Background: Chronic total occlusion (CTO) remains the most challenging procedure in coronary artery disease (CAD) for interventional cardiology. Although some clinical risk factors for CAD have been identified, there is no personalized prognosis test available to confidently identify patients at high or low risk for CTO CAD. This investigation aimed to use a machine learning algorithm for clinical features from clinical routine to develop a precision medicine tool to predict CTO before CAG. Methods: Data from 1473 CAD patients were obtained, including 1105 in the training cohort and 368 in the testing cohort. The baseline clinical characteristics were collected. Univariate and multivariate logistic regression analyses were conducted to identify independent risk factors that impact the diagnosis of CTO. A CTO predicting model was established and validated based on the independent predictors using a machine learning algorithm. The area under the curve (AUC) was used to evaluate the model. Results: The CTO prediction model was developed with the training cohort using the machine learning algorithm. Eight variables were confirmed as ‘important’: gender , neutrophil percentage (NE%), hematocrit (HCT), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), ejection fraction (EF), troponin I (TnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The model achieved good concordance indices of 0.724 and 0.719 in the training and testing cohorts, respectively. Conclusions: An easy-to-use tool to predict CTO in patients with CAD was developed and validated. More research with larger cohorts are warranted to improve the prediction model, which can support clinician decisions on the early discerning CTO in CAD patients. Chronic total occlusion (CTO) is defined as complete luminal obstruction without antegrade flow for an estimated duration of at least 3 months, according to historical clinical data . It is dIn order to improve risk stratification in patients, efforts have been made to develop prognostic predictive tools or risk scores to identify CTO before CAG . AlthougIn this study, a preoperative CTO risk model based on clinical demographics, echocardiography, and laboratory indexes was constructed by using a machine learning algorithm. This may be observed as an unmet need and an emerging opportunity, as promising computational analysis has demonstrated that it provides clinically valuable predictions in CTO risk and beyond.n = 317) or the non-CTO (n = 1156) group based on the procedural outcome. CTO was defined as an occlusion lasting longer than 3 months based on the first occurrence of angina pectoris, previous angiogram, or previous infarction and thrombolysis in myocardial infarction grade 0. Non-CTO was defined as a stenosis of at least 50% of the luminal diameter in at least one branch of the main coronary artery. The CTO was diagnosed independently by two experienced cardiac interventionists (Yongxin Wu and Yanci Liu) and independently checked by another experienced cardiac interventionist (Ze Zheng). Any disagreements between the cardiac interventionists were resolved by discussion with a fourth investigator (Jinghua Liu). The study protocol was approved by the Human Research Ethics Committee of Beijing Anzhen Hospital, Capital Medical University, Beijing, China, and the study adheres to all the principles of the Declaration of Helsinki. The Ethics Committee Approval Code is 2022177X. Given the retrospective study design, informed consent is waived by the Human Research Ethics Committee of the Beijing Anzhen Hospital, Capital Medical University, Beijing, China.In total, 1105 patients with chest pain and suspected CAD who underwent first-time CAG, between January 2019 and December 2019 at Beijing Anzhen Hospital, Capital Medical University, were consecutively enrolled, which formed the training cohort for this study. The patients with CAG or CABG before were excluded. Between January 2020 and December 2020, an independent cohort of 368 consecutive patients was enrolled prospectively with the same inclusion and exclusion criteria. They formed the testing cohort for this study. The entire patients were assigned to the CTO group  is calculated in kilograms divided by square meters of height. Current tobacco use is defined as the ongoing use of more than one cigarette per day for 6 months. Alcohol consumption is defined as drinkers consuming more than 40 g ethanol (men) or 20 g ethanol (women) per day. Blood pressure in the seated position was measured using an aneroid sphygmomanometer after resting for a minimum of 5 min. The average of three measures was recorded as the final measurement. Hypertension is defined as systolic pressure (SBP) ≥ 140 mmHg, diastolic pressure (DBP) ≥ 90 mmHg, or self-declares the usage of any antihypertensive medication. Diabetes is defined as a fasting plasma glucose level of over 126 mg/dL, a non-fasting plasma glucose level of over 200 mg/dL or self-declares the usage of any antidiabetic medication. Blood samples were taken in a fasting state. White blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet (PLT), hematocrit (HCT), neutrophil (NE), neutrophil percentage (NE%), lymphocyte (LYM), monocyte (MONO), glucose (Glu), HbA1C, triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), free fatty acids (FFA), Non-HDL, sdLDL, homocysteine (Hcy), uric acid (UA), creatinine (Cr), brain natriuretic peptide (BNP), NT-proBNP, high-sensitivity C-reactive protein (hs-CRP), creatine kinase-MB (CK-MB), and troponin I (TnI) were measured from blood samples by standardized laboratory methods. The estimated glomerular filtration rate (eGFR) was calculated in the modified calculated using the CKD-EPI study equation. Angiography characteristics included the number of vessel lesions and the location of the CTO lesion, including the left main coronary artery (LM), left anterior descending branch (LAD), left circumflex artery (LCX), right coronary artery (RCA), and diagonal branch (D1). All angiography characteristics were calculated by two experienced interventional cardiologists.t-test. Meanwhile, the categorical variable data is expressed as frequency and percentages, of which the difference between the groups is analyzed using the chi-square test or Fisher’s exact test. Data for continuous variables are expressed as mean ± standard deviation, and the difference between groups is examined using Student’s p-value levels of the inclusion and exclusion criteria were established as 0.05, respectively. SPSS version 23.0  was used to perform statistical analyzes in this study.Univariate logistic regression analysis was performed to identify factors related to CTO