Non-alcoholic fatty liver disease (NAFLD) is associated with atrial fibrillation (AF). Insulin resistance (IR) is the main cause of the high prevalence of AF in NAFLD patients. The triglyceride-glucose index (TyG) is a novel IR-related indicator implicated in the incidence and severity of NAFLD. However, the role of TyG in determining the risk for AF in patients with NAFLD remains unclear.A retrospective study was conducted on 912 patients diagnosed with NAFLD via ultrasonography. These patients were divided into two groups: (1) NAFLD+ AF and (2) NAFLD+ non-AF. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to assess the correlation between the TyG index and the high risk for AF. A receiver operating characteristic (ROC) curve was constructed to evaluate the predictive value for the TyG index for AF. Restricted cubic splines (RCS) were used to test the linear correlation between TyG and the risk for AF.A total of 204 patients with AF and 708 patients without AF were included in this study. The LASSO logistic regression analysis showed that TyG was an independent risk factor for AF . The RCS showed that the risk for AF increased linearly with TyG over the entire TyG range; this risk was also evident when the patients were analyzed based on sex (P for nonlinear > 0.05). In addition, the correlation between TyG and AF was a consistent finding in subgroup analysis. Furthermore, ROC curve analysis showed that TyG levels combined with traditional risk factors improved the predictive value for atrial fibrillation.The TyG index is useful in assessing the risk for atrial fibrillation in patients with NAFLD. Patients with NAFLD and increased TyG indices have higher risks for atrial fibrillation. Therefore, TyG indices should be assessed when managing patients with NAFLD.The online version contains supplementary material available at 10.1186/s13098-023-01012-1. Atrial fibrillation (AF) is the most common arrhythmia observed in clinical practice, with a prevalence of approximately 1 to 4%. Even so, the prevalence and incidence of AF are steadily increasing .Non-alcoholic fatty liver disease (NAFLD) is the most common liver and metabolic disease worldwide. Recent studies have shown that patients with NAFLD have an increased risk of arrhythmias, including AF and ventricular arrhythmias , 4. TherInsulin resistance (IR) is an integral part of the pathogenesis of NALFD . IR is iThe triglyceride–glucose index (TyG), a novel IR-related index, strongly correlates with HOMA-IR and hyperinsulinemia-euglycemic clamp results , 10. TyGIn this study, 912 patients who underwent abdominal ultrasonography (US) and were hospitalized at the Department of Cardiology, Second Hospital of Shanxi Medical University, between July 2021 and July 2022, were retrospectively analyzed. The exclusion criteria were as follows: valvular heart disease or prosthetic valve implantation, ablation of atrial fibrillation, history of alcohol consumption, secondary liver disease , structural heart disease , kidney disease or end-stage renal disease (ESRD), infectious disease, acute infection or malignant tumor history within the last 2 weeks, and incomplete medical records. Finally, 204 patients with nonvalvular AF  and 708 patients without AF (sinus rhythm) were included in the study. The study was approved by the Ethics Committee of our hospital and was conducted in accordance with the principles of the Declaration of Helsinki. Due to the retrospective nature of the analysis, the requirement for informed consent was waived.AF was determined through  (1) ECG NAFLD was diagnosed  based onAnthropometric data and parameters including sex, age, height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), hypertension (HTN), diabetes mellitus (DM), coronary heart disease (CHD), smoking history, and medication use were collected from electronic medical records. Overnight fasting blood samples were obtained to analyze biochemical variables, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and other biochemical indicators. The body mass index (BMI) and TyG indices were also calculated. BMI was calculated as the weight (in kilograms) per height squared (in meters), while the TyG index was calculated using the formula ln [TG (mg/dL) × FBG (mg/dL)/2].Statistical analyses were performed using the SPSS version 26.0 software and R version 4.0.1. Continuous variables were expressed as mean ± standard deviation (SD) or median . Categorical variables were expressed as percentages. The presence and absence of AF were comparatively analyzed in patients. Continuous variables were compared using an independent sample t-test or Mann–Whitney U test. Categorical variables were compared using the Chi-square test or Fisher's exact test. P values were selected based on the results of the homogeneity test of variance. All the variables  between the two groups were included in the least absolute shrinkage and selection operator (LASSO) regression analysis, with AF as the outcome variable. The regularization parameter λ corresponding to one standard deviation from the minimum mean square error (Mean-Squared-Error) was selected as the most appropriate by cross-validation λ and select indicators with non-zero coefficients for multi-factor binary logistic regression analysis. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive value of the TyG index for AF. The trend Chi-square test was used to analyze multiple groups of categorical variables. The Kruskal–Wallis test was used to analyze multiple groups of continuous variables. The correlation between the TyG index and AF was evaluated using restricted cubic splines (RCS) with three nodes . Subgroup analyses were conducted, according to sex, age, BMI, smoking, HTN, diabetes, and CHD, to test the stability of the correlation between the TyG index and AF. Statistical significance was set at P < 0.05 .Data were collected from 912 patients with NAFLD (561 men and 351 women), including 204 patients with AF and 708 without. The patients had a mean age of 68.78 ± 11.15 and 56.25 ± 10.31 years in the NAFLD with and without AF groups, respectively. Table Based on cross-validation, when λ = 0.026, the results of screening AF-related indicators with non-zero coefficients from the above 20 item variables through the LASSO regression algorithm were: gender, age, BMI, DM, Scr, TC, TyG  , . However, the OR value for the second quartile was not statistically significant . Second, the trend test showed a a trend in AF incidence between TyG quartiles (P for trend < 0.001)  for only TyG was 0.615 . After introducing LASSO regression screening factors , the ability of TyG to predict AF significantly improved, and an AUC of 0.857  was observed  and specificity (85.0%) in the diagnosis of IR compared to normoglycemic hyperinsulinemic clamp. Therefore, TyG may be widely used as a marker for IR in clinical practice . NumerouOur results showed a significant correlation between TyG and AF levels in the NAFLD population. In addition, this study found that age and BMI in the AF group were significantly higher than those in the non-AF group. This indicates that age and elevated BMI may increase the risk of atrial fibrillation, which is consistent with previous studies . In addiIn contrast, a meta-analysis  showed tLogistic regression is the most widely used regression model in medical research. Multicollinearity may lead to fluctuations in the regression results and poor model stability . To solvA large sex difference in AF was noted. The mechanisms, etiology, response to treatment, stroke risk, and outcomes differed significantly between the sexes . TherefoThis study had several limitations. First, this study was a cross-sectional study with a small sample; The low prevalence of atrial fibrillation among study participants limits the extrapolation of current results to different types of atrial fibrillation, and a single center and small sample size may lead to bias; Second, we relied on a single ECG and patient self-report for the definition of AF. Therefore, the accuracy of the AF diagnosis may have been affected. Third, we did not differentiate between paroxysmal and persistent AF. Whether there is a difference in the relationship between TyG levels and the incidence of different AF types requires further investigation. Fourth, similar to other observational epidemiological studies, residual confounding caused by unincluded covariates may have biased the results. For example, our variables did not include information on electrolyte disturbances or medications that increase the risk of AF. Finally, because this was a cross-sectional study, the results showed that the TyG index was positively associated with AF in patients with NAFLD but could not claim predictive value. Future large-scale multicenter prospective studies are required to verify the predictive power of the TyG index for the risk of AF in patients with NAFLD.The results showed that TyG levels in NAFLD patients with AF were significantly higher than in non-AF patients with AF. TyG level is a simple and easy-to-obtain parameter that can be used in clinical practice to predict the risk of AF in patients with NAFLD. Therefore, this indicator should be assessed in managing patients with NAFLD.Additional file 1. Additional tables.


