial treatment algorithm for sinus node dysfunction based upon the existing evidence. We detail four separate cases, three of which eventually underwent pacemaker implantation and one of which may require similar treatment in the future.Here, we examine a rare but known phenomenon in which patients with persistently tachycardic baseline heart rates due to previously diagnosed postural orthostatic tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST) demonstrate a transition into periods of either transient or sustained symptomatic bradycardia. This is similar in scope to the known crossover between sinus node dysfunction and more common atrial tachyarrhythmias—most notably, atrial fibrillation and atrial flutter—in older individuals.A 20-year-old woman with a known history of POTS and episodes of syncope starting at the age of 13 years presented for evaluation. At the beginning of her disease course, she experienced palpitations, light-headedness, and dizziness, with positional changes. Her symptoms progressed into her teenage years with two to three episodes of syncope per month and recurrent emergency room and physician visits. She was seen by multiple providers and had been labeled as a psychiatric patient until she was ultimately referred to our electrophysiology (EP) clinic due to elevated heart rates associated with her episodes. She underwent tilt-table testing and experienced symptomatic tachycardia up to 143 bpm; variations in blood pressure (BP) from 119/87 to 103/54; and, ultimately, syncope during the study. After a thorough review of her symptoms, she was diagnosed with autonomic dysfunction and orthostatic intolerance consistent with postural tachycardia syndrome. She was treated with intravenous saline infusions as well as ivabradine after failing multiple other medical therapies, including bupropion, fludrocortisone, nebivolol, and droxidopa. After some initial success with this regimen, she was later admitted to the hospital with debilitating episodes of bradycardia at the age of 19 years. All rate-controlling medications were discontinued and an ambulatory monitor was placed. She was found to be in persistent sinus bradycardia with rates in the 30s and 40s, which did not change with repositioning. Due to intractable symptoms despite withdrawal of all rate-controlling agents and a period of monitoring, she ultimately required placement of a dual-chamber pacemaker, with significant improvements in symptoms observed with atrial pacing at a burden of 60% to 70%.Table 1 for the complete list). About 12 years from the time of her initial diagnosis, however, she experienced an abrupt change in the nature of her syncopal episodes with an advancement in frequency and severity of events and a loss of her usual initial prodrome, raising the potential for significant future trauma. An implantable loop recorder was placed, which revealed new episodes of profound sinus bradycardia with rates dipping into the range of 20 to 39 bpm. Following this discovery, a dual-chamber pacemaker was placed with near-complete resolution of symptoms and requiring pacing at a 60% to 70% burden. She has since returned to a near-normal quality of life a few years out from device placement.A very accomplished 53-year-old female professional musician presented as a patient to our clinic with a long history of debilitating POTS and episodes of syncope, which significantly interfered with her ability to work as well as quality of life. She had undergone extensive evaluation with positive tilt-table testing findings at two prior centers consisting of tachycardia and hypotension prior to referral to our clinic. She had been trialed on multiple medications, including bupropion, droxidopa, and saline infusions, and had shown initial success with medical management with long-term follow-up  or medications such as vasodilators, diuretics, antidepressants, or anxiolytic agents must be established prior to diagnosis.4 Hyperadrenergic states, usually the result of a genetic predisposition, can lead to increased norepinephrine (NE) levels which, together with impaired clearance or decreased uptake, can manifest as anxiety, tremulousness, and elevated diastolic BP.5 Metabolic, systemic, and autoimmune diseases may also manifest as POTS. Common culprits include diabetes mellitus, amyloidosis, heavy metal poisoning, Sjögren’s syndrome, hypermobility syndrome, and paraneoplastic syndrome. In addition, it has been found to be inducible following successful slow pathway atrioventricular nodal ablation.6Primary and secondary forms of POTS are classified based on the proposed etiology of symptoms. Primary partial dysautonomia (or neurogenic) POTS is thought to a pathologic immune-mediated response via serum auto-antibodies to α1-adrenergic receptors in vascular smooth muscle, muscarinic M4 receptors, and α3-Ach receptors on peripheral ganglia.7Distinguishing POTS from similar syndromes depends on adherence to specific clinical criteria, with the differential including IST syndrome, chronic fatigue syndrome, pheochromocytoma, and neurocardiogenic syncope. Specifically, IST has overlapping features with POTS, which can make proper diagnosis a nebulous task as both disorders result in an increase in heart rate with minimal activity. However, POTS is usually associated with elevations in heart rate in response to changes in the body position, whereas this is possible but not essential to make a diagnosis of IST. Both conditions can be severely debilitating to an affected individual, with at least one reported case of an individual with IST experiencing tachycardia-induced cardiomyopathy.8 Low-dose propranolol has also demonstrated efficacy in reducing tachycardia and achieving symptomatic control in POTS.9 Perturbations in serotonin production and regulation can also affect BP and heart rate, signifying a role for selective serotonin reuptake inhibitors in combination with serotonin and NE reuptake inhibitors as a potential adjunct therapy regimen for POTS via the stimulation of the standing vasoconstriction reflex.10 Other medications that have demonstrated success in select cases include fludrocortisone, midodrine, methylphenidate, and pyridostigmine for orthostatic syndromes.13 A promising therapy that has been gaining traction recently is ivabradine, a funny sodium channel blocker (iF blocker) that has demonstrated effects including reducing the heart rate and providing symptomatic relief from POTS as well as IST without significant concomitant drops in BP.15 More invasive methods such as pacemaker placement have also demonstrated efficacy in orthostatic intolerance syndromes that are refractory to medical treatment, specifically with the use of devices capable of responding to BP variations.16Treatment of these related conditions is usually directed toward the modification of autonomic responses as well as rate control initially through medical therapy followed by radiofrequency sinus node ablation for refractory cases. Hyperadrenergic forms of POTS may respond to agents such as labetalol and clonidine due to their sympatholytic activity.17 Particularly, venous dysfunction secondary to impaired innervation can lead to pooling of blood in the legs and improper redistribution of blood to the peripheral circulation, leading to an increase in sympathetic receptor activity on the heart without a concurrent increase in vasoconstriction. Over time, this mismatch in autonomics and circulation may result in circulatory collapse.8 Similar mechanisms behind POTS and IST have been proposed, including intrinsically high sinus node automaticity rates due to ion channel dysfunction and alterations in autonomic nervous system tone together with decreased cardiovagal tone. In particular, abnormal autonomic modulation with elevated sympathetic and diminished parasympathetic tone has been shown to be a component of both POTS and IST.18 In addition, in vitro studies have reported the presence of circulating anti–β-adrenergic receptor antibodies leading to persistent, incremental production of cyclic adenosine monophosphate in IST, suggesting a role for autoimmunity in the development of the condition.20 A deficiency in NE transportation due to a single point mutation has also been identified, which can lead to a lack of clearance of NE, triggering excessive sympathetic activation.21Clear mechanisms have yet to be elucidated but include impaired vascular innervation, elevated NE concentrations, α- and β-receptor sensitivity, and baroreceptor dysfunction.Given the aforementioned mechanisms for POTS and IST, many previously proposed mechanisms for the overlap between much more common tachycardias—most notably, atrial fibrillation—and sinus node dysfunction may serve as potential avenues to explain the observed transition from pathological tachycardia into bradycardia in these in these rarer cases. The first potential mechanism is that increased intrinsic automaticity due to a genetic channelopathy may induce a more rapid rate of nodal fibrosis. As previously suspected for other types of predominately tachycardic dysrhythmias such as atrial fibrillation, there is likely a degree of atrial anatomical and electrophysiological remodeling that occurs with persistent inappropriately elevated rates. While the etiologies in these cases—namely, POTS and IST—for the elevated rate are much rarer phenomena, the mechanism by which the sinus node degenerates may very well be similar. We know that radiofrequency-induced inflammation and fibrosis of the sinoatrial node lead to dysfunction, with progression into bradycardia. If the channelopathy confines itself specifically to the pacemaker cells of the sinus node, it is reasonable to suppose that they may be prone to a faster rate of fibrosis or dysfunction. Additionally, a second possible mechanism is that, if the pathological driving force behind the initially inappropriately elevated heart rate is for one reason or another halted, the long-term adaptation already undertaken by the central nervous system to combat this process in the form of increased baseline vagal tone would now stand unopposed. This may be the case, for example, in those patients with autoimmune-mediated disease with cessation of auto-antibody production or some new form of antagonism to the antibodies.Finally, the third and, likely, the hardest to target is a shift in intrinsic autonomic tone in those patients with significant underlying dysautonomia. In the simplest terms, this would constitute a new shift consisting either of significant downregulation of a baseline high sympathetic tone or upregulation of a baseline low parasympathetic tone, resulting in a transition from tachycardia to bradycardia. With at least some proposed theories available to explain the transition point, a rational scheme for treatment and prevention can be postulated. In the case of progressive nodal fibrosis, if the rate of nodal degradation is linked to the degree of tachycardia, then appropriate rate control is paramount. This would include traditional agents such as β-blockers and central calcium channel blockers as well as newer agents, including iF channel blockers. In the case of autoimmune antibody formation, it is reasonable to presume that, over time, these patients develop increased baseline vagal tone. If the offending antibody is antagonized or its production halted, a transition into initial bradycardia is to be expected. This group would stand to benefit from targeted antibody receptor antagonism or immune suppression to reduce the production of the offending antibody. Following the identification and treatment of the driving pathologic force as well as discontinuation of any other medications that may worsen bradycardia, careful observation may prove to be an effective strategy. Lastly, if severe deviation in sympathetic or parasympathetic tone due to dysautonomia is present, there remain few additional therapies outside of mitigating downstream effects. As a last option, patients with progression from POTS or IST into symptomatic bradycardia may ultimately require pacing support due to unacceptably severe limitations in the quality of life.. Maximally tolerated doses of a β-blocker or calcium channel blocker as well as an iF channel blocker should be considered as primary therapy to limit any associated nodal fibrosis. For patients who demonstrate a transition in baseline rate and symptoms from tachycardia to maintained bradycardia, an event monitor should be deployed and all offending rate-controlling agents should be halted. If bradycardic rates are persistently and inappropriately maintained with associated symptoms, a careful observation period of at least three to four weeks may allow for readjustment in baseline vagal tone. However, if symptoms continue despite these initial steps, the patient should be considered as a candidate for long-term pacing.This framework allows for the proposal of an initial treatment strategy for patients with an appropriate diagnosis of IST or POTS As a rare but recurrent phenomenon, it has been observed in our clinic that patients suffering from POTS as well as IST have an increased propensity for progression into sinus node dysfunction consisting of episodes of either transient or sustained symptomatic bradycardia. A proven mechanism for this transition as well as the best management strategies for these cases remain unknown. We suspect the mechanisms of degeneration of the sinus node may be similar to those seen with other tachycardic dysrhythmias, such as atrial fibrillation or atrial flutter. With this case series, we hope to introduce the observation into the literature as a seed for ongoing investigation and to propose our own preliminary management algorithm.This paper stands as an attempt to describe a witnessed phenomenon at a specialized syncope clinic. Due to the inherently small populations of these patients, the crossover between sinus node dysfunction and POTS/IST is suggested but unproven. A number of patients were evaluated at other centers before being referred to us and every effort was made to accurately summarize prior testing; however, the record may have missing components. Of note, it is a significant limitation that diagnostic electrophysiology studies were not performed preceding pacemaker implantation in these patients.