prediction. Multivariate logistic regression analysis was performed with the selection of univariate logistic regression analysis, in which the The R packages with eXtreme Gradient Boosting (XGBoost), XGBoostExplainer, and machine learning in R were used to create predictive models. The training cohort formed by patients who met the inclusion and exclusion criteria between January 2019 and December 2019 at Beijing Anzhen Hospital, Capital Medical University. The testing cohort formed by patients who met the same inclusion and exclusion criteria between January 2020 and December 2020.The Gini impurity was used to measure the importance of variables, which provided the contribution of the predictive variables to the model . The relThe baseline clinical demographics of the study population are shown in Compared to non-CTO controls, the CTO group had higher WBC, NE%, MONO, TG, non-HDL, Hcy, UA, Cr, BNP, NT-proBNP, CK-MB, and TnI, but lower PLT and HDL. There were no differences in RBC, Hb, HCT, LYM, Glu, HbA1C, TC, LDL, FFA, sdLDL, eGFR, and hs-CRP. The detailed data and units for all variables are shown in n = 1105) and the testing cohort (n = 368). Clinical demographics that included sex, age, current tobacco use, alcohol consumption, BMI, SBP, and DBP were not significantly different between both groups . Additionally, the incidences of hypertension, diabetes mellitus, dyslipidemia, and a history of previous stroke did not have significant differences between both groups . Similarly, there was no statistical significance in echocardiography and laboratory indexes .The baseline clinical characteristics of the training cohort are shown in p-values for each of the variables: gender , NE% , HCT , TC , HDL , EF , TnI , CK-MB , and NT-proBNP  were implicated in the risk of CTO patients.Univariate logistic regression analysis was performed to explore the relationship between all clinical characteristics of the patients  and the p < 0.0001), NE% , HCT , TC , HDL , EF , TnI , and NT-proBNP  were identified as independent factors affecting CTO diagnosis.Multivariate logistic regression analysis was used to determine the significant independent predictors of CTO. Nine predictors selected by the univariate logistic regression analysis were selected using multivariate logistic regression analysis to determine the independent factors that predict CTO before CAG. Eight variables were included in the final model. As shown in After tuning the XGBoost model, the parameters of the XGBoost model were finally max_depth = 4, subsample = 0.63, colsample_bytree = 0.51. Based on the Gini impurity, the important predictors in the CTO prediction model are summarized in p > 0.05).To further assess the performance of the models, the ROC curves and the corresponding AUC were evaluated . As Figuhttp://www.empowerstats.net/pmodel/?m=29484_CTOBeforeCAG, accessed on 4 October 2022). As an example to better explain the model , NE, HCT, TC, HDL, EF, TnI, and NT-proBNP, with relatively accurate prediction ability. To the best of our knowledge, this is the first attempt to develop a predictive model for diagnosing CTO based on machine learning.Although the event of CAD has been related to varied traditional risk factors, as well as sex  and lipid metabolism, their role within the etiology of CTO remains less understood . To dateThe advent of machine learning methodologies could provide a large amount of information available from databases and encourage the development and testing of better predictive models . MachineThe primary machine learning model of our study was the XGBoost gradient boosted tree model. XGBoost represents a technical building set of trees in a progressive way on the loss of from weak decision tree base learners . It can The sex of men and dyslipidemia have previously been linked to the incidence of CTO in patients . ConsistBesides risk factors for CAD, our study revealed that EF and NT-proBNP were independently positively related to CTO prediction. Some CTO lesions develop from an undetected acute myocardial infarction . Acute mIn addition to non-modifiable variables  and traditional risk factors for CAD  of the individual patient, blood routine levels including HCT and NE%, were also predictors in the machine learning model. HCT is an indicator that reflects the extent of hemoconcentration . It appeOn the other hand, testing is also a significant aspect of predictive model construct, since the performance of regression models is usually much higher in the training cohort than in the testing cohort. In our research, the model was validated in a testing cohort and the results were relatively stable, which could reflect the generalizability of the model to a certain extent. Taken together, non-invasive tests have been increasingly used for risk stratification and to facilitate clinical decision making in patients with suspected diseases . SubsequThe parameters easily available and reproducible at admission were necessary and quantitative. To our knowledge, this is the pioneering research to investigate the predictability of CTO in patients with CAD and is well performed. These results supported the notion that the machine learning model could better understand the risk factors for CTO and even offered an easily used and automated assistive tool to predict the diagnosis in patients with CTO before CAG. There are several limitations in our study. First, we only included patients from the Chinese population that the trained models should be further tested in broader groups of patients to ensure additional generalisation of performance. Second, due to the retrospective design, other randomized controlled trials could fully examine its efficacy. Moreover, our results of the present study just represent a first step for CTO, which must be validated in a larger cohort with more variables such as genetic predisposition, best medical therapy, sports and activity. Finally, there is still room for optimization of this predictive model using other advanced statistical methods, such as the least absolute shrinkage and selection operator (LASSO), which may help develop a more accurate prognostic prediction model.In summary, we constructed and validated a relatively accurate machine learning model based on clinical demographics, echocardiography, and laboratory indexes, to help the early prediction of the probability of CTO in patients with CAD. More research with larger cohorts that include more patients and more variables such as genetic predisposition, best medical therapy, sports and activity are warranted to improve the prediction model, which can support clinician decisions on the early discerning CTO in CAD patients.


Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.We systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR.Most studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy.TCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results. Chronic kidney disease (CKD) is a major public-health problem: it increases the risk of end-stage kidney disease (ESKD) and cardiovascular disease, plus other complications. The prevalence of CKD is 10.5–13.1% when defined by the presence of albuminuria and decreased estimated glomerular filtration rate (eGFR)  reviewedIt is recognized that kidney transplantation, as compared to dialysis therapy, offers better patient survival for patients with ESKD . In addiAntibody-mediated rejection (ABMR) is a significant complication following kidney transplantation that contributes towards short- and long-term injury in ~1–10% of kidney-transplant recipients and increases the risk of graft loss . It is cRecently, Mayrdorfer et al. reported on a single-center study that examined the causes of allograft loss in 1642 kidney-transplant recipients. They found that 51.2% of patients had more than one cause contributing to allograft loss. The most frequent primary or secondary causes leading to graft failure were intercurrent medical events in 36.3%, T cell-mediated rejection (TCMR) in 34%, and ABMR in 30.7%. In 77.9%, a primary cause could be attributed to graft loss, of which ABMR was the most frequent (21.5%) . They reported that most graft failures manifested a phenotypic feature of ABMR or mixed rejection, and also underscored the major role of patient’s non-adherence .de novo DSAs can develop early or late after transplantation from either nonadherence or immunosuppression-minimization protocols. Thus, ABMR is seen in up to 5% of first kidney-transplant recipients (Up to one-third of highly sensitized recipients may develop acute ABMR (aABMR) following transplantation, even in those that have undergone a pretransplant desensitization protocol . ABMR iscipients .Treating ABMR remains a big challenge, especially for chronic active ABMR (caABMR). The current strategy for treating aABMR is to use of a combination of therapies to target multiple pathophysiological pathways. The current standard-of-care (SOC) combines plasmapheresis and Intravenous Immunoglobulins (IVIg), with or without steroids –13. HighConversely, in the setting of chronic caABMR, there are still left very few therapeutic options. caABMR was well-defined in the last Banff classification report . EskandaIL-6 is a key cytokine that regulates inflammation and the development, maturation, and activation of T cells, B cells, and plasma cells . Some huTocilizumab (TCZ) is the first-in-class humanized monoclonal aimed at IL-6R: it binds to both soluble and membrane-bound forms of IL-6R. The efficacy of TCZ was first confirmed in a clinical trial involving 28 patients with Castleman disease  and it iBased on these findings, TCZ may have a positive impact in ABMR, by reducing inflammation, alloantibody titers, and by targeting many pathways within the immune response involved in ABMR. Very recently, we and other groups have studied TCZ in the setting of ABMR in kidney-transplant recipients. This prompted us to carry out a literature review to evaluate the efficacy and safety of the anti-IL-6R monoclonal antibody TCZ in the setting of caABMR. Herein, we discuss TCZ’s place in caABMR therapeutic strategies.We performed a systematic review of the literature using the PubMed search engine with the following MeSH terms: kidney transplantation; antibody-mediated rejection; late antibody-mediated rejection; chronic active antibody-mediated rejection; tocilizumab.In There was a total of 117 TCZ-treated kidney transplant recipients. One of the six studies included a control group, i.e., a historical cohort. Three of the studies were single-center open-label. All studies assessed patient- and graft-survival rates, as well as renal function (eGFR) and DSA outcomes. Histology before and after treatment was assessed in all studies except in the case reports where patients only had a biopsy at the time of ABMR diagnosis. Adverse events and tolerability were noted in all studies except for one. Patients were followed for a median period of one-year post-TCZ therapy and most patients were male. Immunosuppressive treatments at baseline were very similar in all studies: i.e., induction included anti-thymocyte globulins (or basiliximab for one study) and a maintenance therapy of calcineurin inhibitors (mostly tacrolimus), an anti-metabolite (mostly mycophenolic acid), and steroids. TCZ was used at a dose of 8 mg/kg monthly with a maximal dose of 800 mg.In three studies, TCZ was given for resistant to SOC caABMR. The overall main results are shown in Choi et al.  were oneRenal function was stable during the study. They also showed a significant decrease in immunodominant DSA (iDSA). iDSA refers to the DSA with the highest mean fluorescence intensity (MFI) in a serum sample and iDSA MFI is well correlated with AMR occurrence. In biopsies, a significant reduction in C4d+ deposition and in the microvascular circulation ‘g plus ptc’ score were seen post-TCZ treatment. Those pathological features have been shown to represent the most relevant signature of ABMR and are associated with worse long-term outcomes . The mosMassat et al.  reported2 pre-TCZ versus 37.2 ± 19 mL/min/1.73 m2 at 6 months (p=0.428) and 37 ± 24 mL/min/1.73 m2 at the last follow-up (p=0.274). This study also showed no worsening in the microvascular inflammation scores (g plus ptc): 4.2 ± 2.0 versus 4.8 ± 1.4; p=ns. However, chronicity score worsened without reaching a statistical significance. Mean total DSAs MFI at the time of therapy was 7272 ± 6698 and remained unchanged post-TCZ: 6273 ± 8480 (p=ns).Another study reported relatively similar results. Kumar et al.  treated The differences between this study and Choi et al. may be explained by the fact that the population had almost a two-fold higher degree of microvascular inflammation with a mean g+ptc score of 4.10 ± 1.52 compared to 1.67 ± 1.11 in the study of Choi et al., and a three-fold higher degree of interstitial fibrosis/tubular atrophy (IFTA) with a mean ci+ct score of 2.80 ± 0.79 compared to 0.93 ± 0.72. Another relevant difference between these two studies was the use of belatacept in seven of ten patients in Kumar et al. study. These results should be considered with caution