The patients’ IHM decreased significantly from 2004–2009 to 2016–2021 for all types of transplants. AF was associated with a higher IHM for all of the types of transplants analyzed, except for heart transplants. (4) Conclusions: The prevalence of AF among patients admitted for solid organ transplants was highest for those who underwent heart transplants. The mortality rate during the patients’ admission for lung, liver, kidney, or heart transplants decreased over time. AF was independently associated with a higher risk of dying in the hospital for those who underwent lung, liver, or kidney transplants.(1) Background: We analyzed the association between atrial fibrillation or atrial flutter (AF) and in-hospital mortality (IHM) among patients who underwent solid organ transplants in Spain from 2004 to 2021. (2) Methods: We gathered information from all hospital admissions for lung, liver, kidney, and heart transplants. (3) Results: A total of 71,827 transplants were analyzed . One third of these were for women. Overall, the prevalence of AF was 6.8% and increased from 5.3% in 2004–2009 to 8.6% in 2016–2021. The highest prevalence of AF was found for heart transplants (24.0%), followed by lung transplants (14.7%). The rates for kidney and liver transplants were 5.3% and 4.1%, respectively. The AF code increased over time for all of the transplants analyzed ( Spain leads the international rankings in organ donation and transplants . The proAtrial fibrillation and atrial flutter are supraventricular arrhythmias that share clinical characteristics, such as predisposing factors, symptoms, and therapeutical strategies. Occasionally, it is not easy to differentiate them with a surface electrocardiogram. For research purposes, both will hereafter be referred to as atrial fibrillation (AF).Many studies have analyzed the incidence of AF both in the short and long term after heart transplants ,3. In thIn recipients of kidney transplants, patients with preoperative  and postoperative or new-onset (“incident”) AF needing hospitalization have been associated with worse outcomes ,7. In thThe relationship between clinical events, like hospital-acquired pneumonia, and IHM among patients undergoing a solid organ transplant has been previously assessed by our group . We haveHence, we intended to examine the prevalence and time trends, from 2004 to 2021, of AF among lung, liver, kidney, and heart transplant recipients. We also aimed to assess the impact of AF on the patients’ IHM after these procedures.We did a retrospective, observational analysis using the Spanish National Hospital Discharge Data (SNHDD) . The SNHWe selected admissions for those aged ≥18 years whenever a lung transplant, kidney transplant, heart transplant, or liver transplant code appeared at any procedural field during a given hospital admission .We identified all episodes of AF using ICD-9-CM codes 427.31 and 427.32 as well as ICD-10-CM code I48.xx for any diagnosis field.We assessed patients’ comorbid conditions by means of the Charlson Comorbidity Index (CCI) , which cWe collected data about patients’ age, sex, year of admission, specific in-hospital infections , complications of the transplanted organs, and leucopenia. For the period of 2016–2021, we added a COVID-19 code (ICD-10-CM code U07.1) .We analyzed IHM and length of hospital stay (LOHS) as independent variables.Time was divided in three periods of six years each . t-test or the Mann–Whitney test and the chi-square test were applied for comparison of quantitative and qualitative variables, respectively.Absolute frequencies and proportions are provided to describe qualitative variables and means or medians with their corresponding standard deviations or interquartile ranges for quantitative variables. The We used multivariable logistic regression analyses to assess the influence of AF, taken as a covariate, on IHM for each type of transplant, providing odds ratios (ORs) with 95% confidence intervals (CIs) to measure the magnitude and significance of the association. To further adjust the model, we did a sensitivity analysis accounting for cardiovascular comorbidities as separate items outside the CCI while also including a modified version of the CCI with no cardiovascular comorbidities. This analysis was aimed to elucidate whether AF was a marker of increased IHM driven by established cardiovascular diseases instead of a mortality risk factor in and of itself. Stata version 10.1 was the statistical software used.The SNHDD is an anonymized database publicly accessible by any researcher, so no ethical approval is needed.p < 0.001)  . p < 0.001) (p < 0.001). Comparing data from 2004 to 2009 with those from 2016 to 2021, the AF rates increased from 4% to 6.8% for kidney transplants, from 3% to 5.2% for liver transplants, from 19.4% to 30.8% for heart transplants, and from 12.5% to 16.4% for lung transplants   (< 0.001) . When we< 0.001) . For all< 0.001) .p < 0.001). The prevalence of AF was higher among men than women (p < 0.001). Patients with AF more frequently suffered kidney transplant complications, urinary tract infections, cytomegalovirus infections, and hospital-acquired pneumonia . The median LOHS was larger in people with AF . The IHM was also higher in patients with AF  and remained stable over time among people with AF (p = 0.08).A total of 45,262 kidney transplants  were performed in Spain from 2004 to 2021 . Age andp values ≤0.001). We detected no significant differences in the LOHS after liver transplants in people with an AF code vs. no AF (p = 0.064). The IHM was higher among people with AF , and there was no significant change over time (p = 0.209).A total of 18,127 liver transplants (26.8% for women) were performed in Spain over the study period . AF was p values < 0.001), but we could see no sex-associated differences in AF coding (p = 0.557). Both the LOHS (p = 0.061) and IHM (p = 0.485) did not differ between people with vs. without AF. The mortality rate decreased over time among people with AF .From 2004 to 2021, a total of 4734 heart transplants (24.9% for women) were completed in Spain . People p values <0.001). The LOHS was significantly longer in people with AF . The IHM was also higher among recipients with AF  but decreased over time in the population with AF, from 27.8% in the first time period to 15.8% in the last one (p = 0.012).A total of 4598 lung transplants (36.4 % for women) were performed in Spain over the study period . People As can be seen in The time trend analysis showed that the IHM was significantly higher in the first period  decreasing significantly until the last one (2016–2021) for all types of transplants. AF was a significant risk factor for IHM for all transplants evaluated, except for heart transplants; the ORs (CIs) for kidney, liver, heart, and lung transplants were 2.17(1.71–2.75), 1.77(1.39–2.26), 1.07(0.89–1.28), and 1.33(1.06–1.67), respectively.In the sensitivity analysis accounting for cardiovascular comorbidities as separate items outside the CCI, AF remained significantly associated with IHM, with ORs that were similar to those found in the main analyses, despite the strong association between cardiovascular conditions and IHM .We found increasing rates of AF for all of the transplants analyzed. Regrettably, we were not able to differentiate between preoperative vs. postoperative (new-onset) AF, since the ICD-9-CM code did not include a “present on admission” label that would have allowed us to categorize the coded diagnoses as “prevalent” vs. “incident”. Indeed, the distinction between both categories was only possible for the last years of the study period after the transition to the ICD-10-CM code, so we decided not to include this dichotomy to avoid eliciting more complex and possibly confounded results.The highest values for AF rates corresponded to heart transplants. These figures were probably driven by preoperative AF, although this argument is merely speculative due to the reason mentioned in the paragraph above. The prevalence of AF in stage IV heart failure has been reported to be as high as 50% in older studies , but morAn AF code was more frequent among men than among women for all types of solid transplants in our study except for heart transplants. Sadly, the design of our study did not let us give a convincing explanation for this finding. We could hypothesize that when diseases leading to transplantation are intrinsic to the heart, the higher rates of AF associated with heart diseases that are more prevalent among men  are counterbalanced by the higher rates of AF associated with heart diseases that are more prevalent among women . Rates of AF might differ among men and women for other types of solid organ transplants because age and comorbidities predisposing patients to AF  are generally not well balanced between both sexes . The good news is that IHM decreased over time for all the transplants analyzed. Strikingly, not many studies focus on short-term mortality: rather, they tend to evaluate long-term outcomes. The study by Awan AA et al. reported a reduction in mortality during the 12-month period after kidney transplantation in the United States . This reWe found that being of an advanced age was a risk factor for IHM among all transplants except for lung transplants in the multivariate analyses. Adjusting for the full set of variables attenuated the association seen in the bivariate analyses between age and IHM in the case of lung transplants. This seems to counter previous knowledge about this type of transplant . The reaIHM was higher among people undergoing kidney, liver, or lung transplants who were coded for AF vs. that of people who were not coded for AF in both the bivariate and multivariate analyses. As the main novelty of our study, we found no differences in IHM among people coded for AF vs. that of people who were not coded for AF during their admission for heart transplants. In the case of kidney ,31,32, l2DS2-VASc score instead of the CHADS2 score) and the use of new direct oral anticoagulants in this more recent manner may have influenced our results.Herein, we present the data of almost 72,000 patients who received solid organ transplants and over 4800 AF codes during a 18-year study period. Our database covered over 95% of the population of our country. However, several limitations must be mentioned. First, we did not differentiate between preoperative vs. postoperative AF for the reasons explained earlier in this section. Second, inaccuracies in coding secondary diagnoses are possible, but significant mistakes in coding organ transplants are unlikely. Third, if the improbable situation occurs in which a patient is admitted to two different hospitals after transplantation, they would appear twice. Fourth, residual confounding variables due to variables not considered in our investigation and associated with IHM cannot be ruled out. Fifth, the cause of death is relevant information that unfortunately is not included in the SNHDD database; if possible, future investigations should collect and analyze these data. And sixth, we did not have the possibility of knowing the anticoagulation treatments used in our population. Indications have changed over time (the use of the CHAIn summary, IHM significantly decreased over time for kidney, liver, heart, and lung transplants in Spain from the year 2004 to the year 2021. The IHM was significantly higher in people coded for AF during their admission for transplants of any solid organ except for heart transplants. Additional studies are needed to understand whether AF influences the short-term outcomes by itself, or rather it is a marker of vulnerability in this setting. A deeper understanding of this association might aid strategies aimed to lower the short-term mortality in this population.