SUMOD on POD1 was not associated with DGF. In conclusion, higher pretransplant sUMOD was independently associated with lower odds for DGF, potentially serving as a non-invasive marker to stratify patients according to their risk for developing DGF early in the setting of kidney transplantation.Delayed graft function (DGF) following kidney transplantation is associated with increased risk of graft failure, but biomarkers to predict DGF are scarce. We evaluated serum uromodulin (sUMOD), a potential marker for tubular integrity with immunomodulatory capacities, in kidney transplant recipients and its association with DGF. We included 239 kidney transplant recipients and measured sUMOD pretransplant and on postoperative Day 1 (POD1) as independent variables. The primary outcome was DGF, defined as need for dialysis within one week after transplantation. In total, 64 patients (27%) experienced DGF. In multivariable logistic regression analysis adjusting for recipient, donor and transplant associated risk factors each 10 ng/mL higher pretransplant sUMOD was associated with 47% lower odds for DGF (odds ratio (OR) 0.53, 95% confidence interval (95%-CI) 0.30–0.82). When categorizing pretransplant sUMOD into quartiles, the quartile with the lowest values had 4.4-fold higher odds for DGF compared to the highest quartile . Adding pretransplant sUMOD to a model containing established risk factors for DGF in multivariable receiver-operating-characteristics (ROC) curve analysis, the area-under-the-curve improved from 0.786 [95%-CI 0.723–0.848] to 0.813 [95%-CI 0.755–0.871,  Delayed graft function (DGF), commonly defined as need for dialysis within the first week after kidney transplantation, affects around 25–50% of patients, and is associated with a higher risk for acute rejection episodes and reduced long-term graft survival ,2,3,4. DUromodulin , is a kidney derived glycoprotein with a molecular weight of around 100 kDa, exclusively expressed by epithelial cells of the thick ascending limb of the loop of Henle and the distal tubule ,12,13. THere, we propose that recipient’s sUMOD plays an important role in the recovery from IRI after kidney transplantation, and thus sUMOD might be of predictive value for the incidence of DGF after kidney transplantation. In this study we evaluated recipient’s sUMOD pretransplant and on postoperative Day 1 (POD1) as a marker for prediction/early detection of DGF in kidney transplant recipients.In this single-center prospective observational cohort study, we recruited 239 patients undergoing kidney or combined kidney-pancreas transplantation following deceased or living donation in our tertiary care hospital. All patients who were able to provide informed consent were included in the study. Local institutional review boards of the Technical University of Munich, Germany approved the study methods. The study adheres to the declaration of Helsinki and the declaration of Istanbul.Serum samples for measuring sUMOD in the recipients were obtained 24 h prior to kidney transplantation in living organ donations and up to 5 h pretransplant in deceased donations, again on the first postoperative day (POD1) and subsequent time points later. Since all patients were hospitalized during the sample collection and no patient withdrew from the study, no patients were lost to follow-up for the primary endpoint (see below).The samples were stored at −80 °C until they were thawed. sUMOD analyses were performed in singlicate using a commercial enzyme-linked immunosorbent assay  based on the manufacturer’s instructions. This assay is based on a colorimetric sandwich immunoassay using a polyclonal antibody against human uromodulin as the capture antibody and a biotinylated polyclonal antibody against human uromodulin as the detection antibody. Quality characteristics of the ELISA are as follows: intra-assay coefficient of variation 1.8–3.2%, inter-assay coefficient of variation 6.6–7.8%, mean linearity recovery 97%, and lower limit of detection 2.0 ng/mL.The primary outcome was DGF, defined as the need for more than one dialysis within one week after transplantation as has been defined in prior clinical studies ,23. For We describe the population using mean (± standard deviation) for continuous variables and number with percentages for binary and categorical variables.Multivariable logistic regression models were used to evaluate the association of sUMOD pretransplant and on POD1 as independent variables and DGF as the dependent variable. We applied a series of nested models: (i) unadjusted; (ii) adjusted for age, body-mass index (BMI) and dialysis vintage; (iii) Model 1 plus serum creatinine on POD1 ; (iv) Model 2 plus cold ischemia time (CIT), living vs. deceased donor transplantation, and expanded criteria donors (ECD) vs. standard criteria donors (“Model 3”). ECD are donors that are either older than 60 years, or 50–59 years old and meet at least two of the following criteria: cerebrovascular death, history of hypertension, and/or last serum creatinine greater than 1.5 mg/dL . Due to The mean age of the cohort was 51 ± 14 years, 31.4% were female, 90 (37.7%) received an organ from a living donor, 79 (33.1%) had cardiovascular disease at baseline. Mean serum creatinine concentration was 6.0 ± 2.3 mg/dL on POD1. Demographics of the entire cohort and stratified by preoperative sUMOD quartiles are shown in p < 0.001). The mean serum creatinine on POD1 was significantly higher in patients with DGF . Referring to donor characteristics, kidney transplants with subsequent DGF were derived from donors who were more often male, had a higher BMI, a higher prevalence of diabetes and had a significantly higher serum creatinine before donation. Furthermore, cold and warm ischemia time were significantly longer for donor kidneys who developed DGF. Further information on DGF vs. non-DGF patients can be found in A total of 64 (26.8%) renal allograft recipients experienced DGF. Patients who experienced DGF were older, more often male, had a higher BMI and a greater prevalence of cardiovascular disease . The timp < 0.001). There was no significant difference in sUMOD levels on POD1 between patients with and without DGF  instead of dialysis vintage. We did not add preemptive transplantation as another covariable in order to avoid overfitting of the model. In this additional analysis with pretransplant sUMOD as a continuous variable, we identified a similar OR for the association of sUMOD with DGF (OR 0.50 (95%-CI 0.28–0.79) per 10 ng/mL higher sUMOD).sUMOD on POD1 was not significantly associated with DGF, neither as a continuous nor a categorical variable .p = 0.05) as presented in In multivariable ROC curve analysis, Model A (including risk factors for DGF without preoperative sUMOD) worked moderately well to predict DGF (area under the curve (AUC) 0.786 [95%-CI 0.723–0.848], In the current study, we demonstrate that a higher pretransplant sUMOD in kidney transplant recipients is independently associated with a lower risk for DGF. Furthermore, preoperative sUMOD was of additional predictive value when added to a model of established risk factors for DGF. Surprisingly, we detected no association between sUMOD on POD1 and DGF.We further mapped the course of sUMOD before, during and in the early phase after transplantation (up to 120 days following kidney transplantation) with and without the occurrence of DGF. We demonstrated that over the longer course after transplantation patients without DGF maintained higher sUMOD levels, while in patients with DGF we detected a subsequent decline in sUMOD in the postoperative period. The subsequent decrease in sUMOD is consistent with a recent study showing decrease in circulating uromodulin following AKI in a cohort of liver transplant patients undergoing surgery , reflectsUMOD has been positively associated with reduced risk for kidney failure, cardiovascular events and mortality in geriatric and chronic kidney disease populations ,28. In kHigher pretransplant sUMOD could represent the anti-inflammatory capacity of the recipient towards the following inflammation due to IRI. Interstitial or sUMOD has been shown to downregulate proinflammatory signaling in the kidney, reflecting its immunomodulatory and reno-protective capacity . RecentlAlthough it is challenging to directly extrapolate results from murine models of IRI to human transplantation, results from these models support our observations, that a higher sUMOD in the recipient just before transplantation is associated with lower risk for DGF . SUMOD iIt is interesting that sUMOD increases initially in patients with or without DGF, which might reflect the release of “donor” sUMOD from the transplanted kidney. Patients with DGF have a subsequent profound and persistent decrease in sUMOD. The fact that we do not see an association between sUMOD on POD1 and delayed graft function could reflect the dynamic pathophysiological process occurring during this early time period in the transplanted kidney, which may be critical to the subsequent course of injury or recovery. The initial increase could represent general reactive reno-protection-intended induction of uromodulin production in the setting of renal IRI, which is related to its immune-modulatory capacities in the interstitium ,17.While sUMOD on POD1 might be influenced by acute inflammation and hypoxic stress, long-term sUMOD should reflect tubular function/mass ,21. HoweOne strength of our study is the use of both pre- as well as the post-transplant period. While we did not directly adjust for residual kidney function in the multivariable approach, we propose that with adjusting for dialysis vintage and kidney transplantation after living donation we also captured residual kidney function to some extent, as it is well known that residual kidney function decreases along with the time spent of dialysis. In general, due to its molecular mass of 95 kDa sUMOD is highly unlikely to be removed by both hemo- and peritoneal dialysis.A major limitation in the present study is that patients without DGF received kidneys from “healthier” donors with shorter ischemia time see , that arIn conclusion, lower pretransplant sUMOD is independently associated with DGF after kidney transplantation and might therefore function as an early non-invasive marker to identify patients at increased risk for DGF following IRI and subsequent complicated course after kidney transplantation.