because of the small number of patients and the absence of control group.A more recent single-center trial was conducted by Noble et al.  to assesp=0.014). There was no statistical difference in the progression of chronicity and C4d-deposition scores. In two cases with interstitial inflammatory edema, a remarkable decrease in inflammation post-TCZ treatment was observed in the follow-up kidney biopsy. Mean MFI values significantly declined after TCZ treatment: 22,600  at pre-TCZ versus 18,200  at post-TCZ; p = 0.002. Adverse events were mostly bacterial infections: four urinary tract infections and one pulmonary infection. Four patients developed hypogammaglobulinemia and three patients had asymptomatic mild alterations in liver enzymes. No hospitalization or TCZ discontinuation was needed.In order to study the efficacy of TCZ as a first-line therapy for caABMR, Lavacca et al.  enrolledIn the retrospective study of Pottebaum et al. , seven pAdverse events are summarized in The aim of this study was to discuss the place of the IL-6R blockers, as TCZ, in the treatment of caABMR. The main reported effect of TCZ is the significant reduction in DSA levels, and possibly a reduction in total inflammation and microvascular inflammation scores, seen in follow-up kidney biopsies. Indeed, three of the six studies showed a reduction in the ‘g plus ptc’ scores. Graft and patient survival were excellent in most studies; renal function stabilized in five studies, i.e. a significant decline in renal function was only seen in one study, but without a significant difference when compared to the historical SOC-therapy group. Adverse events were light to moderate and deaths were not linked to TCZ treatment. The most frequent side-effects were infections, but they did not appear to be more frequent in patients receiving TCZ than in those that received the SOC therapy. These results, although not randomized, are promising for the use of TCZ in resistant or as a first-line therapy for ABMR. These results need to be confirmed in large randomized prospective trials.This Review has some limitations. Of the six included studies, only one was controlled and none were randomized. The studies were, for the most part, retrospective and patient numbers were small due to the low use of TCZ for ABMR. The follow-up times were, for the most part, 1 year, which remains quite short when studying caABMR rejection.+ T cells into effector T-cell subsets. In combination with TGF-β, it preferentially induces the differentiation of naive CD4+ T cells into Th17 cells. The pathogen-specific effector Th17 cells eliminate extracellular pathogens from the host and the IL-6–induced dominance of Th17 cells over Tregs may account for the disruption of the immune tolerance that is involved in the development of autoimmune and inflammatory diseases. The use of TCZ may be of interest to restore the immune balance between Th17 and Treg, and to avoid excessive immune stimulation.IL-6 is a pleiotropic cytokine composed of 184 amino acids: it was first identified as a B-cell stimulatory factor 2 that promoted immunoglobulin synthesis by activated B cells . IL-6 isp = 0.03). This suggest that using TCZ in the early stages of graft inflammation, and even before the rejection stage, could prevent long term graft damage.A randomized controlled trial that included 30 kidney transplant patients with stable graft function, with subclinical inflammation defined on a routine biopsy as moderate interstitial inflammation (Banff classification i or ti 1–2 and t0) was performed by Chandran et al. . Subject+ iDSAs seemed to have the strongest association with allograft failure (p=0.09), IgG1 , IgG2 , and IgG3  levels significantly or nearly significantly decreased at post-TCZ, whereas there was no significant reduction at post-treatment in the control group. This suggests that TCZ reduced the levels of major IgG components, IgG1, IgG2 and IgG3, resulting in total IgG reduction and, thus, this suppression by TCZ is unlikely to be subclass-specific. IgG4 levels did not change at post-TCZ, and the control group showed a significant reduction at post-treatment , probably linked to rituximab treatment. This shows that TCZ suppresses Ig-producing B cells including anti-HLA-IgG-producing B cells, and possibly including plasmablast and plasma cells, through inhibition of IL-6, a B cell, and plasmablast growth factor. This might be one of the factors contributing to the beneficial effect of TCZ observed in cABMR patients.It has been shown that ABMR is partly mediated by complement activation and antibody-dependent cellular cytotoxicity, mostly induced by IgG1 and 1Gg3 subclasses DSAs. A high risk of renal- and liver-allograft failure with anti-HLA IgG3 DSAs has been reported , 38. Hig failure . That is failure  performe failure . Of the Clazakizumab is a humanized monoclonal IgG1 antibody with high affinity for IL-6 and a long half-life of approximately 30 days compared to TCZ, which is shorter, dependent on the concentration. This antibody has been systematically evaluated to treat rheumatoid and psoriatic arthritis in clinical trials, but has not yet been approved for clinical use. An investigator-driven, randomized, double-blind, placebo-controlled, parallel-group phase II pilot trial was conducted and published in 2021 . In thisAnother relevant point that was raised by Choi et al.  is a potImmunosuppressive treatment associated with TCZ should be explored to treat caABMR but also for maintenance treatment after kidney transplantation. In the study of Noble et al. , one patFinally, TCZ has also been used in desensitization protocols in highly sensitized kidney-transplant candidates . A decreTocilizumab may be an alternative to SOC therapy in DSA positive caABMR or aABMR in kidney transplant recipients, either as a first-line treatment or after failure of SOC therapy. TCZ seems to reduce DSA levels and decrease kidney inflammation and microvascular lesions and seems to have a protective effect on renal function. Further studies are important to support and explore these results, in particular randomized and controlled studies.JN, PM, and LR designed the study. LC made the literature search. LC and JN wrote the paper. TJ, BJ, and LR edited the manuscript. DG reviewed the kidney allograft biopsies from our patients. All authors contributed to the article and approved the submitted version.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.