This meta-analysis aims to compare the efficacy and safety of peritoneal dialysis (PD) and hemodialysis (HD) in the treatment of diabetic kidney failure.Five databases were selected to retrieve research on PD and HD for diabetic kidney failure until 6 August 2022. A fixed-effects or random-effects model was utilized to calculate the standardized mean difference (SMD) or odds ratio (OR) based on the heterogeneity among studies.Sixteen studies were included. The results showed that patients with diabetic kidney failure treated with PD had lower levels of albumin, total protein, and systolic blood pressure (SBP) and higher levels of urine volume, creatinine, and blood urea nitrogen (BUN) and lower risk of cardiovascular and bleeding events, with significant statistical difference when compared with patients treated with HD .This meta-analysis summarized the advantages and disadvantages of PD and HD for treating diabetic kidney failure patients. Compared with HD, PD is more effective in preserving residual kidney function, reducing hemodynamic effect, and lowering the risk of bleeding and cardiovascular events in diabetic kidney failure patients, but it also predisposes to protein-energy malnutrition and increases the risk of infection. This syFive electronic databases including Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and WANFANG DATA were systematically searched for randomized controlled trials (RCTs) comparing PD and HD for treating diabetic kidney failure patients up to 6 August 2022, by two researchers (W ZF and C JX), to provide a comprehensive evaluation of both clinical efficacy and safety in treating patients with diabetic kidney failure. The search keywords were “peritoneal dialysis,” “hemodialysis,” “diabetes,” “kidney failure,” and “end-stage renal disease.” The detail of the search strategy was listed in The selection process was conducted by two independent researchers (J YJ and C JX). Title, abstract and full text of retrieved studies were evaluated strictly in accordance with the inclusion and exclusion criteria. A third researcher (W ZF) was consulted in disputed studies between the two researchers to make a final decision on the inclusion or exclusion of the study in the quantitative synthesis. The inclusion criteria were presented as participants, interventions, comparisons, outcomes, and study design (PICOS) protocol. Participants: the study participants were all patients with diabetic kidney failure. Intervention and comparison: the treatment method for HD and PD were included in the study, and the clinical efficacy and safety of the two treatment methods were compared in treating patients with diabetic kidney failure. Outcomes: the study included, but was not limited to, clinical signs, laboratory tests, and patient complications. Study design: only RCTs were included for ensuring good quality of combined results. Exclusion criteria : (1) The full text was unavailable. (2) Literature such as reviews, conferences, lectures, case reports, and abstracts that we cannot obtain the data required for meta-analysis were excluded. (3) The same trial was repeatedly published. (4) The study design had significant flaws, or the results were reported with significant bias.Two researchers (J YJ and C JX) extracted the data listed below from each study that met inclusion criteria by using a pre-designed data extraction table to establish the database. It contained basic information about the included study such as journal, title, first author, year of publication, and baseline characteristics of the study population like the number of diabetic kidney failure patients included in the study, grouping, age, duration of treatment, and indicator related to clinical efficacy and safety which cover clinical signs before and after treatment, laboratory indicators, complications. In addition, the inclusion and exclusion criteria of the study population, and indicators related to the study design were documented. A third researcher (W ZF) would crosscheck the data after completing the data extraction for data consistency.Two independent researchers (J YJ and C JX) used the risk of bias assessment section of the Cochrane Handbook which is the most widely used and valid tool after multiple verifications for the quality assessment of RCTs. Research meeting the criteria was included in the quantitative synthesis . The eva2I test. p-value and 2I value were combined to determine the heterogeneity and homogeneity among studies. If p > 0.05, homogeneity was considered among studies in the Q test. Otherwise, it was heterogeneity. 2I values of 0%–39%, 40%–59%, and ≥60% were considered low, medium, and high heterogeneity between studies, respectively  and its 95% confidence interval (CI) were calculated for continuous variables to compare the clinical efficacy and safety of the two treatment methods in patients with diabetic kidney failure. The odds ratio (OR) and the 95%CI were compared for dichotomous variables. A forest plot was used to show the meta-analysis results for each indicator. Egger linear regression was utilized to assess the publication bias of the result. Besides, the sensitivity of the pooled effect size was evaluated by Duval and Tweedie’s trim and fill test  , 21. Allectively . A fixedill test , 23. If n = 598; review or in vitro/animal studies or letter or editorial or conference paper n = 454; not related to hemodialysis and peritoneal dialysis n = 352; not related to clinical efficacy or safety n = 1,348). Subsequently, six studies were excluded from the full-text evaluation process because they were not available or translated into valid data. Finally, 16 studies were included in the meta-analysis  acute cardiovascular or cerebrovascular events within 2 months, (2) clinically detectable acute or chronic infections, (3) patients with a malignant tumor, severe hepatic impairment, active immune system disease and hormone or immunosuppressants usage, and (4) a history of trauma or surgery within 1 month. Therefore, most of the studies had no significant missing data that would have compromised the power of the test but a limited extrapolation of the results. Both biases were rated as low risk of bias. But blinding of participants and personnel and blinding of outcome assessment were uncontrollable in this field. Almost all performance bias and detection bias in this Meta-analysis were rated as high risk. In addition to this, the overall assessment of the remaining included RCTs was considered a low risk of bias, indicating the good quality of this meta-analysis and the high reliability of the results ,B.The meta-analysis results showed that diabetic kidney failure patients treated with PD had lower levels of albumin, total protein (TP), and systolic blood pressure (SBP) compared to diabetic kidney failure patients treated with HD, with statistically significant differences  from the body by diffusion and ultrafiltration. In addition, PD has less impact on human hemodynamics and kidney blood flow, which can ensure kidney perfusion to protect residual kidney function better , 44. To Calcium and phosphorus metabolism disorders are common in maintenance dialysis patients, with the main clinical manifestations being metastatic calcification, osteodystrophy, and hypercalcemia. Studies have found that long-term calcium and phosphorus metabolism disorders in maintenance dialysis patients can increase the risk of adverse cardiovascular events, which is a significant cause of death , 45. HypThis meta-analysis found that diabetic kidney failure patients treated with HD had a higher incidence of bleeding and cardiovascular events than PD. The usage of anticoagulants, operation of dialysis access puncture and extracorporeal circulation, poor hemodynamics control, and susceptibility to microangiopathy damages during HD were responsible for these complications. However, patients treated with PD need to be vigilant about aseptic procedures to reduce the risk of infection.The main limitations of this meta-analysis are as follows. First, the studies included in this meta-analysis were mainly focused on the Chinese region. Therefore, whether the findings of this study can be extrapolated to other countries needs to be confirmed by more studies in the future. Second, the follow-up time of some of the RCTs was too short to assess the long-term effects of both dialysis methods on diabetic kidney failure patients. Therefore, more RCTs with large samples of diabetic kidney failure patients around the world and long follow-up periods were needed to confirm the advantages and disadvantages of PD or HD in treating diabetic kidney failure patients. Meanwhile, new studies should be integrated with existing results of the meta-analysis for comparison and to reinforce the long-term effect and regional applicability of meta-analysis results.This meta-analysis summarized the advantages and disadvantages of PD and HD in treating diabetic kidney failure patients. First, PD is effective in preserving residual kidney function in diabetic kidney failure patients and reducing hemodynamic effects, but it also predisposes to adverse effects such as protein-energy malnutrition and an increased risk of infection. In contrast, HD can significantly improve patients’ hypoproteinemia but also increases the risk of bleeding and cardiovascular events. Therefore, factors such as the advantages and disadvantages of both dialysis methods, patients’ specific conditions, and long-term prognosis should be considered comprehensively to improve patients’ health and reduce the incidence of adverse events.The original contributions presented in the study are included in the article/ZW, YJ, and SL: critical revision of the manuscript. ZW, YJ, JC, and SL: substantial contribution to the conception and design of the work. ZW, JC, XH, and JL: manuscript drafting and acquisition, analysis, and interpretation of the data. ZW, YJ, JC, XH, JL, and SL: revising the manuscript critically. All authors contributed to the article and approved the submitted version.This paper was supported by the Zhangjiakou City Science and Technology Research and Development Plan (grant no. 1911021D-6).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.