Background: Adrenal myelolipoma (AML) is a nonfunctional benign neoplasm from the adrenal cortex, composed of mature fat and hematopoietic tissue. Usually, patients have no symptoms. However, some patients with hypertension and blood pressure normalize after AML surgery, indicating some connections between AML and hypertension.Materials and Methods: This was a retrospective cohort study of 369 patients diagnosed with AML from September 2008 to December 2018 collected in the Urology Department of West China Hospital, Chengdu, Sichuan, China. We collected clinical records of patients before surgery. Postoperative follow-up was also carried out for those with hypertension and whether patients needed to take antihypertensive drugs and postoperative blood pressure were recorded. We aim to explore the characteristics of both patients with AML having hypertension and having remission of hypertension in 1 year after surgery.Results: There were 369 patients with AML included in the study, 156 men and 213 women, aged 49.86 ± 11.61 years old. Among them, 121 (32.8%) patients presented with hypertension. Body mass index was significantly higher in the hypertension group than that in the nonhypertension group, even after adjusting other variables . Sixty patients were followed up for 1–9 years, with a median follow-up of 52 months. The duration of hypertension in the remission group was shorter than that in the non-remission group (P = 0.020), and the tumor lateralization was significantly different between the two groups (P = 0.005).Conclusions: Nearly one-third of patients with AML suffered from hypertension in our study, and there existed some potential links between AML and hypertension. To be more specific, AML-related hypertension was more likely to result from obesity and renal compression by perirenal fat than from endocrine disorders or blood vessels compression. Patients with AML and with more than 3 years of hypertension might have less possibility to recover. Adrenal myelolipoma (AML) is generally considered a non-functional benign tumor originated from the adrenal cortex, made up of a variable proportion of mature fat and hematopoietic tissues . The numThis was a retrospective cohort study of 369 patients diagnosed with AML from September 2008 to December 2018 collected in the Urology Department of West China Hospital, Chengdu, Sichuan, China. The study was approved by the Ethics Committee of West China Hospital of Sichuan University . Informed consent was exempted because all clinical records were acquired retrospectively from the hospital inpatient system (HIS) when patients were admitted to the hospital for diagnosis and treatment, without revealing the privacy of patients. All patients were treated with surgery.The including criteria of this study were as follows: (1) neoplasm from adrenal presented by computer tomography ; (2) adrThe excluding criteria of this study were as follows: (1) diagnosis of other tumors by postoperative pathological examination, such as pheochromocytoma, primary aldosteronism (PA), and other adrenal diseases that may cause hypertension; (2) diagnosis of congenital adrenal hyperplasia and primary adrenocortical hypofunction.We collected clinical records of patients before surgery, consisting of gender, age, leading complaints , history of diabetes, tumor lateralization, tumor diameter, body mass index (BMI), duration of hypertension, blood pressure, the number of antihypertensive drugs, preoperative plasma renin activity (PRA), and plasma aldosterone concentration (PAC). Postoperative follow-up was also carried out for those with hypertension and whether patients needed to take antihypertensive drugs and postoperative blood pressure were recorded.All eligible patients were divided into two groups: hypertension and non-hypertension, based on the complication of hypertension . Based on the outcomes of follow-up, those with hypertension were divided into two groups: the remission group and the non-remission group. The remission of hypertension after the operation is defined as stopping the use of antihypertensive drugs for 3 months and the blood pressure coming down to normal (<140/90 mmHg), which lasts till the end of follow-up.t-test. The multivariate logistic regression model was utilized to test selective variables in previous univariate analyses. The receiver operation characteristic (ROC) curve was utilized to examine the efficacy of a diagnostic model. P < 0.05 was applied to certify the statistical significance between the two groups of data. The normality of the distribution was tested using the Shapiro–Wilk test.All the procedures were finished on the statistical software, IBM SPSS Statistics 22. Discrete variables were reported as a percentage and continuous variables as mean ± SD or median (quartile). For analysis of categorical variables, Pearson's chi-square test or Fisher's exact test was used. Differences between means were tested with Student's There were 369 eligible patients with AML enrolled in our study, comprising 156 men and 213 women. Around 10 patients were with open surgery. The average age was 49.86 ± 11.61 years, among which 121 patients were complicated with hypertension. The duration of hypertension ranged from 1 day to 30 years, and the mean systolic and diastolic pressures in the hypertension group are 168.89 ± 23.18 and 99.29 ± 14.82 mmHg, respectively. Antihypertensive drugs included nifedipine, amlodipine, captopril, irbesartan, metoprolol, prazosin, furosemide, and so on. The incidence of hypertension in AML is 32.8%.2, P < 0.001 for both univariate and multivariate analyses). In addition, BMI was significantly higher in almost all subgroups, except for subgroups 20–29 and 60–79 . LL, LC, and LZ data analysis and/or interpretation. LL, YZ, and LZ drafting of the manuscript and/or critical revision. YZ and LZ approval of the final version of manuscript. All authors contributed to the article and approved the submitted version.The work was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZY2016104), the Innovation Spark Project of Sichuan University (2018SCUH0061), and the National Natural Science Fund of China (81800667).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD.Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically  Oftentimes, the most common indicator of kidney function, namely eGFR, is used. However, eGFR has major limitations such as a weak sensitivity in detecting early stage CKD and poor prediction of the course of CKD [Chronic kidney disease (CKD) is a leading cause of death around the world and is associated with a major risk for cardiovascular (CV) and all-cause mortality ,2. CKD ie of CKD . They hae of CKD ) but thee of CKD . Serum le of CKD ,9,10,11.Endothelial dysfunction is a pathological condition of the vascular endothelium that is a mainstay of CKD and is known to increase the risk for CV disease . There aAnother feature of CKD is the accumulation of uremic toxins in the blood . They arThe present study is a follow-up of our previous work . The chaThe baseline characteristics of the cohort analyzed in the present study are presented in The association of miR-126 with the endothelial markers MMP-7, ANGPT2, Sdc-1, and VCAM-1 was studied by using a Spearman’s correlation. miR-126 was found to be associated with eGFR, Sdc-1, VCAM-1, and MMP-7 but not with ANGPT2 .Next, a multiple linear regression analysis of the three biomarkers significantly associated with circulating levels of miR-126 was performed . We confWith the intent to detect links between circulating levels of miR-126 and levels of uremic toxins, a set of correlation analyses between four of the main uremic toxins, IS, PCS, PCG, and IAA was performed. Both total and free plasma concentrations were considered. cel-miR-39 , the Net Reclassification Improvement (NRI), Harrell’s C-index, and the Akaike Information Criterion (AIC) using our parameters . Out of Our former study was the first to evaluate the serum expression of miR-126 as a potential diagnostic and prognostic biomarker in a large cohort of patients with CKD at various stages of the disease, including a group of controls without CKD . FurtherIn a previous work focusing on the present cohort   free pCSThe detrimental effect of IS and other protein-bound toxins has been amply demonstrated in the CKD course ,26. IS iIn summary, our results suggest a role of miR-126 in endothelial dysfunction in a large cohort of CKD patients. Other miRNAs have been described as potential biomarkers of CKD and/or cardiovascular damage , such asIn total, 562 patients afflicted with CKD stages G1 to G5 ) were included in this single-center study at the outpatient clinic of the Nephrology Section of the Ghent University Hospital . Inclusion into the study was from January 2011 to January 2014. The exclusion criteria were an age under 18, active infection, pregnancy, malignancy, or transplantation history. Outcome parameters were monitored for 5,5 years until June 2017. Patients with CKD were categorized into subgroups according to their estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), following KDOQI guidelines. Eight subgroups were compared, including six CKD subgroups not on dialysis , one CKD subgroup on RRT (stage G5D), and healthy controls. Hypertension was defined as a systolic blood pressure >140 mmHg and/or a diastolic blood pressure >90 mmHg, or as the need for anti-hypertensive medication. In this study, we mostly studied the six CKD subgroups not on dialysis. To address the batch effect during the determination of the serum miR-126 levels and other endothelial markers, samples were collected, aliquoted, and stored at −80 °C until batch analysis. A new aliquot was used for each analysis and no thaw/freeze cycle was applied. For the endothelial markers, a human magnetic luminex assay was used and a premix multiplex was ordered. The same lot number (L123484) was used for all patient samples.This study was approved by the local ethical committee at the Ghent University Hospital . Written informed consent was obtained from all participants. The study complied with the tenets of the Declaration of Helsinki and its amendments.Caenorhabditis elegans miR-39 was spiked-in to be used as an internal control, as described in [RNA was extracted from patient blood and RT-qPCR was performed as described in detail previously . Venous ribed in . RNA wasThese quantifications were described in detail in . BrieflyThese quantifications were described in detail in . Brieflyp-value of <0.05 in the univariate analysis were analyzed by multivariate analysis. Statistical analyses were conducted using GraphPad Prism®® software version 6 and SPSS®® software version 21 unless stated otherwise. The Harrell’s C-index and AIC were estimated using the Cox model, whereas NRI and IDI were calculated using the package « SurvIDINRI » of software R version 4.0.5 through interface RStudio software version 1.0.143—© 2009–2016 RStudio, Inc. The threshold for statistical significance was defined as p < 0.05 in all tests.Correlations between patient characteristics and various levels were performed with Spearman’s rank correlation tests. Multiple linear regression analyses were performed to investigate the association between the parameters and the expression of miRNAs. In the case of non-normal distribution, the data were log-transformed. All the parameters with a miRNAs are promising new biomarkers in the CKD field. They need, however, more validation. Here, we show in a large cohort that the alterations in miR-126 levels are correlated with markers of endothelial dysfunction and cardiovascular disease, further expanding knowledge on the physiopathology of this non-coding RNA in CKD. In the future, long non-coding RNAs can also be developed as better biomarkers of CKD, as they are known to be more tissue-specific than miRNAs .