In recent years, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated beneficial renoprotective effects, which culminated in the recent approval of their use for patients with chronic kidney disease (CKD), following a similar path to one they had already crossed due to their cardioprotective effects, meaning that SGLT2i represent a cornerstone of heart failure therapy. In the present review, we aimed to discuss the pathophysiological mechanisms operating in CKD that are targeted with SGLT2i, either directly or indirectly. Furthermore, we presented clinical evidence of SGLT2i in CKD with respect to the presence of diabetes mellitus. Despite initial safety concerns with regard to euglycemic diabetic ketoacidosis and transient decline in glomerular filtration rate, the accumulating clinical data are reassuring. In summary, although SGLT2i provide clinicians with an exciting new treatment option for patients with CKD, further research is needed to determine which subgroups of patients with CKD will benefit the most, and which the least, from this therapeutical option. Chronic kidney disease (CKD) of any etiology is on the rise on a global scale. Caused by multiple conditions, such as diabetic kidney disease (DKD), hypertension, glomerulonephritis and various infections, in 2017, it was estimated to affect ~10% of the world’s adult population . The preSGLT2i received approval for treatment in T2DM nine years ago. In that period, they have evolved from a novel hypoglycemic agent, to a potent cardio- and renoprotective option in the T2DM and heart failure treatment arsenal, and recently, to an exciting standalone therapeutical prospect for CKD, regardless of the presence of T2DM. It all started with phlorizin, a natural product used to treat fever and infectious diseases, first isolated in 1835 by a French chemist ,7. AboutThis triggers the following question: what in fact makes the renal part of SGLT1/2 inhibition so attractive? Diving deeper into the mechanism, the glucose reabsorption in the kidney is facilitated by active sodium removal by the Na+/K+-ATPase on the basolateral membrane, which creates the electrochemical force for glucose entry via sodium driven sodium-glucose cotransport with the SGLT1/2 through the apical membrane ,11. GlucAfter almost a decade since the approval of the first inhibitor, the SGLT2i now represent a mainstay in the therapeutical guidelines of T2DM and HF. What is most interesting, and is in fact the focus of this article, is that SGLT2i have been widely shown to also provide substantial renoprotective effects, thus further expanding the plausible implications of this drug . Some auWith the mechanism of SGLT2i that occurs in the renal proximal tubule, the effects on the kidney itself, both direct and indirect, are unsurprisingly numerous .Firstly, SGLT2 inhibition reduces glomerular hyperfiltration, a pathophysiological mechanism that operates in T2DM, leading to the progression of CKD ,27,28. I2 homeostasis, verifying that diabetic kidneys displayed reduced baseline pO2 in both cortex and medulla, while SGLT inhibition by phlorizin improved cortical pO2, but reduced medullary pO2. The latter finding, interestingly, suggests a possible redistribution of active transport to distal nephron segments, resulting in the observed medullary hypoxia [Secondly, in order to fulfill its metabolic demand, the kidneys use up an unproportionally large amount of energy, as much as 10–15% of glucose . As earl hypoxia . Another hypoxia . An in vitro study by Ishibashi et al. further explained how SGLT2 inhibition ameliorates hypoxia, proposing that SGLT2-mediated glucose entry into the tubular cells is central to oxidative stress and inflammatory response that occurs in proximal tubular cells . An earlTo summarize the three broadly divided mechanisms, the first one, the reduction in hyperfiltration, and therefore glomerular injury, is DM-related through the TGF, but has also been speculated to be glucose-independent. The second, the reduction in energy consumption, and therefore hypoxia, is by definition glucose-dependent and greatly amplified in the presence of diabetes, although in theory, it occurs even in the absence of it. The third, the inhibition of inflammatory, fibrotic and proapoptotic response, to a significant extent does not necessarily relate to diabetes. This shows the great scope of SGLT2 inhibition’s direct effects on the kidney and provides explanations for its effectiveness in both diabetic and non-diabetic chronic kidney disease.Having discussed the direct effects of SGLT2 inhibition on the kidney at length, in this subsection, we will acknowledge the many indirect effects of SGLT2 inhibition on the kidney, whether this is through changes in hormones, metabolism or reduction in other risk factors for CKD. SGLT2 inhibition-induced glycosuria improves endogenous glucose production, pancreatic beta-cell function and insulin sensitivity. Consequently, it reduces insulin and increases glucagon secretion, shifting substrate utilization from carbohydrate to lipid ,60,61,62Multiple studies have reported other glucosuria-related effects of SGLT2i on multiple conditions that can have a profound impact on the kidneys, such as body weight and blood pressure. For example, obesity is known to increase renal blood flow and glomerular filtration, leading to albuminuria and long-term injury ,65. A grWith regard to blood pressure, multiple studies and meta-analyses have found a beneficial effect of SGLT2 inhibition on hypertension ,71,72,73circulus vitiosus, as CKD is known to decrease high-density lipoproteins (HDL) and increase triglycerides, while nephrotic syndrome is even more atherogenic by increasing low-density lipoproteins (LDL) and total cholesterol (TC) [Although dyslipidemia does not seem to have a direct impact on the progression of CKD, its detrimental effect on the kidney is funneled through damage to the cardiovascular system, which is, in fact, in many ways associated with CKD. Dyslipidemia and CKD, thus, form a sort of a rol (TC) . SGLT2 irol (TC) ,75,76.2 [SGLT2i have many protective effects on endothelial cells, such as promoting proliferation, migration and differentiation of said cells, while also increasing the bioavailability of nitric oxide derived from endothelium, which subsequently promotes vasodilation in multiple organs, including the kidneys itself, thus reducing the burden on the organ ,77. Hype2 . The putHematocrit and the reticulocyte levels increase with SGLT2i, an effect that was assumed to be a consequence of the