Music Performance Anxiety (MPA) is a prevalent condition among musicians that can manifest both psychologically and physiologically, leading to impaired musical performance. Physiologically, MPA is characterized by excessive muscular and/or autonomic tone. This study focuses on the cardiovascular blood pressure responses, autonomic tone and baroreceptor sensitivity changes that occur during musical performance due to MPA.Six professional pianists perform a piece for piano written only for the left hand by Alexander Scriabin. The following parameters have been studied during the performance: ECG, non-invasive beat to beat continuous arterial blood pressure and skin conductance. Sympathetic and parasympathetic autonomic flow was studied with Wigner-Ville analysis (W-V) from R-R ECG variability, and baroreceptor sensitivity with the Continuous Wavelet Transform (CWT).During the concert a significant increase of heart rate, systolic, mean and diastolic arterial pressure were observed. No significant differences were found in skin conductance. The W-V analysis, which studies frequency changes in the time domain, shows a significant increase of sympathetic flow and a decrease of parasympathetic flow during the concert which is associated with a significant decrease in sympathetic and vagal baroreceptor sensitivity.The study of cardiac variability using the Wigner-Ville analysis may be a suitable method to assess the autonomic response in the context of MPA, and could be used as biofeedback in personalized multimodal treatments. Music is a cultural product which is inherent to the lifestyle of humanity over time. For musicians, to make a difference with respect to the rest of the performers, it is imperative to achieve a level of performance that meets the expectations of themselves and their audience. Meeting these requirements may generate performance-related anxiety or Music Performance Anxiety (MPA), in most cases causing a worsening of musical performance . This ciThe prevalence of MPA varies across different studies, but it is generally a widespread problem among interpreters. Fernhol estimates the prevalence to be between 16.5 and 60% . AdditioThe MPA can manifests as both psychological stress or physiological changes and, it can occur from the preparation of a performance to late periods after the performance itself .Psychologically, symptoms can be cognitive on one hand, displayed as a heightened state of alertness, with a greater focus on the possibility of making mistakes rather than on the interpretation itself, accelerated tempo due to altered time perception, increased attention to irrelevant tasks, loss of attention, self-awareness and sense of control ; or, on Physiologically, the MPA manifests itself in two different ways. As an increase in muscle tone and /or as an increase in autonomic tone. As suggested by MPA is also associated with an exaggerated autonomic tone , which iThe neurovegetative response to physical or psychological stress involves the supraencephalic activation of the brainstem nuclei involved in the control of sympathetic activity. The main structure in charge of relating emotional states and anxieties is the so-called “Anterior Limbic Circuit” made up of the insular cortex, the anterior cingulate cortex and the amygdala. This circuit interconnects with the prefrontal cortex, which regulates emotional behaviour and decision  through As the stressful conditions increase or the psycho-cognitive influence is less inhibited, the stimulation of the hypothalamic regions increases markedly, thus generating a massive sympathetic discharge . This phMPA heart rate changes during piano performance are well known, but no information exists about possible continuous blood pressure changes. Thus, the main objective of this work was to record beat to beat arterial blood pressure during MPA piano performance and to analyse the possible changes and the origin of these changes.The study was carried out at the CIMES Autonomic Nervous System Laboratory under controlled conditions of temperature (24° degrees) and relative humidity (30%).9 young professional classic pianists participated as volunteers . They were all right-handed and had an average training experience of 14.16 ± 1.08 years, and an average age of 22 years and 4 months. All of the participants had completed the Higher Degree of interpretation at the Superior Conservatory of Music of Malaga (Spain). All subjects were healthy non-smokers, without any medical problems or medications that could have influenced their autonomic responses. All volunteers granted a valid written informed consent.As a result of various circumstances encountered during the recording process, including movements artifacts, recording failures and signal loss, the cardiovascular parameters of 3 of the volunteers were unable to be calculated. The final number of thoroughly examined pianists was six.ECG in DII, beat to beat arterial blood pressure and cutaneous cholinergic sympathetic response were continuously recorded during a piano concert. The work to be performed was composed in 1894 by Alexander Scriabin (1862–1915), written only for the left hand, and entitled: “Prelude et Nocturne op. 9 no 1,” written in C # Major and 3/4-time signature. The mean time of personal study of the work was 2.49 h ± 28 min.The goal of selecting a piano piece written only for the left hand was to leave the right hand free to be used in data recording. By using the free right-hand, interferences were minimized in the recording of beat-to-beat blood pressure and cutaneous sympathetic activity. The measuring instruments were positioned in a way that caused minimal discomfort, creating minimal pressure on the fingers. Additionally, the arm rested on a support cushion that each pianist adjusted. The angle, height, lateralization, and even some movement could be customized as the cushion had wheels at its base. Due to these accommodations, the interference with the interpretation were minimal.The following protocol was carried out.Recording of autonomic parameters in sitting position during 5 min of relaxation in the absence of stimuli. We named this phase “Initial rest.”Recording of autonomic parameters for 5 min in which the volunteers could freely play scales, arpeggios, thirds, trills, etc. … on the piano … We named this phase “Warm-up.”Recording of autonomic parameters during a 5-min break. We named this phase “Pre-Concert Rest.”Recording of autonomic parameters, during 5 min of interpretation of the piece, in the presence of professional pianists and professors. We named this phase “Concert.”To standardize and establish a correlation between the changes documented in the recordings and the individual components comprising the musical composition, a consistent tempo of ∫ = 50 (Larghetto) was employed throughout the entire performance. To ensure temporal consistency, a metronome was initiated 30 s prior to the beginning of this phase.5. Recording of autonomic parameters during 5 min of relaxation in the absence of stimuli. We named this phase “Post-Concert rest.”Continuous beat-to-beat non-invasive blood pressure recording was obtained with a Bmeye Nexfin® photoplethysmography system. The sensor cuff was located in the second phalanx of the middle finger of the right hand with a hydrostatic compensator in the little finger. The system was calibrated and contrasted with the data recorded using an OMROM M6 Comfort IT blood pressure monitor with PC connection .ECG in DII (Cardioline-Delta 1 Plus®) was recorded with disposable adhesive button foam standard ECG Ag/AgCl electrodes. The recording of sympathetic cutaneous cholinergic activity was performed on the tip of the first phalanx of the ring and index fingers of the right hand with two non-polarizable Ag/AgCl electrodes (TSD203) through changes in skin conductance (GSR 100C amplifier) .Signals were digitalized with the Biopac® MP160 CE multi modular system converter and analysed with the Acqknowledge 5.04 signal analysis software.Mean heart rate, RRI, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and cutaneous conductance values were measured continuously during each 5 min.In order to assess cardiac autonomic modulation, we performed Wavelet analysis using the Wigner-Ville transform (W-V) for time/frequency domain analysis with standard MatLab software. We determined sympathetic and parasympathetic modulation of RR intervals (RRI) in the low frequency  and high frequency  ranges . LF moduData recording and storage was obtained using 3 computers with Windows 10 operating system connected in a network.The instrument of choice for musical study was a Yamaha P125 digital piano, and for performance was a Kawai CA-63 upright electric piano.Throughout the process, volunteers were videotaped with a Logitech C-390 camera.This study in no case can be considered as clinical experimentation in human beings. The ethical principles contained in the Declaration of Helsinki of the World Medical Association (2013) have been followed at all times. The volunteers granted a valid written informed consent and the protocols followed were approved by the Research Ethics Committee of the province of Málaga . Personal and clinical data are confidential and treated in accordance with the provisions of Regulation (EU) 2016/679 “General Data Protection” and Organic Law 3/2018, of December 5, on “Personal Data Protection.”Data processing was carried out using statistical package GraphPad Prism 9. Descriptive analysis of continuous quantitative variables was performed, obtaining mean, standard deviation, minimum and maximum for each parameter.p < 0.05. Repeated measures of one-way ANOVA with the Geisser–Greenhouse correction were used. Tukey multiple comparisons test, was used as a post hoc test for multiple comparisons after ANOVA . In all cases, graphical representations in the form of box plot have been used.For analytical statistics, data were grouped into five comparison groups according to the moment of the study . The significance level was established at The mean heart rate during the “Initial rest” was 89.67 ± 4.1 bpm (from 70.56 bpm to 98.4 bpm), “Warm-up” 95.71 ± 3.56 bpm (from 85.2 to 107.11 bpm), “Pre-Concert rest” 90.75 ± 3.44 bpm (from 75.3 to 100.12 bpm), “Concert” 109.1 ± 3.85 bpm (from 94.27 to 120.91 bpm), and “Post-Concert rest” 90.20 ± 3.76 bpm (from 77.79 to 106.46 bpm).The following significant changes in heart rate were obtained :The results show an increase in heart rate during the concert .The systolic blood pressure during “Initial rest” was 122.17 ± 2.75 mmHg (from 109.24 to 128.33 mmHg), “Warm-up” 134.55 ± 3.72 mmHg (from 119.73 to 145.32 mmHg), “Pre-Concert rest” 121.55 ± 3.28 mmHg (from 108.34 to 130.78 mmHg), “Concert” 146.13 ± 5.11 mmHg (from 128.99 to 165.52 mmHg), and “Post-Concert rest” of 123.53 ± 5.61 mmHg (from 106.1 to 144.25 mmHg).The following significant changes in systolic blood pressure were obtained :The results show an increase in systolic pressure during the Warm-up and the Concert .The diastolic blood pressure during “Initial rest” was 75.47 ± 1.13 mmHg (from 70.43 to 78.92 mmHg), “Warm-up” 81.86 ± 1.26 mmHg (from 77.73 to 87.21 mmHg), “Pre-Concert rest” 75.74 ± 1.24 mmHg (from 71.26 to 80.2 mmHg), “concert” 86.89 ± 2.1 mmHg (from 82.01 to 96.92 mmHg), and “Post-Concert rest” 76.33 ± 2.53 mmHg (from 68.89 to 86.76 mmHg).The following significant changes of diastolic blood pressure were obtained :The results show an increase in diastolic pressure during the Warm-up and the Concert .−2 ± 8.10−4 μΩ, “Warm up” 8.833.10−2 ± 6.2.10−4 μΩ, “Pre-Concert rest” 8.797.10−2 ± 5.5.10−4 μΩ, “Concert” 9.341.10−2 ± 4.1.10−3 μΩ, and “Post-Concert rest” 8.852.10−2 ± 1.58.10−3 μΩ.The mean cutaneous conductance during “Initial rest” was 8.875.10No significant differences were observed between groups.