Chronic kidney disease is highly prevalent across the globe with more than 2 million people worldwide requiring renal replacement therapy. Interdialytic weight gain is the change in body weight between two sessions of haemodialysis. Higher interdialytic weight gain has been associated with an increase in mortality and adverse cardiovascular outcomes. It has long been questioned whether using a lower dialysate sodium concentration during dialysis would reduce the interdialytic weight gain and hence prevent these adverse outcomes.This study was a single blinded cross-over study of patients undergoing twice weekly haemodialysis at the Aga Khan University Hospital, Nairobi and Parklands Kidney Centre. It was conducted over a twelve-week period and patients were divided into two groups: dialysate sodium concentration of 137 meq/l and 140 meq/l. These groups switched over after a six-week period without a washout period. Univariate analysis was conducted using Fisher’s exact test for categorical data and Mann Whitney test for continuous data.p = 0.970). Mean blood pressures were as follows: pre-dialysis: DNa 137 meq/l: systolic 152.14 ± 19.99, diastolic 78.99 ± 12.20, DNa 140 meq/l: systolic 156.95 ± 26.45, diastolic 79.75 ± 11.25 . Post-dialysis: DNa 137 meq/l: systolic 147.29 ± 22.22, diastolic 77.85 ± 12.82 DNa 140 meq/l: systolic 151.48 ± 25.65, diastolic 79.66 ± 15.78 .Forty-one patients were included in the analysis. The mean age was 61.37 years, and 73% were males. The mean duration for dialysis was 2.53 years. The interdialytic weight gain was not significantly different between the two groups (2.14 for the 137 meq/l group and 2.35 for the 140 meq/l group, There was no significant difference in the interdialytic weight gain as well as pre dialysis and post dialysis systolic and diastolic blood pressures between the two groups. Therefore, using a lower dialysate sodium concentration does not appear useful in altering the interdialytic weight gain or blood pressure although further studies are warranted with a larger sample size, taking into account residual renal function and longer duration for impact on blood pressures. Globally CKD has a prevalence of 13.4%, with 10.6% being in stage 3–5 of the Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD between the year 2000 to 2014 [Chronic kidney disease (CKD) is the presence of kidney damage or decreased kidney function for three or more monthsUsually, the operator of the dialysis machine (nurse) must set the dialysate concentration for the dialysis session. During the process of dialysis, sodium is lost from the blood by ultrafiltration into the dialysate fluid. According to Flythe et al., the dialysate sodium concentration therefore has to be lower than the serum sodium so as to allow diffusion to occur and the serum sodium to be lowered . Using a higher dialysate sodium concentration results in ‘sodium-loading’ and thus activates the centre of thirst in the hypothalamus which makes the patient drink more water with subsequent weight gain and volume expansion. There is also an increase in sympathetic tone and release of vasopressin which may result in increased blood pressure and cardiovascular sequelae . Moret eInterdialytic weight gain is ‘the change in body weight between two sessions of haemodialysis . With tiTherefore, the aim of this study was to determine if dialysate sodium concentration has any bearing on interdialytic weight gain and blood pressure control. Most studies that have been done are observational with very few clinical trials. Furthermore, in most centres where these studies were done, patients were undergoing thrice weekly dialysis. In our set-up, majority of our patients undergo twice weekly dialysis, which would predispose them to a higher interdialytic weight gain due to a longer duration between dialysis sessions.The primary objective was to determine the association between the dialysate sodium concentration and interdialytic weight gain in patients undergoing haemodialysis twice weekly. The secondary objective was to determine the relationship between dialysate sodium concentration and blood pressure in patients undergoing haemodialysis twice weekly.The study setting was the Aga Khan University Hospital dialysis unit and Parklands Kidney Centre. The Aga Khan University Hospital is a private, not-for-profit teaching hospital and the dialysis unit at the hospital has 9 dialysis machines, with approximately 18 patients undergoing dialysis every day. There are approximately 48 patients in total on dialysis at the unit, out of which 30 are on twice-weekly dialysis. Parklands Kidney Centre is an outpatient dialysis unit that has 19 dialysis machines and approximately 90 patients in total, out of which approximately 45 are on twice-weekly dialysis.The study was a randomized single blind crossover study design. Each group was dialysed using a dialysate sodium of 140 and 137 meq/l at different time periods. The study was conducted at the Aga Khan University Hospital dialysis unit and Parklands Kidney Centre dialysis unit in Nairobi, Kenya on patients undergoing twice weekly dialysis over a period of 12 weeks.The inclusion criteria was as follows: age greater than 18 years, patients undergoing dialysis twice a week, patients who consented to be a part of the study. The exclusion criteria was as follows: patients with blood pressures less than 100/60, hospital in-patients. Withdrawal criteria was as follows: patients who develop intradialytic hypotension  , 13.Figure Categorical data were presented as frequencies and percentages whereas continuous data were presented as means and standard deviations. Univariate analysis was conducted using Fisher’s exact test for categorical data and Mann Whitney test for continuous data. The comparison between IDWG and mean systolic and diastolic blood pressure with each sodium group chosen for this study was conducted using the mean IDWG and mean systolic/diastolic blood pressure using Mann Whitney test.The mean age of participants was 61.39 years (SD = 13.82) with a predominantly male population (73%). The most common cause of CKD in these patients was hypertension, followed by diabetes mellitus. Most patients were oliguric. Fifty-nine percent of patients had a fistula for dialysis access, whereas the remainder had internal jugular permanent dialysis catheters. Only 45% of patients were on diuretics. The mean number of years of the patients on dialysis was 2.53. Table p value of 0.970, as seen in Table The primary outcome was the interdialytic weight gain between the two groups of dialysate sodium. The average interdialytic weight gain was 2.14 kg in the low dialysate sodium group (DNa 137 meq) and 2.35 in the high dialysate sodium group (DNa 140 meq), with a The mean pre-dialysis systolic blood pressure was152.14 151.54 in the low DNa group and 156.95156.05 in the high DNa group, while the mean pre-dialysis diastolic blood pressure was 78.99 in the low DNa group and 79.8580.81 in the high DNa group. The average post-dialysis systolic blood pressure was 147.296 in the low DNa group and 151.48 in the high DNa group, while the average post-dialysis diastolic blood pressure was 77.85 in the low DNa group and 79.6680 in the high DNa group. None of these differences were statistically significant between both groups as shown in Table Patients with hypertension were subanalysed to determine if there was a difference in weight gain in this subgroup and there was no significant difference.Of the 41 patients, two patients experienced hypotensive episodes. The first patient had asymptomatic hypotensive episodes on their 8th and 12th sessions of dialysis at dialysate sodium concentration of 140 meq/l. The second patient developed an asymptomatic hypotensive episode in the 4th session of dialysis at dialysate sodium concentration of 137 meq/l and a hypotensive episode on the 2nd session of dialysis at dialysate sodium concentration 140 meq/l. The latter required disconnection of the dialysis machine 30 min prior to completion. None of these episodes required saline infusion.This study has established that there is no association between dialysate sodium concentration and interdialytic weight gain. Furthermore, there was no association between dialysate sodium concentration and blood pressure. This was similar to what was found by Beduschi et al. when comparing DNas of 135 and 138 meq/l where there was no significant difference in the interdialytic weight gain or the blood pressure . This waIt is important to note that there was no exclusion of patients with residual renal function in this study, yet residual renal function (defined as urine output of greater than 200 ml/day) theoretically has a physiologic role in sodium balance . Ipema eIt has also been established in some studies such as that by Titze et al. that large amounts of sodium can be accumulated without water retention by the sodium ions binding to extracellular matrix components such as glycosaminoglycans . In addiThere is also theory that every individual has their own individual osmolar setpoint based on parameters such as dietary salt intake, urinary sodium excretion, tissue sodium stores as well as physiologic response of the body to sodium. For this reason, a change in the dialysate sodium concentration may not have that much of an impact on the interdialytic weight gain and blood pressures unless the sodium level is individualised. This was shown in a study conducted by Radhakrishnan et al. where they compared a set dialysate sodium concentration of 140 meq/l to an individualised dialysate sodium concentration. There was a significantly lower interdialytic weight gain and pre-dialysis systolic blood pressure in those patients who had an individualised dialysate sodium concentration in comparison to the standard dialysate sodium concentration of 140 meq/l .This study showed no significant difference between the systolic or diastolic blood pressure in both dialysate sodium concentration groups. Charra et al. described the concept of ‘lag time’, whereby it takes several months for the correction of the extracellular volume overload (in our case from the high sodium) to manifest as improvement in blood pressure . This stAn important finding on the study was the average interdialytic weight gain regardless of the dialysate sodium concentration used. The mean interdialytic weight gain was 2.14 kg and 2.35 kg for dialysate sodium 137 meq/l and 140 meq/l respectively. Comparing to other studies, for instance the PanThames renal audit done by Davenport et al. undergoing dialysis three times a week showed an interdialytic weight gain range of 1.7 to 2.75 kg . TherefoIt is recommended that the same study be conducted using a larger sample size to assess the association between dialysate sodium concentration and interdialytic weight gain. It would also be beneficial to do a comparison study of the same outcomes of interdialytic weight gain and blood pressure control in patients on twice weekly versus thrice weekly dialysis to ascertain whether the different dialysate sodium concentrations are affected by the frequency of dialysis. A limitation of the study was that pre-dialysis sodium concentrations were not obtained and hence dialysate plasma sodium gradient was not calculated. Also, the study duration was short, and therefore as far as blood pressure is concerned, it would take time for the effects of a reduction of dialysate sodium to reduce the extracellular volume and for this to have any effect on reduction in blood pressure.In summary, our study showed there was no difference in the interdialytic weight gain between the low dialysate sodium concentrations (DNa 137 meq/l) and high dialysate sodium concentration (DNa 140 meq/l) for patients undergoing twice-weekly haemodialysis. The interdialytic weight gain in both groups was however, generally lower compared to other studies despite patients undergoing twice-weekly dialysis (as opposed to thrice-weekly). Furthermore, the blood pressures were also not different in either dialysate sodium group and this was similar to some studies. However our study did not take into account residual renal function, dietary fluid and salt intake. In addition, the duration of the study was too short to compare blood pressures amongst the two groups due to the lag time between changes in dialysate sodium and the correction of the extracellular volume. There is the possibility of clinical significance, despite no statistical significance for both interdialytic weight gain and blood pressures, since both were lower in the low DNa group compared to the high DNa group.