diuretic effect. However, it is theorized that this occurs also because of the enhancement of erythropoiesis, which is a result of an increase in erythropoietin levels 80). Taken together, the increase in hematocrit during SGLT2 inhibitor therapy may indicate improvement of hypoxia and oxidative stress in the tubulointerstitial region of the renal cortex, as well as recovery of erythropoietin production by “neural crest-derived” fibroblasts . Taken t.As previously mentioned, SGLT2i have profound benefits on the cardiovascular system. SGLT2i have been observed to significantly lower the risk of not only renal, but heart failure as well ,87,88,89Over the last decade, there has been a great number of studies that have analyzed the clinical outcomes of SGLT2i on the kidney. A vast majority of them studied patients with DKD. Clinical evidence is summarized in 2. It found that SGLT2i attenuated the annual decline in eGFR and reduced the risk of composite renal outcomes [2 in patients started on SGLT2i, seemingly with no effect on the later outcomes [The EMPA-REG OUTCOME trial studied 6952 patients with DKD categorized into subgroups of albuminuria and eGFR, reaching a conclusion that empagliflozin significantly reduced kidney outcomes and reduced yearly loss of eGFR, which was consistent across all subgroups . A meta-outcomes . Anotheroutcomes . An exploutcomes . An addioutcomes ,97,98. Soutcomes . As prevoutcomes . A studyoutcomes . A lateroutcomes . Furtheroutcomes .Comparing dapagliflozin to a placebo over 6 weeks in patients with T2DM, a small randomized double-blind study found that dapagliflozin decreased albuminuria by 43.9% and eGFR by 5% . It alsoA meta-analysis showed that a reduction in albuminuria with dapagliflozin cannot be predicted by baseline characteristics or changes in most of the other metrics, such as HbA1c and body weight. Urinary albumin to creatinine ratio (UACR) reduction, although proven with SGLT2i, remains an individual characteristic with 46% patients in the study classified as ‘‘non-responders’’ . 2, concluded that canagliflozin improves renal outcomes independent of the baseline level of kidney function and a history or high risk of cardiovascular disease [Many studies analyzed both the renal and cardiovascular outcomes of SGLT2 inhibition therapy, reaching various interesting conclusions related to different sets of patients, according to the presence of different cardiovascular morbidities. An analysis of the CANVAS program, which studied the effects of canagliflozin versus a placebo on 10,142 patients with T2DM and eGFR > 30 mL/min/1.73 m disease ,104. Sim disease . In pati disease . A meta- disease .In a randomized controlled trial that included 4401 patients with T2DM and albuminuric CKD, canagliflozin reduced the risk of end-stage renal kidney disease, a doubling of creatinine level, or death from renal causes by 34% . SignifiAs shown, the studies about SGLT2i usage in DKD patients are numerous and the clinical evidence for their benefit is vast. The same cannot yet be said for the population of patients without DM; however, the existing evidence is worth a closer look.2 and ACT of 200–5000 mg/g. The DAPA-CKD concluded that regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with the placebo [Heerspink et al. have been one of the first and most consistent groups in discussing the possibility of SGLT2i having beneficial effects on the kidney, independently of diabetes. In line with this, one of their early studies in 2016 showed that canagliflozin slows the progression of CKD, independently of its glycemic effects . However placebo . The sci placebo .Having experienced this success in the adult population, SGLT2 inhibitors are thought to have the same effect in children; however, their use has not yet been approved due to a lack of data. Nevertheless, it is believed that “no pathophysiological clues exclude their application”  in childRelevant studies have found similar effects in regard to sex ,122 and Another important population that currently lacks evidence for the use of SGLT2i is the kidney transplant patients, since most large studies automatically do not include them due to safety concerns. The existing data, although limited, do show a modest impact of SGLT2i on glycemic control, body weight, serum uric acid levels and blood pressure, while “the frequency of reported adverse effects does not appear to exceed those found in nontransplant patients” . FurtherAll in all, the SGLT2i are slowly but surely being proven as effective and safe in all relevant populations, with no concerning evidence being forwarded as of yet.2 and ≥25 mg/mmol, respectively. Interestingly, the UKKA guidelines recommend initiation of SGLT2i in patients with eGFR 25–60 mL/min per 1.73 m2 irrespective of DM, and even in the case of albuminuria when there is a need to modify cardiovascular risk, thereby considering the powerful cardioprotective effects of SGLT2 inhibition [SGLT2i are a cornerstone of clinical guidelines and recommendations for treatment of HF, DM and now, as is the focus of this review, CKD as well. This is due to the previously discussed studies that have propelled them into worldwide use, SGLT2i recommendations, such as the United Kingdom Kidney Association (UKKA) guidelines, are subsequently incorporated in patient settings that were included in the aforementioned studies. Therefore, the eGFR and UACR cut offs for SGLT2i use in both diabetic and non-diabetic kidney disease are set to ≥25 mL/min per 1.73 mhibition . It is nhibition .For similar reasons, with regard to the patients studied in the most important trials, such as CREDENCE and DAPA-CKD, SGLT2i are currently, as previously mentioned, not recommended to kidney transplant patients, and likewise, to patients that have taken any immunological therapy in the prior 6 months. Apart from DKD, other etiologies of CKD that have been studied in large trials, and therefore included in recommendations, are as follows: ischemic nephropathy, IgA nephropathy, FSGS, chronic pyelonephritis and chronic interstitial nephritis ,127.Whereas in DM settings, SGLT2 inhibitors are usually combined with metformin , in non-Due to their pharmacokinetics, all SGLT2i are taken once daily. Being the medication with the most clinical evidence for non-diabetic CKD, 10 mg of dapagliflozin is currently the most frequently used SGLT2i  in this In conclusion, SGLT2i have already become an important part of our therapeutical arsenal versus DM, DKD and non-diabetic CKD. The latter setting is dominated by the most