−1 ± 2.18.10−2 μΩ. Using these new data, the following significant differences appear  were in “Initial rest” 79.00 ± 5.43 nu, “Warm-up” 80.43 ± 2.72 nu, “Pre-Concert rest” 79.44 ± 2.72 nu, “Concert” 88.35 ± 3.29 nu, and “Post-Concert rest” 77.86 ± 2.67 nu.The following significant changes were obtained :The results show an increase in sympathetic activity (LF) during the concert.The variability values for the parasympathetic activity in power normalized units (HFnu) were in “Initial rest” 21.00 ± 5.43 nu, “Warm-up” 23.77 ± 2.72 nu, “Pre-Concert rest” 21.13 ± 4.53, “Concert” 11.79 ± 3.29 nu, and “Post-Concert rest” 22.14 ± 2.67 nu.The following significant changes were obtained :The results show a decrease in parasympathetic activity (HF) during the concert.The variability values for the sympathetic/parasympathetic ratio (LF/HF) at “Initial rest” were 4.10 ± 1.34, “Warm up” 3.27 ± 0.52, “Pre-Concert rest” 4.08 ± 1.41 “Concert” 8.39 ± 3.26, and “Post-Concert rest” 3.59 ± 0.61.The following significant changes were obtained :The results show that sympathetic activity was increased at rest. During the concert an increase of sympathetic activity (LFnu) with a decrease in parasympathetic activity (HFnu) is observed .The vagal baroreceptor sensitivity values for LF at “Initial rest” were 8.83 ± 1.48 ms/mmHg (from 4.02 to 15.3 ms/mmHg), “Warm up” 6.77 ± 0.73 ms/mmHg (from 4.17 to 8.73 ms/mmHg), “Pre-Concert rest” 8.18 ± 1.25 ms/mmHg (from 4.09 to 13.41 ms/mmHg), “Concert” 5.65 ± 0.6 ms/mmHg (from 3.62 to 6.93 ms/mmHg), and “Post-Concert rest “7.9 ± 1.18 ms/mmHg (from 2.8 to 10.78 ms/mmHg).No changes were observed in vagal baroreceptor sensitivity during the concert .The sympathetic baroreceptor sensitivity values for LF at “Initial rest” were 9.17 ± 1.32 ms/mmHg (from 4.75 to 14.8 ms/mmHg), “Warm up” 6.79 ± 1.06 ms/mmHg (from 4.14 to 11.57 ms/mmHg), “Pre-Concert rest” 7.46 ± 1.15 ms/mmHg (from 4.68 to 12.52 ms/mmHg), “Concert” 4.64 ± 0.77 ms/mmHg (from 2.8 to 8.1 ms/mmHg), and “Post-Concert rest “7.91 ± 1.31 ms/mmHg (from 3.15 to 13.01 ms/mmHg).The following significant changes were obtained :The results show a decrease in sympathetic baroreceptor sensitivity during concert. .The objective of the present study was to elucidate blood pressure and autonomic responses that arise during and surrounding a musical performance, within a laboratory simulated live concert setting. We believe that the presence of other expert pianists, as well as, graduate and postgraduate piano teachers during the concert was a contributing factor in generating MPA.This study shows that during a concert with a heightened level of stress there is a significant increase of heart rate, systolic, mean and diastolic arterial pressure. The W-V analysis shows a concomitant significant increase of cardiac adrenergic sympathetic flow and a decrease of parasympathetic flow together with a significant decrease in baroreceptor sensitivity. During Warm-up an increase in arterial blood pressure together with a decrease in sympathetic baroreceptor sensibility were also observed, although in a lesser extent. No changes were observed in sympathetic cholinergic sudomotor activity except for a short and transient increase just before the beginning of the concert, during a 30 s’s pre-metronomic phase.As previously expressed, we needed to select a work for piano with a non-operative right hand due to the presence of the recording sensors. Blood pressure was recorded by means of a pressure cuff placed on the second phalanx of the middle finger of the right hand. This circumstance was also used to record sympathetic skin conductance between the tips of the index and ring fingers of the right hand. We selected the “Prelude et Nocturne op. 9 no 1” written by Alexander Scriabin, who had chronic pain in the right hand and was therefore prone to writing works for the left hand . There aInitially, being all pianists right-handed, we supposed that a piece for the left hand could increase anxiety. However, one of the pillars of piano training is to develop ambidexterity in the performer, which is the ability to use both the right and left hand to play equally well, to tackle works that are part of the piano literature. The piece was chosen, in addition to leaving one hand free for data recording purposes, to be a work with technically undemanding interpretative characteristics for a professional pianist, so it should be performed with ease. Therefore, the impact of selecting the left hand for interpretation in the current study should have minimal effects. However, technically demanding pieces may be perceived with anxiety depending on the hand for which they were written. This is a question should be addressed in future studies.The average heart rate increases during the concert and decreases again at final rest. No significant changes are found in warm up.These changes in heart rate during musical performance are widely described in the literature . Our resAfter the concert, at the final rest, cardiac sympathetic tone decreases and parasympathetic tone increases. During the Warm-up, we did not observe an increase in cardiac sympathetic or parasympathetic flow, which indicates that the interpreter is more relaxed.To our knowledge this is the first study in which continuous beat-to-beat non-invasive blood pressure is recorded during a piano musical performance.Diastolic and systolic blood pressures increase from rest to Warm-up, which is consistent with the need for increased blood flow to the structures involved in musical performance, the nervous and muscular systems.During the concert, the increase in blood pressure is even greater, indicating an increase in the activity of the adrenergic sympathetic nervous system, probably secondary to the stress and anxiety of performing in front of an audience. This effect is observed both at the level of systolic pressure, which would indicate an increase in cardiac adrenergic sympathetic activity, and at the level of diastolic pressure, which indicates and increase in vascular tone and resistance due to an increase in peripheral adrenergic sympathetic activity.After the concert, final rest, cardiac and peripheral sympathetic tone decreases to normal values.The importance of this study lies in demonstrating for the first time what empirical knowledge pointed out during musical performance on blood pressure.It is striking that there were no significant differences in sudomotor activity in the four periods studied. As in previous papers , we wereOnce it was verified that during the concert there was a significant increase of heart rate and blood pressure, we analysed which changes in autonomic flow were responsible for these responses. To achieve this, we used the Wigner-Ville analysis, a technique based on Wavelet’s analysis, which analyses frequency changes in the time domain.In musical performance, the changes in the recorded variables depend to a great extent on the emotional involvement and the technical difficulty of the elements that constitute a musical work. These changes are sometimes so fast that their effects cannot be detected by conventional methods of heart rate variability analysis Fast Fourier Transform (FFT) or Regression Analysis (AR). It is necessary to use a different technique that works not only in the frequency domain but also in the domain of the temporality of the work .The Wigner-Ville analysis evaluates frequency changes in the time domain, demonstrating greater sensitivity to detect fast changes in cardiac sympathetic and parasympathetic activity variability in very short periods of time like in music performance. This analysis has been previously used to evaluate the variability of heart rate in non-musically trained listeners as a response to emotions induced by music, resulting in a suitable method of study .At rest, we observed high values of sympathetic flow  associated with low parasympathetic activity , thus the sympathetic/parasympathetic relationship was bigger than 1, showing that volunteer musicians presented a certain degree of stress induced by the experimental conditions.The W-V analysis also shows that during the concert the increase in heart rate and blood pressure is produced by an increase in cardiac adrenergic sympathetic tone together with a decrease in cardiac parasympathetic activity. To allow this increase in blood pressure, baroreceptor sensibility, which relates blood pressure and heart rate changes, decreases, thus resetting the baroreceptor response and allowing simultaneous increases of blood pressure and heart rate. This allows for adequate blood perfusion to meet the demand of active organs.The results also show the appearance of an increase in cardiac adrenergic sympathetic activity during warm up. This increase in sympathetic tone is due to an increase in the demand for blood flow to the structures involved in musical performance, mainly brain and muscles of the left limb. During the concert, cardiac sympathetic flow increases even more, while parasympathetic activity decreases, indicating an elevated state of anxiety or stress in the interpreter. After the concert, during the post-concert rest, both cardiac sympathetic and parasympathetic tone returned to Initial rest values.Our results are consistent with those of other studies reported in the literature. These authors ,b found,We also reinforce the studies that demonstrate emotional involvement in musical performance. These works show an increase in the heart rate and the sweating rate just at the beginning of the execution of the work. These responses are due to an increase in the activity of the sympathetic adrenergic and cholinergic nervous system, in addition, they found a decrease in parasympathetic tone .Our work has shown to be effective in the quantitative and qualitative study of neurovegetative activation during musical performance. Judging from our study and previous studies in the literature, it appears that the degree of autonomic activation correlates with MPA levels . The metCurrently, there is a range of treatment options that can be offered for MPA: psychoanalytic or psychodynamic therapy, cognitive behavioral therapy, multimodal therapy, and in more refractory or severe cases, pharmacotherapy .Multimodal therapy is shown to be an effective treatment approach for MPA. This therapeutic approach is customized to meet the unique needs of each patient and combines in-depth psychodynamic insight into the individual’s prior performance experiences and their management, with cognitive-behavioural therapy to promote desensitization. The latter involves gradually exposing the musician to progressively more challenging and stressful performance scenarios . The aimMultimodal therapy integrates biofeedback of neurovegetative parameters to support the treatment. The easiest to use are heart rate and respiratory rate. More difficult, but possible, is to use blood pressure, skin conductance or muscle tone recording. This therapy is supported by exercises with the instrument or voice, as well as relaxation techniques to avoid the motor and neurovegetative response derived from MPA .Lastly, in refractory or severe cases, beta-blockers may be used to reduce the neurovegetative responses generated by MPA. Nevertheless, it is common to rely on beta-blockers as the primary therapeutic intervention . The useFinally, the prevention of MPA is important for the performer to develop without the limitations that this condition supposes. To achieve this, teachers should promote awareness of performance-related anxiety to their students from childhood and adolescence onwards and provide them with the necessary tools to address it from multiple perspectives in a personalized way .The main limitation in this study is the reduced number of participants due to the difficulty of finding professional pianists as volunteers, however, the sample size is comparable to other published studies. Another limitation is that the sample comprises only young subjects. We think it could be interesting to extend this study to healthy musicians of different age ranges and performing experience. It is well-known that autonomic responses decline with aging . AnotherTo our knowledge, this study is the first to continuously analyse beat-to-beat blood pressure, demonstrating changes in blood pressure during musical performance. Additionally, this is the first time that the Wigner-Ville analysis is used to directly detect sympathetic and parasympathetic activity in MPA. We believe that this method of analysis, applied through the recording of instant heart rate frequency, could be an ideal method for working with MPA using biofeedback in multimodal therapy.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Research Ethics Committee of the province of Málaga . The patients/participants provided their written informed consent to participate in this study.JM-G, medical doctor and professional pianist, conducted all the experiments, data collection, data analysis and wrote the first manuscript draft and revisions. ML-G and CR made a significant contribution to data analysis and data interpretation, and revisions. AC-E contributed with Wigner Ville and continuous Wavelet transform analysis. MD-M designed the study, contributed to the data collection, data analysis, interpretation, and revisions to the manuscript. All authors contributed to the article and approved the submitted version.The study was supported by a program grant Junta de Andalucía, Group no. CTS-156, Spain. Part of the final study was supported with the Own Funds Program of the University of Málaga.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.


Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) show high rates of cardiorenal outcomes. In addition, the progression towards renal failure and cardiovascular events rises as CKD worsens. Several studies suggest that the activation of the mineralocorticoid receptor (MR) induces cardiac and renal injury, including inflammation and fibrosis. Finerenone is a novel, nonsteroidal, selective MR antagonist (MRA) which has demonstrated anti-inflammatory and anti-fibrotic effects in pre-clinical studies. Moreover, two large trials (FIDELIO-DKD and FIGARO-DKD) investigated the renal and cardiovascular outcomes in patients with mild to severe CKD in type 2 diabetes which received finerenone. On these bases, this comprehensive review aims to summarize the current knowledge regarding finerenone and its effects on CKD and the cardiovascular system, emphasizing its role in modifying cardiorenal outcomes. Cardiovascular disease (CVD) and chronic kidney disease (CKD) are closely connected since they share common risk factors and pathophysiological pathways and influence mutual evolution. Indeed, a reduced cardiac performance, such as in a heart failure (HF) setting, affects renal functions through an activated neurohormonal and inflammatory cascade, and increases the venous pressure and hypoperfusion of the kidneys. In contrast, CKD impacts cardiovascular functions by inducing hypertension and vascular calcification ,2,3. In p < 0.001) . Dr. Dr16]. Specifically, although a potential clinically relevant induction of CYP3A4 was shown in in vitro experiments, a weak induction was confirmed in vivo ,64. In a2 for up to 3 weeks after stopping the drug administration ..68].p < 0.0001–0.0107) and reduced rates of hyperkalemia  [In the phase II Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) trial, the authors demonstrated a similar efficacy of the daily finerenone treatment (5 or 10 mg) compared to spironolactone in patients suffering from HF with a reduced ejection fraction and mild CKD and with lower increases in the serum potassium levels and slight reduction in the eGFR . Specifi= 0.048) .Additionally, the phase IIb ARTS-Diabetic Nephropathy (ARTS-DN) trial showed the efficacy and safety of finerenone in patients with DM and high or very high proteinuria due to an improvement in the urinary albumin–creatinine ratio with no difference in the rate of hyperkalemia and the eGFR reduction compared to the placebo . ConcordThe two largest trials that explored the clinical benefit of finerenone on the renal and cardiovascular outcomes in patients with mild to severe CKD and type 2 DM, on top of the maximum tolerated renin–angiotensin system inhibition, were the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD)  and the 2 and the presence of diabetic retinopathy, or persistent, severely increased albuminuria (UACR ≥300–≤5000 mg/g) with an eGFR of ≥25–<75 mL/min/1.73 m2 [2), a sustained ≥40% decrease in the eGFR from the baseline over at least four weeks, or renal death [p = 0.034) regardless of the presence of previous CVD.FIDELIO-DKD was a double-blind, placebo-controlled trial in which the patients were randomized 1:1 to finerenone (10 or 20 mg) or placebo treatments. Different from the previous studies, the patients with previous HF with a reduced ejection fraction were excluded from the study . Chronic/1.73 m2 . The caral death . OtherwiA lower incidence of the composite renal outcome was also achieved in the finerenone-treated group compared to the placebo , particularly in the patients with CVD . In addi2, or persistent, severely increased albuminuria (UACR ≥ 300–≤ 5000 mg/g) with an eGFR ≥ 60 mL/min/1.73 m2 [2 for at least four weeks), a sustained decrease from the baseline of at least 40% in the eGFR, or death from renal causes [p = 0.03). The secondary outcome occurred in 9.5% of the treatment group vs. 10.8% of the placebo-treated patients [The FIGARO-DKD was a randomized, double-blind, placebo-controlled study where patients with type 2 diabetes and CKD were randomly assigned for finerenone treatment or placebo . Chronic/1.73 m2 . The pril causes . The pripatients . Remarkapatients . Interespatients . This stpatients . Considepatients  and renapatients .Based on the above trials, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the marketing of finerenone in routine clinical care for patients with CKD and DM, although studies are currently ongoing to formulate economic models to evaluate its use. Indeed, drug utilization in the real world is unequal from nation to nation and is influenced by drug reimbursability ($22.13 per unit in USA), local care factors, and standard medical therapy. The ongoing FINE REAL study aims to evaluate the use of finerenone in a variety of states by relating it to specific routine clinical care, and by assessing its impact in terms of its improvement in the progression of microvascular complications and renal functions .This comprehensive review aimed to summarize the current knowledge regarding finerenone and its effects on chronic kidney disease and the cardiovascular system. As CKD and CVD are strictly related, we firstly analyzed this association to explain the worse CV outcomes in patients with CKD compared to those with normal renal functions. Secondly, we evaluated the crucial role of the RAAS and mineralocorticoid overactivation, which negatively affect both the renal and cardiovascular systems, favoring inflammation, oxidative stress, and fibrosis, and subsequently the progression of kidney and heart failure. Notably, we strongly believe that a deep knowledge of pathophysiological mechanisms is essential to understand the beneficial effects of this novel drug on the cardiorenal system.Nevertheless, this study had several limitations. Firstly, due to its nature, this non-systematic review was not conducted according to a specific protocol and/or guidelines, thus influencing the quality and significance of the data reported. Secondly, this review was carried out while different clinical trials were ongoing, so we could provide only preliminary results. Lastly, considering the novelty of this drug, further studies are needed in order to evaluate its efficacy and safety in the long term.Patients with chronic kidney disease show a high cardiovascular risk, with cardiovascular death as the main cause of death. Finerenone administration in diabetic patients with CKD could reduce the overall cardiovascular risk, independently from the presence of the baseline cardiovascular disease. Indeed, patients with CKD and type 2 diabetes treated with finerenone showed a lower incidence of cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure compared to the placebo. Moreover, due to its pharmacokinetic profile, this novel drug did not induce antiandrogen and anti-steroidogenesis effects. In addition, compared to spironolactone, finerenone induced smaller mean increases in potassium levels and reduced rates of hyperkalemia.In conclusion, finerenone confers significant renal and cardiovascular benefits in patients with CKD, resulting in effectively slowing the progression of kidney failure in patients with CKD and reducing the risk of major adverse CV events in this population, thus playing a crucial role in the cardiorenal system.As discussed above, finerenone represents a novel promising therapeutic agent for patients with CKD, conferring significant renal and cardiovascular benefits. Although still not approved for the use in a heart failure context, finerenone could play a crucial role in the management of HF patients, taking into account how patients with impaired renal function cannot benefit from optimized cardiovascular medical therapy. However, further studies and clinical trials are needed to evaluate the efficacy and safety of finerenone in patients with CKD and CVD, considering the possible interaction and synergic effects of new therapeutic strategies .