Among these factors, only FMI z-score showed an independent association with abnormal ABPM using multivariate logistic regression analysis (p = 0.037). Our data highlight that body fat plays a key role for an abnormal ABPM in CKD children. The assessment of FMI may have clinical utility in discriminating CV risk in children and adolescents with early stages of CKD.Cardiovascular disease (CVD) risk factors are present early in life in children with chronic kidney disease (CKD), consequently cardiovascular morbidity presents in early adulthood. However, risk factors of CVD have been rarely addressed in children with early stage of CKD. This study included 63 children and adolescents aged 8- to 18 years-old with CKD stage G1–G4. Cardiovascular assessments consisted of 24-h ambulatory blood pressure monitoring (ABPM), arterial stiffness index, and echocardiography. We also applied dual-energy x-ray absorptiometry (DXA) scanning to analyze percentage body fat (PBF), lean body mass index (LBMI), fat mass index (FMI), and the android to gynoid fat ratio (A/G ratio). Up to 63.5% of CKD children had abnormal changes in BP detected by ABPM. CKD children with abnormal ABPM were older, had higher numbers of CKD stage G2 to G4, hyperuricemia, obesity, and higher FMI z-score and A/G ratio compared to individuals with normal ABPM (all  Patients with chronic kidney disease (CKD) exhibit a marked risk for cardiovascular (CV) comorbidities and mortality , whereasSimilar to adults, risk factors of CVD among children with CKD are also related to the traditional risks . ChildhoThe purpose of our study, therefore, was to assess body composition parameters with DXA and find out their associations with ABPM and other surrogate markers  in pediatric CKD.2, on dialysis maintenance, or ever received renal transplantation; or (4) were incapable of consenting to the follow-up protocol or cooperated with the procedures. All recruited patients were followed up to progression to end-stage kidney disease.All study procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The prospective cohort study was approved by the Institutional Review Boards (IRB) of the Chang Gung Medical Foundation at Taoyuan, Taiwan 201601181A3). A total of 101 children and adolescents aged 3 to 18 years with CKD stage G1–G4 attending the pediatric clinic at Kaohsiung Chang Gung Memorial Hospital was enrolled between December 2016 and October 2018. All of the participants parents gave their written informed consent. CKD was defined by kidney damage or reduced kidney function over at least three months 01181A3. . ParticiThe following assessments were performed on each participant at the same clinic visit: (1) history taking and physical examination; (2) anthropometry; (3) office BP and ABPM measurements; and (4) laboratory investigations. The congenital anomalies of the kidney and urinary tract (CAKUT) includes a wide range of structural anomalies like renal agenesis, posterior urethral valves, horseshoe kidney, kidney hypo-/dysplasia, duplex collecting system, multicystic kidney dysplasia, and ureter abnormalities . The etiBody height was measured (in cm to the nearest 0.1 cm) with a rigid stadiometer. Body weight was measured (in kg to the nearest 0.1 kg) with an electronic body weight scale. The BMI was calculated as body weight in kilograms divided by the square of body height in meters. BMI percentile for age-and-gender and z-score were determined based on Health Promotion Administration, Ministry of Health and Welfare in Taiwan. Obesity was defined as BMI percentile higher than and equal to the 95th percentile. The fat mass index (FMI), lean body mass index (LBMI), percent body fat (PBF), and the android to gynoid fat ratio (A/G ratio) were measured by DXA . FMI and LBMI were calculated as both fat mass and lean body mass in kilograms divided by the height in meters squared. FMI for age-and-gender z-scores and LBMI for age-and-gender were based on the reference values underlying the calculator courtesy of the American Journal of Clinical Nutrition .Office BP was recorded using a validated and electronic sphygmomanometer after a subject sat for five minutes. High office BP was defined as systolic blood pressure or diastolic blood pressure >95th percentile. The cuff size had a bladder length by a 1:2 to 2:3 width-to-length ratios based on arm circumference. Data from 24-h ABPM were collected for subjects aged 6–18 years using an Oscar II monitoring device  as previously reported ; (2) 25%Carotid ultrasound and echocardiography were done at the same visit. Carotid ultrasound assessment was performed by an experienced pediatric nephrologist (Pei-Chen Lu) using a ProSound α7 ultrasound device . This system consisted of computer assisted analysis software  . Pediatrp < 0.05 indicated statistical significance.All analyses were performed using SPSS version 22.0 . Continuous variables with non-normal distribution were presented as medians and interquartile ranges while categorical variables were reported as number (%). The Chi-square test or nonparametric test examined the differences in variables between children with an abnormal ABPM and with a normal ABPM. Multivariate logistic analysis was performed to investigate the associations between risk factors  and an abnormal ABPM. A probability level of 2/min including 70 CKD stage G1 subjects (69.3%), 19 G2 subjects (18.8%), ten G3 subjects (9.9%), and two G4 subjects (2%). CAKUT accounted for 64.4% of the etiologies (n = 65). Since 38 subjects were too young to receive the DXA scan and CV assessments, 63 children were grouped from this CKD cohort and defined as the DXA group for subsequent analysis. Participants in this DXA group were older and had higher creatinine levels compared to the whole study group. However, other characteristics were comparable between these two groups.A total of 101 subjects were enrolled in this study. In the DXA group, 18 subjects (28.6%) were obese. Regarding the complications of CKD, our data showed anemia in one subject (1.6%) with CKD stage G4, mineral bone disease in three subjects (4.8%) with CKD stage G3 or G4, hyperlipidemia in 11 subjects (17.5%), hyperuricemia in 19 subjects (30.2%), and hypertension (by office BP) in 20 subjects (31.7%). These data indicate that almost all participants in this group showed the nature of early or mild-to-moderate CKD.p = 0.006), and showed a larger proportion of CKD stages G2–G4 (p = 0.017), obesity (p = 0.039), and hyperuricemia (p = 0.005).Unlike office BP, up to 63.5% of subjects (40/63) had an abnormal ABPM. ABPM identified ten patients (15.9%) with 24-h hypertension, 11 patients (17.5%) with daytime hypertension, 17 patients (27%) with nighttime hypertension, 32 patients (50.8%) with increased BP load, and 26 patients (41.3%) with non-dipping nocturnal BP. These subjects were classified by ABPM abnormalities in p = 0.001). However, there was no difference in PBF and LBMI z-score between two groups. Additionally, body composition parameters did not differ statistically between subjects with CKD stage G2–G4 and subjects with G1 , indicating that body composition was not affected by CKD stage in this study. Moreover, we observed that AASI, LVMI, and cIMT in CKD children with abnormal ABPM were comparable with those with normal ABPM.Then, we determined body composition by DXA. As shown in p = 0.037).Using multivariate linear regression analyses, we specified the specific role of risk factors of abnormal ABPM . A multiIn the current study, we provide novel insights into factors involved in subclinical CVD in children with CKD. Our data indicate that body fat plays a key role for an abnormal ABPM in these children. FMI looks like a more trustworthy index than BMI to assess obesity in relation to abnormal ABPM in CKD children as it considers the body composition.In line with previous reports ,4,8, ourOur study revealed children with an abnormal ABPM were associated with several factors including age, CKD stage, hyperuricemia, obesity, FMI z-score, and A/G ratio. Age-related increases in BP have been observed in adults but not in children . Our regAlthough obesity is a risk factor for the development of CKD, it is paradoxically linked with greater survival in patients with advanced CKD . This obNo comparable associations were identified for cardiovascular assessments in our study, despite previous studies reporting that they may increase CV risks in children with CKD ,6,8. GivOur study was not without its limitations. First, we acknowledge that the study results may not be generalizable for the entire CKD pediatric population because sampling was performed in one hospital. A multi-center population-based cohort recruiting a large number of patients may be warranted to elucidate the true relationship in the future. Second, considering the long-term nature of childhood CKD, more assessments of body composition with longer follow-ups are required. Third, most participants in our cohort had early stages of CKD. There is a need for further validation of our results in other pediatric cohorts with more advanced CKD. Additionally, dietary intake of salt was not recorded, which comprises a limitation of the present study. Finally, an ethnic difference may be considered because we applied reference values for ABPM, FMI, and LBMI from studies in Europe ,22.Our data provide evidence that the assessment of fat distribution may be useful in determining CV risk in children with CKD in early stages. Considering the exploding obesity epidemic in children, further research is warranted to replicate our findings in other cohorts, monitor body composition parameters with longer-term CV outcomes, and develop effective control at reducing body fat in children with CKD.