frequently studied dapagliflozin, but at this rate, it will soon be enhanced by the arrivals of the others. There is a similar tendency of widening the scope of indications and reducing the number of counterindications due to the unknown, which will, hopefully, and most significantly, result in the addition of non-albuminuric CKD to worldwide recommendations, and also the inclusion of the currently excluded kidney transplant patients.There have been various studies that have assessed the potential adverse effects of SGLT2i. One of the more discussed potential adverse effects of SGLT2i is the apparent risk of urinary tract infections (UTIs) and genital infections. A meta-analysis carried out in 2017 verified an increased risk for the latter, but not the former . This viIn the previous years, several case reports and observational studies associated SGLT2i with acute kidney injury (AKI), presumably through the mechanism of increased diuresis and subsequent volume depletion. Nevertheless, all the relevant studies in the meantime have not only heavily rejected that notion , but havFor many years, there has been a concern that SGLT2i might be associated with euglycemic diabetic ketoacidosis (DKA). A possible mechanism was found in their insulin-independent reduction in blood glucose and ensuing hyperglucagonemia . SimilarConsidering their principal mechanism of action, i.e., reducing blood glucose, SGLT2i have been suspected to cause hypoglycemia. However, studies have shown that the risk is increased only when SGLT2i are combined with other glucose lowering agents, such as insulin or sulfonylureas , which cSimilar to the previously discussed hypoglycemia, SGLT2i have also been hypothesized to cause hypotension, since one of the main consequences of increased glucose and sodium reabsorption in the proximal tubule is increased diuresis and possible volume depletion. All the recent studies have, to a lesser or greater extent, confirmed that hypothesis, putting the focus on the need to adjust diuretic and/or antihypertensive treatment accordingly ,135,136.Perhaps the most controversial topic regarding SGLT2i adverse effects has been their effect on bone metabolism and fractures. It is believed that increased diuresis induced by SGLT2i might disturb calcium and phosphate homeostasis, leading to bone mineral losses . HoweverSGLT2i have also been associated with a higher risk of lower limb amputation, notably canagliflozin , while nDM induces hyperglycemia and tubular growth, which enhance the amount of sodium and glucose reabsorbed by the proximal tubule, and in turn increase GFR through the physiology of TGF and tubular back pressure. Consequently, higher tubular rates of transport and oxygen consumption ensue. SGLT2i offer a myriad of direct and indirect and renoprotective effects, thus halting the progression of CKD, even in patients without DM. Particular attention was paid to transient GFR reduction, which in fact contributes to GFR preservation in the long term. Importantly, the use of mathematical modeling provided new insights that explain why renoprotective effects that arise from SGLT2 inhibition are preserved in CKD, in spite of reduced blood glucose effects. On the other hand, it was brought into question whether SGLT2i might contribute to AKI in susceptible patients, such as volume depleted or patients receiving radiocontrast agents, especially considering the hypoxic effect of SGLT2i on the outer medulla. Nevertheless, although these claims have been disproved by clinical evidence, further consideration in this regard, but also concerning euglycemic DKA, is warranted. Currently, selective SGLT1 inhibition, as well as dual inhibition of SGLT2/SGLT1 are also being explored as potential new therapeutic strategies in CKD. Furthermore, in the upcoming years, we will also have an answer as to whether SGLT2i may be valuable for patients with type 1 DM. In summary, although SGLT2i provide clinicians with an exciting new treatment option for patients with CKD, further research is needed to determine which subgroups of patients with CKD will benefit the most, and which the least, from this option.


Background: To evaluate the immunogenicity and safety of the COVID-19 vaccine (Vero cell), inactivated, in a population aged ≥60 years with hypertension or(/and) diabetes mellitus. Methods: A total of 1440 participants were enrolled and divided into four groups, 330 in the hypertension group, 330 in the diabetes group, 300 in the hypertensive combined with diabetes group (combined disease group), and 480 in the healthy population group. Two doses of the COVID-19 vaccine (Vero cell), inactivated, were administered at a 21-day interval and blood samples were collected before vaccination and 28 days after the second dose to evaluate the immunogenicity. The adverse events and changes in blood pressure and blood glucose levels after vaccination were recorded. Results: The seroconversion rate of the COVID-19 neutralizing antibodies was 100% for all participants. The post-inoculation geometric mean titer (GMT) in the four groups of the hypertension, diabetes, combined disease, and healthy populations were 73.41, 69.93, 73.84, and 74.86, respectively. The seroconversion rates and post-vaccination GMT in the hypertension, diabetes, and combined disease groups were non-inferior to the healthy population group. The rates of vaccine-related adverse reactions were 11.93%, 14.29%, 12.50%, and 9.38%, respectively. No serious adverse events were reported during the study. No apparent abnormal fluctuations in blood pressure and blood glucose values were observed after vaccination in participants with hypertension or(/and) diabetes. Conclusions: The COVID-19 vaccine (Vero cell), inactivated, showed good immunogenicity and safety in patients aged ≥60 years suffering from hypertension or(/and) diabetes mellitus. Since the outbreak of Coronavirus disease COVID-19) in late 2019, a massive global pandemic ensued with an enormous public health crisis and devastating socioeconomic impact. To date, 526 million people have been infected, resulting in 6.28 million life losses ) by the 50% cell culture infectious dose. Serum was successively diluted 1:4 to the required concentration by a 2-fold series, and an equal volume of challenge virus solution was added. After neutralization in a 37 °C incubator for 2 h, a 1.0~2.5 × 105/mL cell suspension was added to the wells (0.1 mL per well) and cultured in a CO2 incubator at 37 °C for 4 days. Titers expressed as the reciprocal of the highest dilution protecting 50% cell