Background and Objectives: Early improvements to graft function are crucial for good outcomes in kidney transplantation (kTx). Various factors can influence early graft function. This study aimed to evaluate the pre- and post-transplant hydration statuses of kTx recipients using bioimpedance analysis (BIA) and lung ultrasonography (LUS) and to investigate the hydration status’ relationship with the function of the transplanted kidney during the first year after transplantation. Materials and Methods: This observational prospective cohort study included deceased kidney recipients transplanted in the Hospital of the Lithuanian University of Health Sciences between September 2016 and January 2023. BIA and LUS were performed before transplantation, on days 3 and 7, and at discharge. Data on recipient and donor clinical characteristics were collected. Graft function was evaluated according to the serum creatinine reduction ratio and the need for dialysis. Hydration status was evaluated by calculating B-lines (BL) on LUS and the ratio of extracellular/total body water on BIA. Results: Ninety-eight kTx recipients were included in the study. Patients with immediate graft function (IGF) were compared to those with slow or delayed graft function (SGF + DGF). Recipients in the SGF + DGF group had a higher sum of BL on LUS before transplantation. After transplantation in early postoperative follow-up, both groups showed hyperhydration as determined by BIA and LUS. After one year, recipients with no BL before transplantation had better graft function than those with BL. Logistic regression analysis showed that having more than one BL in LUS was associated with a 2.5 times higher risk of SGF or DGF after transplantation. Conclusions: This study found that lung congestion detected by LUS before kTx was associated with slower graft recovery and worse kidney function after 1 year. Meanwhile, the hyperhydration status detected by BIA analysis did not correlate with the function of the transplanted kidney. Kidney transplantation (kTx) is a treatment option for patients with end-stage renal disease (ESRD) . The earThe evaluation of the hydration status of patients with ESRD is challenging. Several articles advise on how to monitor the hydration status of patients with ESRD using different physical and instrumental methods ,7,8,9. TTo our knowledge, only a few studies have attempted to assess the hydration status of kTx recipients using BIA ,7 and noThe observational prospective cohort study included all consecutive recipients of the deceased kidney transplantation program at the Lithuanian University of Health Sciences Kauno Clinics hospital between September 2016 and January 2023. Approval (29 December 2015 Nr. P1-BE-2-9/2014) to perform this study was given by the Kauno region biomedical ethics committee. Informed consent was signed by every participant before kTx.Twenty-two definitions of DGF have been proposed in the literature based on the need for HD, serum creatinine levels, urine output or a combination of these ,12,13,14There were 120 cadaveric kTx performed during the study period. KTx recipients who received a kidney from a living donor (n = 4), had early surgical complications, renal artery or vein thrombosis (n = 4), PNF (n = 4), data limitations (n = 7) or incomplete follow-up (n = 3) were excluded. In the initial analysis, we included 98 patients. For the follow-up analysis after 1 year, we tracked 74 kidney transplant recipients out of the 98 patients (24 recipients were excluded due to data limitations after 1 year due to further patient follow-up in another transplant center). Recipients were either pre-emptive or on chronic HD or peritoneal dialysis treatment before kTx. HD immediately before kTx was performed when the patient was dialyzed more than 2 days before transplantation, had serum potassium levels > 5.5 mmol/L and/or II or III degrees of venous stasis was found in the chest X-ray. A standard immunosuppression induction was administered before kTx: methylprednisolone, mycophenolate mofetil and Basilixumab or ATG in the case of high immunological risk. The prescription of fluid therapy after kidney transplantation was determined according to the local protocol, which included a basic volume load of 1 L of isotonic solution and 1 L of 5% glucose solution with additional compensation of extra losses. All deceased kidneys were preserved using the cold storage immersion method. We collected data about recipients’ demographic and clinical characteristics, donors’ clinical characteristics and graft function in the early post-transplant phase and during the first year after transplantation. For an evaluation of hydration status, we performed BIA using an InBody S10 analyzer , and for pulmonary congestion, LUS using a Mindray model Z5 with curvilinear probe model 35C50EA for enrolled subjects.All subjects underwent BIA and LU from the same investigator before kTx and after kTx on days 3 and 7 and on discharge. The following variables before kTx were also included: residual diuresis, serum sodium levels and total protein levels. During the hospitalization period, data about fluid therapy on the day of transplantation and after transplantation and diuresis volume were collected.When performing BIA, we took into account the ratio of ECW/TBW. BIA was performed according to the instructions of the manufacturer. If HD was undertaken before transplantation, BIA was performed after the HD session. For the methodology of LUS, we used recommendations for point-of-care lung ultrasound . We usedWe performed a post hoc analysis on 73 patients’ echocardiography data before kTx that were available in a local database. We collected data about left ventricular mass index (LVMI) and ejection fraction. We divided patients into two groups according to left ventricular hypertrophy (LVh); according to the American Society of Echocardiography and/European Association of Cardiovascular Imaging, LVH is defined as an LVMI greater than 95 g/m in women and greater than 115 g/m in men . We compt-test was used. The Kruskal–Wallis or Mann–Whitney U-test was applied if variables were not normally distributed. Logistic regression analysis was performed using binary logistic regression. All reported p values were two-sided. A p value of 0.05 or less was considered significant.Data were analyzed using SPSS 28 statistical software. Values were expressed as means (SD) or median (IQR) according to their distribution for continuous variables or as counts and percentages for categorical variables. Categorical data were analyzed using Pearson’s chi-square exact test. The mean square contingency coefficient was used as a measure of association between two binary variables. For normally distributed continuous variables, Student’s unpaired p = 0.952). The ECW/TBW ratio did not differ between the groups. A total of 98 patients were enrolled in the study between September 2016 and January 2023. Of these 98 patients, 51 recipients had IGF and 47 had SGF or DGF. A comparison of donor and recipient characteristics in two groups is shown in In the unadjusted analysis, more than 1 BL in LUS was associated with a higher risk of getting SGF or DGF after kTx  (model 1). However, after adjusting for potentially relevant confounders with high significance in the univariate analysis, such as cold ischemic time and deceased donor age, this relationship was no longer apparent  (model 2). . Given tp = 0.068). Early infection status was excluded in all patients; however, in the group SGF+DGF, the serum CRP level was significantly higher (17.2 (7.5–26.0) mg/L vs. 27.0 (11.9–46.56) mg/L, p = 0.013). In the SGF+DGF group, the measured glomerular filtration rate (mGFR) and 24-h diuresis were significantly lower compared to patients with IGF. More details are shown in Comparing the groups of patients with IGF and SGF+DGF, the hydration status was not different between BIA and LUS on day 3 after transplantation. Fluid therapy per 24 h on day 3 was administered at an equal volume to the groups (46.86 (17.68) mL/kg/24 h vs. 39.55 (17.42) mL/kg/24 h, p = 0.064); however, the volume of fluid therapy per 24 h was significantly higher in this group (54.68 (18.13) mL/kg/24 h vs. 38.83 (34.58) mL/kg/24 h) (p = 0.004), as shown in On the seventh day after kTx, all patients were in a hyperhydration state as determined by BIA and LUS methods. The tendency for lung congestion to reduce faster was observed in the IGF group (3.2 (3.39) vs. 4.83 (4.55), kg/24 h) . There w2 vs. 41.57 (17.79) mL/kg/1.73 m2, p = 0.001) and patients in this group were more anemic  mL/kg/1.73 me anemic . p = 0.037), and during observation periods, lung congestion was not reduced until discharge day, as shown in The manufacturer of the BIA analysis equipment provides a cut-off point of >0.390 for ECW/TBW to state overhydration. In both groups, overhydration was not observed before kTx and overhydration was established in both groups during the observation period after kTx without significant differences between the groups. The BL sum showed a hyperhydration state of the lungs before kTx in the SGF + DGF group (0.92 (1.67) vs. 2.07 (3.25), During the follow-up period after kTx, all participants were found to have excess hydration, which was determined by the two methods LUS and BIA, as shown in p = 0.031) with a positive relationship Phi correlation of 0.224, p = 0.031. On days 3 and 7 and discharge days, no relation was found between BL and the Scr reduction ratio. No correlation was found between the ECW/TBW ratio before and after the kTx and Scr reduction ratio.The Pearson chi-square test showed that patients without BL in LUS before kTx were related to IGF  compared to 1 or more BL before kTx (n = 45) (52.09 (SD 19.89) vs. 38.9 (SD 17.73) mL/min/1.73 m2 by CKD-EPI equation, p = 0.034). During the 1-year follow-up period, 74 out of 98 patients were observed. The mean function of the transplanted kidney after 1 year was 46.85 (SD 20.77) mL/min/1.73 mp = 0.033).A moderate negative correlation was found between the sum of BL before transplantation and the estimated glomerular filtration rate (eGFR) after 1 year  and no hyperhydration (ECW/TBW ≤ 0.39) groups before kTx. No significant differences were found between the groups in terms of eGFR and Scr levels at 1-year follow-up. Additionally, no correlation was found between ECW/TBW ratio and eGFR after 1 year.2) and those with worse kidney function after 1 year (eGFR < 30 mL/min/1.73 m2). In the group with worse kidney function, there were 13 patients, accounting for 17.6% of the total. An adjusted analysis was performed, taking into account relevant cofounders: more than 1 BL in LUS, the age of the deceased donor and cold ischemic time. However, only the age of the donor remained a significant cofounder  and ECW/TBW ratio (0.378 (0.373–0.383) vs. 0.384 (0.368–0.389), p = 0.142) were not different in the groups with and without LVh. We did not find a correlation between the LVMI and the sum of BL and ECW/TBW before kTx. The ejection fraction did not show a significant difference between groups, and no correlation between ejection fraction and BL, or ECW/TBW before kTx, was observed.In the LVh group, there were 49 patients (67%). The sum of BL before kTx (1 (SD 1.56) vs. 1.8 (SD 3.74), This study focused on changes in the patient’s hydration state after kTx and its relation to graft function. We hypothesized that a hyperhydrated state would be beneficial for early and later kidney function but our study showed the opposite: signs of lung congestion before kTx were associated with SGF recovery and worse kidney function after 1 year. This association was found using LUS but not BIA analysis for evaluating the hydration state. This study suggests a new possibility of using LUS before kTx to predict the early function of the transplanted kidney and function after 1 year and to make early interventions.Similar results were presented by Smudal A. et al. According to their study, DGF was related to lower residual diuresis, higher intradialytic weight gain and higher fluid balance during the first postoperative day . AnotherThe hydration status of the patient can be determined with various principles. We chose noninvasive methods: BIA and LUS. BIA analysis shows the whole-body hydration status and LUS shows the lungs’ extracellular water in the lung parenchyma. Both methods are cheap, harmless and quick and can be performed close to the patient’s bedside. Our study shows that all patients underwent a hypervolemic state after kTx, as determined by both methods. However, we did not find a correlation between these methods. According to Panuccio V.’s pilot study, LUS showed more accurate results in detecting lung congestion at a preclinical stage in euvolemic acute kidney injury patients . In contTo avoid the incidence of DGF, high-volume fluid is administered, aiming to preserve renal blood flow. Consequently, we could achieve a hypervolemic state. We observed that all patients underwent a hyperhydration state after kTx, as assumed by BIA and LUS. The same results were found in Guetin V.’s study. The authors showed that patients after kTx are associated with hydration disorders, established by BIA, and, like in our study, all patients after kTx were in a hyperhydration state .The question is what volume of fluids is not harmful or critical to the patient. Volume overload can cause respiratory complications, infection and increased overall mortality ,24,25. FThe lungs are a critical area at the interface with the central circulation . StudiesFluid overload, intermittent HD and uremic intoxication are risk factors for damaging endothelial glycocalyx in patients undergoing HD ,30. The We suggest that venous congestion and probably glycocalyx damage may be the reasons for our observation that fluid overload and lung congestion before transplantation are harmful to renal transplant recovery and function after transplantation. LUS data may show us the consequences of highly damaged glycocalyx levels in chronically hyperhydrated patients before kTx.This study has several limitations. The main limitation is the small sample size. Although the significant hypervolemic state, as indicated by BL in LUS, was not a significant factor in the multivariate analysis, we hypothesize that, with a larger sample size, it could potentially become significant. In future studies, it will be necessary to broaden the scope of the patient hydration status assessment. Echocardiography performed before and after kTx, along with the collection of endothelial injury biomarkers or N-terminal pro B-type natriuretic peptide (NT-proBNP) samples, could provide valuable information. It is important to note that the evaluation of lung congestion does not provide a complete picture of congestion levels in the venous system. However, such an evaluation could offer additional insights into fluid intolerance and the potential for worsening systemic venous congestion and damage to the endothelial glycocalyx .This is the first clinical study to investigate the value of LUS in relation to kidney transplant function during the early postoperative period.This study found that LUS-revealed lung congestion before kTx was associated with slower graft recovery and worse kidney function after 1 year. Meanwhile, the hyperhydration status detected using BIA did not correlate with the function of the transplanted kidney.