Lower eGFR was associated with a higher FDG blood pool activity for all uptake values. In FDG-PET/CT studies with LVV patients, we recommend using SUL over SUV, while caution is advised in interpreting SUV and SUL measures when patients have impaired kidney function.The aim of this study is to investigate the influence of sex, age, fat mass, fasting blood glucose level (FBGL), and estimated glomerular filtration rate (eGFR) on blood pool activity in patients with large vessel vasculitis (LVV). Blood pool activity was measured in the superior caval vein using mean, maximum, and peak standardized uptake values corrected for body weight (SUVs) and lean body mass (SULs) in 41 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans of LVV patients. Sex influence on the blood pool activity was assessed with t-tests, while linear correlation analyses were used for age, fat mass, FBGL, and eGFR. Significantly higher SUVs were found in women compared with men, whereas SULs were similar between sexes. In addition, higher fat mass was associated with increased SUVs (r = 0.56 to 0.65; all  VOIAct is the activity concentration measured in the VOI; the administeredAct is the net administered activity corrected for physical decay of FDG to the start of the acquisition; and 1 mL of tissue is assumed to weigh 1 g -fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). The SUV is a simple, unitless metric in which the amount of activity within a volume of interest (VOI) in the PET scan is corrected for the injected radiotracer dose and for body weight. In 1993, Zasadny et al. recommended to use the SUV normalized to lean body mass (LBM), referred to as SUL, due to the SUV’s dependency on body weight FDG-PET/CT imaging in oncological diseases recommend the use of SUL for semi-quantitative analysis instead of the commonly used SUV . In inflTo compare between patients and for consistent treatment strategies it is of utmost importance that imaging metrics correctly reflect the severity of the disease. The population variation of LVV patients, including GCA and Takayasu’s arteritis, is large . Large dBesides SUL, the target-to-background ratio (TBR) is also a metric that may be more reliable in some diseases, especially in therapy follow up studies, and is recommended by guidelines for LVV imaging using blood pool as background . BecauseContradictory to previous research ,20,21, wWe did find a negative correlation between blood pool activity values and eGFR. This is in line with results from previous studies. Rosenblum et al. showed in both Takayasu’s and GCA patients a negative correlation between blood pool activity and GFR during 1-h imaging . Derlin Our study has some limitations. First, the number of patients included was relatively small. To make recommendations for specific cutoff values in renal function or lower administration of radiotracer dose for example, a larger sample size would be necessary. However, our results coincide with previous research in other diseases and therefore show the importance of consistent scoring in LVV. Second, the variance in FBGL was small and levels itself were mostly low compared with previous proposed cutoff values. Last, only one author delineated the SCVs and therefore interobserver variability analysis was not done. However, intra-observer reliability was rated excellent or good.In conclusion, fat mass has a significant influence on blood pool SUVs, resulting in differences between sexes. SUL scores are not dependent of the amount of body fat in a patient and thus result in more realistic scores and potentially more consistent treatment strategies than SUV measurements. In addition, eGFR influences blood pool activity in a negative proportional manner. Therefore, we recommend using SUL instead of SUV as quantitative measurement in [18F]FDG-PET scans of patients with LVV and to be cautious with the interpretation of quantitative measurements when patients have impaired renal function.


Periodontitis, referred to as gum disease, is a serious bacterial infection that damages the surrounding structures of the teeth, including the bones, lastly resulting in tooth loss without prompt treatment. The disease primarily occurs as a result of improper maintenance of the oral cavity, eventually causing gum infections, and teeth that are filled with food, tartar, and bacterial deposits. These harmful bacteria under the influence of various environmental and genetic risk factors may migrate to the blood vessels and reach various other organs, including the kidneys, thereby triggering the infection and resulting in the progression of the systemic diseases. In this study, we focused on identifying the levels of gum-disease-causing bacteria and their byproducts, namely, TNF alpha in patients with or without chronic kidney disease. The study comprised 120 participants categorised into 4 groups on the basis of patients who had gum disease and a kidney disorder. Gum, renal, and diabetic parameters were recorded. The bacteria and their products were assessed and found to be higher in patients having both gum disease and CKD disorder. This study indicates that patients with severe gum disease and poor oral health are at risk of developing kidney problems. Thus, the early prevention of gum ailments might reduce the risk of future kidney diseases.Prophyromonas gingivalis (P.g), Treponema denticola (T.d), and Tonerella forsythia (T.f) were assessed, and the obtained results were statistically analysed. Among the various demographic variables, age showed a level of significance. Mean PI, GI, CAL, and PPD (the proportion of sites with PPD ≥ 5 mm and CAL ≥ 3 mm) were elevated in the P + CKD group. Diabetic parameters such as fasting blood sugar (FBS) and HbA1c levels were also greater in the P + CKD group. Renal parameters such as eGFR and serum creatinine levels were greater in CKD patients. The estimation of red complex periodontal pathogens such as Pg, Td and Tf levels were significantly greater in the P and P + CKD groups. Pearson correlation analysis revealed significant correlation of red complex bacteria with all variables. Greater levels of P.g, T.d and T.f were found in the P groups, thus indicating their important role in the initiation and progression of inflammation of periodontitis and CKD, with diabetes as one of the confounding factors. The study also confirmed a log-linear relationship between TNF-α levels and red complex bacteria, thereby demonstrating the role of inflammatory biomarkers in periodontal disease progression that could contribute to the development of systemic inflammation such as CKD.Scientific evidence shows a positive association in the etiopathogenesis of periodontitis and chronic kidney disease (CKD). Various confounding factors, such as obesity, diabetes, and inflammation, also play a significant role in the progression of CKD, which remains unexplored. We hypothesise the role of red complex bacteria with various confounding factors associated with chronic kidney disease. The study comprised a total of 120 participants categorised into 4 groups: the control group (C), periodontitis subjects without CKD (P), periodontally healthy chronic kidney disease subjects (CKD), and subjects having both periodontitis and CKD (P + CKD), with 30 subjects in each group. Demographic variables, and periodontal, renal, and diabetic parameters were recorded. Tumour necrosis factor (TNF)-α levels and those of red complex bacteria such as  Chronic kidney disease (CKD) affects the quality of life of affected individuals. It can easily progress to advanced stages, thereby leading to greater morbidity and mortality rates. CKD is more prevalent in Asian populations in comparison with other ethnic groups. . The disPeriodontitis, on the other hand, is an inflammatory condition caused by Gram-negative bacteria associated with both local and systemic immune responses that lead to the destruction of the periodontium . PeriodoPeriodontitis is a common and alterable risk factor for CKD, where it is hypothesised to cause renal impairment through an inflammatory pathway . InflammP.g, T.d and T.f in association with confounding factors such as GFR, serum creatinine, FBS and HbA1c levels on chronic kidney disease individuals in the presence or absence of periodontitis. The first null hypothesis of the current study is that there are no significant differences when comparing the levels of TNF-α and red complex bacteria in chronic periodontitis patients with or without chronic kidney disease. The second null hypothesis of this study is that there is no influence of diabetic status in these patients with periodontitis with or without chronic kidney disease.The present research was conducted to assess the role of demographic and periodontal parameters, TNF-α, and red complex bacteria such as A cross-sectional study was performed following STROBE guidelines to report observational studies. The sample size was calculated using G-Power software to be 120 subjects with a power of 95%. The current study was conducted between January 2019 and February 2020 in Thrissur, Kerala, India, where patients were enrolled from PSM College of Dental Science and Research, Thrissur, and Thrissur Dialysis Center, India. Among the 180 examined subjects, 30 volunteers had come for a master health check-up in the general hospital of PSM College of Dental Science and Research, Thrissur, were both periodontally and systemically healthy, and were categorised as the control group (C). We enrolled 40 periodontitis patients without CKD from the PSM Dental College of Sciences, Kerala, India, of which 10 patients were excluded as they had other systemic conditions. Lastly, 30 patients were selected with glomerular filtration rate > 90 mL/min, determined in accordance with the classification of CKD_EPI 2009, and hence were grouped as the P group. We recruited 43 periodontally healthy patients, diagnosed with CKD (Stages 2–4) from Thrissur Dialysis Center, India. Among them, 13 were excluded for having other systemic conditions and adverse habits such as smoking. Hence, 30 patients were selected for the CKD group. We recruited 47 periodontitis subjects with CKD from Thrissur Dialysis Center, India, and 17 patients of which were excluded as they did not consent to be part of the study, thereby leading to a total number of 30 patients in the CKD + P group . FollowiLastly, the study comprised four groups: C group: 30 systemically and periodontally healthy subjects; P group: 30 systemically healthy periodontitis subjects; CKD group: 30 periodontally healthy subjects with CKD; P + CKD group: 30 CKD patients with periodontitis. Inclusion criteria: (a) willingness to participate; (b) age range: 35–65 years; (c) individuals with at least 12 natural teeth in the oral cavity; (d) in the case of CKD and C groups, subjects with intact periodontal health were recruited; (f) in the case of the P and CKD + P groups, individuals with periodontitis in accordance to the American Academy of Periodontology and European Federation of Periodontology 2017 classification were recruited, where interdental CAL was detectable at >2 nonadjacent teeth with CAL ≥ 3 mm and probing pocket depth >3 mm present in >2 teeth . 2 accounted for the C group. The CKD group comprised individuals clinically diagnosed with renal failure with a GFR range from 89 to 15 mL/min, and in predialysis conservative management 17], PPD,ontology .Diabetic parameters such as HbA1C levels and fasting blood sugar levels were recorded for all participants. Serum creatinine values were determined using an automated method from the collected blood samples with a semiautomated biochemical analyser. Estimated glomerular filtration rate (eGFR) was calculated with the serum creatinine values using the CKD-EPI equation of 2009. The concentration of inflammatory biomarker TNF-α was analysed using the ELISA method through the analysis of the venous blood samples collected from subjects of all four groups. Human TNF alpha ELISA kit (ab181421) was used to determine the marker by adhering to the instructions provided by the manufacturer. Prior to analysis, standardisation was performed, and samples were maintained to room temperature. The concentration of TNF-α levels was measured in picograms per millimetre (pg/mL).P.g, T.d and T.f). Genomic DNA was isolated from the samples by using a rapid DNA kit ) by adhering to the protocol provided by the manufacturer. These extracted DNA samples were quantified using a spectrophotometer, where further complementary DNA (c-DNA) synthesis and RT-PCR analysis were performed using the Stratagene MX3000P . The amplification of c-DNA samples was performed in triplicate to eliminate errors, adhering to the standard operating procedure provided by the Takara kit .Subgingival plaque samples collected from the subjects were subjected to RT-PCR for the detection and quantification of red complex bacteria  using species-specific primers was utilised in the detection of PCR products were visualised with 2% agarose gel electrophoresis and 100 bp molecular marker DNA with ethidium bromide control. Gene quantity was calculated with the comparative cycle threshold unit (CT) method. CT was used for the expression of the number of red complex bacteria, and CT values were inversely proportional to bacterial counts. Statistical Package for Social Science  software program version 17) for Microsoft Windows was used to statistically analyse the obtained data.p value ≤ 0.05. Normal distribution of data was observed. Descriptive statistics were presented with the aid of numbers and percentages. Mean and standard deviation for every parameter  was determined for every group, and the level of significance was determined. To observe significant differences among groups, ANOVA was used. Pearson correlation coefficient analysis was performed to correlate the red complex bacteria with all the other parameters. It was considered to be statistically significant if Mean age was significantly greater in P + CKD (61.47 + 10.99) as compared to that in the other groups. Other demographic variables did not reach the level of statistical significance among the groups. Male subjects had more prevalence in the CKD and P + CKD groups as compared to females, but they were insignificant .Mean PI (2.27 + 0.23), GI (2.42 + 0.18), PPD (3.18 + 0.24), CAL (1.14 + 0.48), average proportion of sites with PPD ≥ 5 mm (21.87 + 7.49), and mean proportion of sites with CAL with ≥ 3 mm (1.14 + 0.4) were greater in the P + CKD group than those in the other groups and statistically significant. Diabetic parameters FBS (130.03 ± 52.07) and HbA1c levels (7.62 ± 1.46) were greater in the P + CKD group, which was statistically significant. Among renal parameters, serum creatinine (1.08 + 0.19) was greater in the CKD group, whereas eGFR (68.43 + 12.45) was significantly greater in the P + CKD group .Mean TNF-α levels were significantly greater in the P group (72.75 ± 22.86), followed by the P + CKD group (69.28 ± 18.07), when compared with the other groups .P.g, T.d and T.f among the groups were lowest in the P + CKD group , followed by the P group. CT value was inversely proportional to the levels of the bacteria; hence, P.g, T.d, and T.f levels were significantly greater in the P+ CKD group, followed by the P group , P (30 patients), CKD (30 patients), and P + CKD (30 patients). Demographic variables, and diabetic, renal, inflammatory, and periodontal parameters were evaluated. Subgingival plaque samples were collected for the identification of Demographic variables sex, body mass index (BMI), and socioeconomic status did not show any differences among groups and matched for further comparison among groups except for age. Age was significantly greater in the P + CKD group. Findings were accordance with those of studies by Mahendra et al., and Elango et al., who also matched demographic parameters while studying the association of periodontitis with pre-eclampsia and coronary heart disease, respectively ,24. ThisThe comparison of periodontal parameters among groups showed that mean PI, PPD, GI, CAL, percentage of sites with PPD ≥ 5 mm, and CAL ≥ 3 mm were significantly greater in the P + CKD group. According to the World Workshop of Periodontology (2017), percentages of sites with PPD ≥ 5 mm and CAL ≥ 3 mm are two important factors in determining the severity of periodontitis. Similarly, a study by Borawski J et al. also found greater periodontal indices in patients with CKD . A studyp = 0.02) had significant association between periodontitis severity and the increase in CAL in chronic kidney disease patients [Regarding renal parameters, serum creatinine was greater in the CKD groups than that in the other groups. A study by Naghsh and Narges et al. suggested that the serum level of creatinine  destroys the bacterial nitric oxide synthase (iNOS) that is nuclear factor kappa B-dependent, thus contributing to phagocytosis of macrophages, which may trigger renal inflammation [P.gingivalis fimA could be one of the contributing factors for the progression of CKD.The virulence factors of ammation . This fuammation . Hence, T.f virulence factor, the serine proteinase inhibitor (serpin) protein, inhibits serine protease production from neutrophils. As a result, T.f is protected from the proteolytic activity of neutrophils, thereby eliciting the immune responses that may further affect renal function  [Similarly, ., 2015) .P. gingivalis, F. nucleatum, and T. denticola in the kidneys, thus showing the association of periodontal bacteria with compromised renal function [Chukkapalli et al. identified the genomic DNA of function . Periodontal pathogens enter renal tissue and damage mesangial cells of the renal matrix, glomerulus, glomerular capillaries, and renal endothelium . Hence, Overall, this study shows telescopic knowledge on the periodontal inflammation and its influence on chronic kidney disease. Red complex bacteria and TNF-α levels are significantly associated with the aetiopathogenesis or aggravation of periodontitis and CKD. The study confirmed that the greater prevalence of red complex bacteria and TNF-α in CKD patients, with diabetes as one of the confounding factors, has emerged as one of the major contributors for the progression of periodontitis, which paves the way for perirenal continuum. This is the first study to assess bacterial status, and inflammatory, diabetic and renal biomarkers in an Indian population diagnosed with predialytic status with and without periodontitis, with diabetes as a confounding factor. A limitation of the study was that it lacked intervention. Further interventional longitudinal prospective studies are required to strengthen the role of periodontal management such as SRP, as one of the effective treatment modalities in controlling bacterial load and periodontal inflammation, thereby reducing the risk for impaired renal function in CKD patients.Red complex bacteria are prevalent in the periodontitis and predialysis CKD patients when compared with those in the other groups, developing a different pathogenic mechanism interlinking the risk of CKD and periodontitis. This proposed link was further reinforced by the elevation of periodontal parameters and TNF-α levels, which substantiate the relationship between periodontal disease and progression of CKD, with diabetes as one of the confounding factors. Routine dental check-ups, providing gold-standard nonsurgical therapy , and the administration of evolving adjuncts such as parabiotics, probiotics, and postbiotics can be more effective in reducing oral inflammation and the risk of its systemic spread by reducing the bacterial load of periodontal-disease-causing pathogens.


The MEGA (MEchanism underlying the Genesis and evolution of Asthma) project is a multicenter cohort study carried out in eight Spanish hospitals, gathering clinical, physiological, and molecular data from patients with asthma and multimorbidities in order to gain insight into the different physiopathological mechanisms involved in this disorder.We report the baseline clinical and physiological characteristics and biomarker measures of adult participants in the project with the aim of better understanding the natural history and underlying mechanisms of asthma as well as the associated multimorbidities across different levels of severity. We carried out a detailed clinical examination, pulmonary function testing, measurement of fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick tests, chest computed tomography scan, asthma questionnaires, and multimorbidity assessment in 512 asthmatic patients.When compared to patients with milder disease, severe asthmatic patients showed greater presence of symptoms, more exacerbations, lower asthma control, increased airflow obstruction, and higher frequency of chronic rhinosinusitis with nasal polyps, severe rhinitis, anxiety and depression, gastroesophageal reflux, and bronchiectasis.The MEGA project succeeded in recruiting a high number of asthma patients, especially those with severe disease, who showed lower control and higher frequency of multimorbidities. Recent studies show that over 50% of patients with asthma are not controlled,The present and future research projects should attempt to identify asthma phenotypes using data collected from multiple cohort studies with sufficiently large sample sizes, integrating data from several domains of the disease repeatedly measured over time. The MEchanism underlying the Genesis and evolution of Asthma (MEGA) projectThe aim of the present study is to describe the baseline characteristics of the adult asthmatic participants that make up the project cohort in terms of their clinical features, frequency of multimorbidities, functional features, and inflammatory biomarkers, so as to better understand the natural history of asthma in patients with different levels of disease severity.22.1We conducted a multicenter prospective cohort study of 512 adult patients with asthma. Consecutive (unselected) sampling was used to recruit patients from eight university hospitals in Spain.2.2Standard data collection methods were used in all participating research centers. A electronic database and case report form (CRF) were designed to collect study data.2.3Asthma severity has been made according to the classification of the Global Initiative for Asthma (GINA).20) and induced sputum are performed at baseline and subsequently every 24 months. Chest computed tomography (CT) scan and skin prick tests (SPT) with common aeroallergens were performed at the beginning of the study.Methacholine challenge . SPTs will be considered positive at wheal diameters of at least 3 mm compared to the negative control ; histamine (10 mg/ml) will be used as a positive control.The panel of aeroallergens comprised the following: Atopy is defined as the presence of at least one positive SPT or aeroallergen‐specific immunoglobulin E (IgE) in serum.The DNA, serum, exhaled breath condensate, and sputum supernatants have been stored at −80°C in each of the recruiting centers for further analysis. The detailed protocol has been published elsewhere.2.4t‐test for Gaussian samples and Mann–Whitney U‐test for non‐Gaussian samples. Normality was analyzed using the Kolmogorov–Smirnov test. Analysis of variance with Bonferroni post hoc test was performed for comparisons between more than two groups of Gaussian samples, and Kruskal–Wallis with Dunn post hoc test was applied for non‐Gaussian distributions. A p value less than 0.05 was considered significant. In addition, Spearman's correlation was used to measure the association between clinical parameters.Comparisons between groups were performed using the unpaired, two‐tailed Student’s Statistical calculations and graphs were performed with GraphPad Prism 6 (GraphPad Software Inc.).1/FVC <70% post‐BD), univariate and multivariate regression analyses were performed  to airflow obstruction ; of these, 84% (n = 104) had severe persistent asthma and 16% (n = 20) intermittent or mild persistent asthma (p = 0.0269). Currently, 88% of the patients live in an urban setting, but when these same patients were children this percentage was lower (65.6%), and significantly higher in the most severe asthma patients (p = 0.054). Fifty percent of