Renal hemodynamics is impaired since the early stage of cardiometabolic disease. However, in obesity, its noninvasive ultrasound assessment still fails to provide pathophysiologic and clinical meaningfulness. We aimed to explore the relationship between peripheral microcirculation and renal hemodynamics in severe obesity.ex-vivo complete microcirculatory assessment. Media-to-lumen ratio (M/L) and vascular response to acetylcholine (ACh), alone or co-incubated with NG-nitro arginine methyl ester (L-NAME), were measured.We enrolled fifty severely obese patients with an indication for bariatric referring to our outpatient clinic. Patients underwent an extensive reno-metabolic examination, paired with Doppler ultrasound and measurement of the renal resistive index (RRI). On the day of the surgery, visceral fat biopsies were collected to perform an P = 0.042). Multivariable analysis showed a relationship between M/L and RRI  and between albuminuria and the inhibitory response of L-NAME to Ach vasodilation . Notably, all these correlations were consistent also after adjustment for confounding factors.Patients were stratified according to their normotensive (NT) or hypertensive (HT) status. HT had lower estimated glomerular filtration rate and higher RRI compared to NT, while the presence and extent of albuminuria were similar between the two groups. Concerning microcirculatory assessment, there were no differences between groups as regards the microvascular structure, while the vasorelaxation to ACh was lower in HT (The RRI and albuminuria relationship with microvascular remodeling in patients affected by severe obesity supports the clinical implementation of RRI to improve risk stratification in obesity and suggests a tight pathophysiologic connection between renal haemodynamics and microcirculatory disruption. Obesity increasing prevalence  is deemeHowever, the noninvasive exploration of several vascular districts in patients with obesity often fails to convey clinical meaningfulness. With particular regard to the kidney, some authors suggest that the renal resistive index (RRI) might reflect the presence of arteriolosclerosis and interstitial fibrosis, which follows the development and progression of chronic kidney disease . IntrapaThe difficult interpretation of the current evidence might partially be due to the lack of studies exploring RRI and microvascular remodeling by reliable techniques simultaneously. Indeed, many studies suggest that obesity , as wellWe conceived the present study to explore the relationship between peripheral microcirculation and renal hemodynamics in severe obesity. In particular, we aimed to investigate whether an ultrasound-based assessment of renal hemodynamics (e.g. RRI) might be a proxy for systemic morphofunctional microvascular alterations and whether this relationship is independent of systemic blood pressure and other acknowledged confounders. Secondly, we investigated whether albuminuria, another marker of renal microvascular dysfunction, is associated with systemic microvascular alterations. Finally, we explored whether any of those relationships are conditioned by the concomitance of arterial hypertension (i.e. a systemic hemodynamic perturbance).2) on the waiting list for bariatric surgery. We selected individuals with the following characteristics: having participated in a research protocol including the ex-vivo microvascular structure and function assessment by our laboratory between 2015 and 2019, and having performed a presurgery renal ultrasound with RRI assessment as part of their routine clinical workup. Thus, it should be noted that a large portion of the study participants has previously taken part in published studies involving microcirculatory exploration by our lab  for variables with normal or skewed distribution, respectively. Continuous variables with a normal distribution were compared between individuals with or without hypertension by the Student's Statistical tests were performed using JMP Pro 16.3.0  using a two-sided α level of 0.05.The main anthropometric and biochemical characteristics of the study participants are summarized in Table By definition, the HT group had higher SBP, PP and MBP, while no difference was shown in DBP and HR between groups. The mean estimated glomerular filtration rate (eGFR) was significantly lower in the HT group, while the presence and the extent of albuminuria were similar, with the same prevalence of albuminuric patients in both groups.Finally, there were no differences in lipid and hepatic profile, uric acid and inflammatory markers between the two groups Table . NotablyP = 0.002).Concerning renal ultrasound, there was no difference in longitudinal renal diameter between groups, while the HT group had significantly higher values of RRI . In contrast, no differences between groups were shown in vasorelaxation after the inhibition with L-NAME.Concerning microcirculatory assessment , SBP , PP  and media-to-lumen ratio ; RRI and the inhibitory response of L-NAME to ACh vasodilation showed a positive trend . No correlation was found between RRI and BMI, MBP, as well as parameters of kidney function such as albuminuria and eGFR, and the other microcirculatory parameters .In univariate analysis, the RRI was positively correlated with age , MBP  and negatively with the inhibitory response of L-NAME to ACh vasodilation, a direct measure of endothelial function . No correlations were found between albuminuria and age, BMI, SBP, PP, eGFR, and structural parameters of microcirculation such as media-to-lumen ratio and MCSA.Albuminuria was positively correlated with DBP , independent of confounding factors such as age, sex, MBP and HbA1c. This association was confirmed either in NT or in HT . This association, too, was confirmed either in NT or in HT. ; similarly, albuminuria was confirmed to be independently associated with L-NAME-to-Ach vasorelaxation .We repeated those analyses by replacing MBP with PP in the model to verify the impact of pulsatile rather than the steady component of systemic pressure. RRI remained significantly associated with M/L , the progressive high-impedance microvascular ambient deriving from this structural remodeling would be the main factor associated with the simultaneous increase in the RRI in severe obesity. This could be independent of the analogous changes that hypertension induces at the microvascular level.Higher RRI has been associated with subclinical signs of kidney damage in lean patients with primary hypertension without CKD, demonstrating a direct link with albuminuria , and a sex-vivo assessment of endothelial function. Very few studies [In our study, we found that, in severe obesity, albuminuria is associated with a reduced inhibitory effect of L-NAME on ACh vasodilation. L-NAME blocks the endothelial NO synthase, allowing a direct  studies  explored studies ,42. Howe studies . Another studies ,45. Fina studies . On the et al.[We did not find any association between eGFR and endothelial dysfunction, either. This might also be explained as they are two different and independent factors of cardiometabolic impairment. A similar association has also been reported by Kakutani et al., even thet al..et al.[2 and SBP/DBP 133.8 ± 2.8/77.5 ± 1.3 mmHg) vs. n = 12 patients with metabolic syndrome and obesity  had no significant differences in terms of M/L and MCSA . However, further studies should address this interesting pathophysiological finding.In our exploration, the inhibitory effect of L-NAME was not related to systemic blood pressure after adjustment, and we did not observe any difference between normo- and hypertensive patients. However, it is acknowledged that endothelial dysfunction is a feature of essential hypertension that is not related to systemic arterial blood pressure levels . Also, bet al. further Our study has some limitations. First, the cross-sectional setting limits the implication of causality and calls for longitudinal studies to address the potential of RRI as a predictor of microvascular remodeling over time and following specific interventions (e.g. bariatric surgery). Similarly, the absence of a control group and of a group of patients with hypertension and without obesity, as well as the unavailability of other hemodynamic parameters, limit the depth of the pathophysiological exploration. Second, the small sample size as well limits the appreciation of effects of smaller magnitude. Third, although an invasive assessment of the microcirculation has been performed, given that the patients included in the present analysis come from different research protocols, the measures of inflammatory markers, endothelial NO bioavailability, and differences in gene expression are consistently available only for a very few numbers of patients to provide a reliable mechanistic exploration. Thus, we do not have included them in the analysis. However, as we stated, we designed our study as a pilot observation to generate hypotheses and promote prospective studies addressing all these relevant clinical, pathophysiological and mechanistic points.In conclusion, we found that, in patients with severe obesity submitted to bariatric surgery, RRI is related to microvascular remodeling, independent of systemic blood pressure or hypertensive status. These findings suggest that clinical implementation of RRI should be performed in patients with obesity to improve risk stratification. Indeed, obese patients with higher RRI might benefit from more intensive treatment, such as early bariatric surgery, which has proven to rescue microvascular structure and function . FurtherAuthor contributions: D.M. and A.M. have made substantial contributions to conception, data collection, statistical analysis and they have been involved in drafting the manuscript. E.D. and F.C. have made contributions to data acquisition. S.T. and M.N. have been involved in revising it critically for important intellectual content. R.M.B., A.V. have made substantial contributions to data interpretation, they have been involved in writing of the manuscript.Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.The authors declare no competing interests. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.