patients had a first‐degree relative with a history of asthma. As for smoking, 53.4% of patients were nonsmokers, 31% ex‐smokers, 8.2% smokers, and 7% passive smokers. Asthma severity is not related with smoking habit. Occupational asthma was found in 7.7% of patients, and 13.4% had work‐related asthma.A total of 512 patients were included in the study (66% women). Most patients were Caucasian (92%). Obesity, defined as a BMI > 30, was found in 25% of patients (n = 26), 17% mild asthma (n = 90), 33.4% moderate asthma (n = 171), and 39.6% severe asthma (n = 203) , with 67% of them (n = 24) experiencing persistent severe asthma. The age of severe patients is significantly higher than those with less severity.Regarding the severity of asthma, 5% of patients had intermittent asthma  had severe asthma (p < 0.001). Of the 24 patients diagnosed with food allergy, 37.5% (n = 9) have severe asthma and 42% (n = 10) moderate persistent asthma.Of the 74 patients diagnosed with NSAID hypersensitivity, 54% (3.2n = 370) had at least one positive SPT to the aeroallergen tested. Atopy is significantly lower in moderate and severe asthma compared to mild asthma . One hundred eighteen patients (23%) had positive SPT to dog, 22% (n = 110) to cat, 45% (n = 230) to mites, 15% (n = 76) to pollen, 8% (n = 42) to Aspergillus, and 5.5% (n = 28) to Alternaria  had allergic rhinitis, 10% (n = 52) atopic dermatitis, 18% (n = 90) allergic conjunctivitis, 29% (n = 148) had chronic rhinosinusitis with nasal polyps (CRSwNP), 14.5% (n = 74) showed hypersensitivity to NSAIDs, and 4.7 % (n = 24) were diagnosed with food allergy. Of the 148 patients with CRSwNP, only 1 patient had intermittent asthma, 10 mild asthma, 49 moderate asthma, and 88 (59%) presented severe asthma (p < 0.001).Also, 52% of patients (n = 409) had a peripheral eosinophil count of ≥150 cells/mm3, 53.3% (n = 273) had a count that was equal to or higher than 300 cells/mm3, 38.8% (n = 197) had a count of ≥400 cells/mm3, and 28.3% (n = 145) had levels above 500 cells/mm3 . There were no significant differences in eosinophil or FeNO levels according to asthma severity  was found in 64 patients (30.2%), a neutrophilic profile (<3% of eosinophils and >61% of neutrophils) in 25 patients (11.8%), a paucigranulocytic pattern (defined as <61% neutrophils and <3% of eosinophils) in 52 patients (24.5%), and we observed a mixed pattern (>3% eosinophils and >61% neutrophils) in 64 patients (30.2%).3) and in sputum (>2% and >3%). The results show that there are more patients with above 300 cells/mm3 eosinophilia in sputum, as shown in Figure 3 in peripheral blood and more than 2% eosinophils in sputum .Correlations have been made with different levels of eosinophilia in peripheral blood . The Mini‐AQLQ questionnaire showed a mean score of 5.48 ± 1.38. These results are reflected in Figure ACT scores of <20 were recorded for 34.5% of patients n = 34. The Mp < 0.0001).Correlations were made with the Fisher test to determine whether patients with ACT levels <20 had more exacerbations in the previous year, and a statistically significant association was found (p < 0.001) between patients with severe asthma and other severity levels. Patients with severe disease had scores compatible with depression in 17%, and scores for 39% of patients were compatible with anxiety. Patients with moderate persistent asthma had values compatible with depression in 8.9% of patients and with anxiety in 37.8% of patients; among patients with intermittent and mild persistent asthma, 8% had levels compatible with depression and 24% that were compatible with anxiety.Anxiety and depression were assessed using the HADS Questionnaire, revealing statistically significant differences (p < 0.001), with higher SNOT‐22 values associated with more severe asthma.We performed the SNOT‐22 test, comparing the results across different levels of asthma severity. Statistically significant differences were found  were using a metered‐dose inhaler, and more than half of them used a spacer. Seventy‐six percent (n = 291) of the subjects used dry powder devices: 47.07% (n = 137) Turbuhaler, 22% (n = 64) Accuhaler; 14.4% (n = 42) Ellipta, 13.4% (n = 39) Nexthaler, and 4% used other devices. In all patients, data concerning the inhalation technique was obtained by direct observation, and 97% of patients rated their treatment as adequate (n = 373).During the study period, 386 patients were using an inhaled corticosteroid (ICS)/long‐acting beta2‐agonist combination, 24% (n = 69), 19% with mepolizumab (n = 18), 4% with reslizumab (n = 4), and another 4% (n = 4) with benralizumab.Regarding the treatment with biological drugs, there are 95 patients treated with a biological medication, that is, 73% with omalizumab  were correlated with more severe asthma. It is also important to note that NSAID intolerance was strongly associated with asthma severity in this cohort.It was not possible to calculate the average dose of ICS that patients receive due to a wide variety of devices and formulations available in the Spanish market. However, all patients were classified by severity according to the medication needed to achieve asthma control. Patients with mild asthma required low doses , while moderate asthma required moderate doses , and severe patients required high doses (801–1600 μg/day). We were also unable to measure the average dose of systemic corticosteroids due to the different corticosteroid presentations used as well as the use of depot formulations.When interpreting these data, it is important to note the good results obtained with regard to the inhalation technique (adequate in 97%) and adherence (adequate in 82%) in comparison to other cohorts.3, and 28.3% had levels above 500 cells/mm3. An assessment of eosinophilic inflammation based on differential cell count in induced sputum samples revealed that 73% of the patients presented more than 2% of eosinophils, indicating levels above other cohorts described in the literature.3 is a risk factor for having worse asthma control (ACT < 20), though no statistically significant differences were detected. Furthermore, no differences were found between patients with eosinophil counts above or below 400 cells/mm3 and early‐onset disease debuting in childhood or adolescence. Furthermore, we have found a positive correlation between the levels of eosinophilia in blood and in sputum when the cut‐off point of eosinophils in sputum was set at more than 2% and in peripheral blood higher than 300 cells/mm3, a better correlation index was obtained than establishing the sputum cut‐off point at more than 3% (correlation index 0.5235 vs. 0.4819). The latter may be due to the high proportion of patients with CRSwNP (29%) and atopy included in the sample (71%). Blood eosinophil counts above 500 cells/mm3 correlated with the presence of atopy. It is important to note that in this cohort, eosinophil levels are not associated with asthma control or age at disease onset.We found elevated peripheral blood eosinophil counts in 53.3% of patients, as indicated by mean values above 300 cells/mmIn asthma, sensitization to fungal, perennial, or seasonal allergens increases the risk of uncontrolled symptoms, exacerbations, and poor disease outcomes.The study has a number of limitations, such as the lack of a control group and the fact that patients were recruited in specialized centers with a higher number of severe asthma patients than mild cases. In addition, the diagnosis of CRSwNP was based on data obtained from the clinical history.To conclude, among the patients with asthma included in this cohort, eosinophilic asthma was the predominant phenotype, and many were atopic. An increase in disease severity was associated with a higher number of comorbidities, more exacerbations, worse disease control, a greater tendency to experience anxiety and depression, and worse lung function. The characteristics of the patients included are consistent with those previously reported in other cohorts. This cohort is useful for characterizing different asthma phenotypes and in identifying associated biomarkers as well as the stability of these biomarkers over time.Continued follow‐up of these patients will shed light on the long‐term factors that may influence disease severity and will likely provide insight into the treatments that can influence the progression of the disease, identifying the possible causes of the exacerbations and how such exacerbations affect the clinical course of the disease.Dr. Rial reports nonfinancial support from CIBER de Enfermedades Respiratorias (CIBERES), during the conduct of the study; personal fees from GSK, personal fees from Allergy Therapeutics, personal fees from AstraZeneca outside the submitted work. Dr. González Barcala reports personal fees from ALK, personal fees from AstraZeneca, personal fees from Bial, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Gebro Pharma, personal fees from GlaxoSmithKline, personal fees from Laboratorios Esteve, Menarini, Mundipharma, Novartis, Rovi, Roxall, Stallergenes‐Greer, Teva, and Grants from Mundipharma outside the submitted work. Dr. Quirce reports personal fees from AstraZeneca, personal fees from Novartis, personal fees from Sanofi, personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from ALK, personal fees from Mundipharma, personal fees from GSK, personal fees from Chiesi, personal fees from Leti, outside the submitted work. Dr. Romero‐Mesones reports personal fees from Teva, personal fees from GSK, outside the submitted work. Dr. Soto‐Retes reports non‐financial support from CIBER de Enfermedades Respiratorias (CIBERES), during the conduct of the study; personal fees from Stallergennes‐Greer, personal fees from Menarini, personal fees from Novartis, personal fees from GSK, personal fees from Hal Allergy, personal fees from Allergy Therapeutics, personal fees from AstraZeneca, grants from Sociedad Española de Alergologia e Inmunología Clinica SEAIC, grants from Sociedad Española de Neumologia y Cirugia Torácica SEPAR, outside the submitted work. Dr. Martinez Rivera reports grants and personal fees from AstraZeneca, grants and personal fees from Teva, grants and personal fees from GSK, personal fees from Novartis, personal fees from Mundipharma, outsider the submitted work. Dr. Munoz reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, grants and personal fees from GlaxoSmithKline, grants from Menarini, personal fees from Novartis, personal fees from Teva, personal fees from Mundifarma, grants and personal fees from Chiesi, personal fees from Faes, outside the submitted work. Dr. Sastre reports grants from Sanofi, during the conduct of the study; grants and personal fees from Sanofi, personal fees from GSK, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Mundipharma, personal fees from Faes Farma, outside the submitted work. Dr. Luna‐Porta reports other from Astra Zeneca, outside the submitted work. Dr. Olaguibel reports grants from Sanofi during the conduct of the study; personal fees from AstraZeneca, personal fees from Mundipharma, outside the submitted work. Dr. Mullol reports personal fees and other from Sanofi‐Genzyme and Regeneron, personal fees and other from Genentech and Novartis, grants and personal fees from Mylan Pharma, grants and personal fees from Uriach Group, personal fees from Mitsubishi Tanabe, personal fees from Menarini, personal fees from UCB Pharma, personal fees from AstraZeneca, personal fees from GSK, personal fees from MSD, outside the submitted work. Dr. Plaza reports grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Merck, grants and personal fees from Chiesi, personal fees from Novartis, grants from Menarini, personal fees from Sanofi, outside the submitted work. Other authors have no conflicts of interests.Manuel J. Rial analyzed the patient data and was a major contributor in writing the manuscript. Joaquín Sastre and Victora del Pozo interpreted the patient data and designed the statistical study. All the authors have provided data to be able to carry out the study. All authors read and approved the final manuscript.TABLE S1Click here for additional data file.