from virus challenge. Convalescent sera are included as an internal positive control in every assay. Serum testing technicians were masked to the specific study subgroups. Based on the test results, the seroconversion rate of SARS-CoV-2 neutralizing antibodies and the GMT level were evaluated. Seroconversion rate (seroconversion) was defined as post-injection titer of at least 1:16 if the baseline titer was below 1:4 or at least a 4-fold increase in post-vaccination titer from baseline if the baseline titer was at least 1:4.Guidelines for classification standards of Adverse Events in Clinical Trials ofProphylactic vaccines issued by the State Medical Products Administration of China. Participants were observed for 30 min after each dose of vaccine and the occurrence of adverse events within 21 days of vaccination was recorded in a diary logbook. The solicited adverse events recorded in the diary included local adverse events  and systemic adverse events , arthralgia, dyspnea, non-injection site pruritus (no skin lesions), skin mucosal abnormalities, acute allergic reactions, facial nerve symptoms). Serious adverse events (SAEs) were collected through telephone interviews and actively reporting by all participants. The classification of adverse reactions was in accordance with the Blood pressure upper arm monitor (Brand: Omron) and blood glucose monitor (Brand: Verio Flex) were purchased by researchers. Each participant in the hypertension/combined disease group was given a blood pressure monitor, and each in the diabetes/combined disease group was given a blood glucose monitor. For those with hypertension, blood pressure was measured at 9 time points, before vaccination, 30 min after vaccination, and on days 1–7 after vaccination. Data before and 30 min after vaccination were acquired by staff on site, and others were tested at home by participants with the Omron blood pressure monitor. All data were recorded accurately in the diary logbook. In the diabetic population, fasting and 2 h postprandial blood glucose was measured at 5 time points, before and on days 1, 3, 5, and 7 after vaccination. All measurements were conducted by participants with the Verio Flex blood glucose monitor and data were recorded accurately in the diary logbook as well. Specialized staff trained hypertension/diabetes/combined disease participants on site on how to use blood pressure and blood glucose monitors to ensure that they were operated and recorded accurately and met the requirements of specific measurement time points.We report baseline characteristics using descriptive statistics and summarize continuous variables using mean, standard deviation, median, and categorical variables using n (%). Immunogenicity was statistically analyzed using SAS 9.4 statistical software. Differences in rates between groups were compared using the Chi-square test or Fisher’s exact test; differences in antibody GMT between groups were compared using the generalized linear model (GLM) and differences in antibody GMT between the three disease groups and healthy controls were compared using multiple comparisons (DUNNETT test). We further stratified the analyses by ages and genders. A non-inferiority test was performed on the post-vaccination antibody seroconversion rate, the lower bound of over −10% of the 95% confidence interval of the difference between the post-vaccination antibody seroconversion rate of the hypertension group/diabetes group/combined disease group and the healthy control group was used as the criterion for determining non-inferiority. For the non-inferiority test of post-vaccination antibody GMT, the lower bound of over 0.67 of the 95% confidence interval of the post-vaccination antibody GMT ratio between the hypertension group/diabetes group/combined disease group and the healthy control group was used as the criterion for non-inferiority. The mean values of blood pressure and blood glucose of each group and at various time points were used to describe the changes in blood pressure and blood glucose before and after vaccination.Although study participants contributed in important ways to this study, it was not feasible to involve them in the design, conduct, reporting, or dissemination plans of our study. We did not involve members of the public in this research owing to resource and time constraints.A total of 1440 study participants were enrolled in this study. With the exclusion of 8 cases of protocol violations due to an inclusion error, a total of 1432 study participants  were included in the safety analysis data set. With the exclusion of 19 cases who failed to obtain blood samples after vaccination or missed the window for the collection time, a total of 1413 study participants  were included in the immunogenicity analysis data set. The flow chart of the study participants’ grouping and inclusion are shown in p = 0.722). There were no significant difference for the GMTs among the four populations in males and females . The GMT ratio of the hypertension group, diabetic group, and combined disease group was 0.98 , 0.93 , and 0.99 , respectively, compared to the healthy control group. The lower bound of the 95% confidence interval for all ratios was greater than 0.67, indicating that the GMT levels in each group were all non-inferior to those of the healthy controls. After being adjusted for age and gender, there was no significant difference in the GMTs between the three disease populations and the healthy population , 69.93 , 73.84 , and 74.86 , respectively. The difference in the neutralizing antibody GMT post vaccination was not statistically significant between the groups (pulation .p = 0.786). There was no significant difference for the GMTs among the four populations in males and females . The differences in the GMT levels were not statistically significant in the hypertension group (p = 0.977), the diabetes group (p = 0.911), and the comorbid disease group (p = 0.930) compared with the healthy control group.The analysis of the immunogenicity results in the 60–69 age group showed that the post-vaccination neutralizing antibody GMT in the hypertension, diabetes, combined disease, and healthy control group was 74.05 , 72.93 , 78.81 , and 75.88 , respectively. The difference in the neutralizing antibody GMT post vaccination among groups was not statistically significant (p = 0.500). There was no significant difference for the GMTs among the four populations in males and females . The differences in the GMT levels were not statistically significant in the hypertension group (p = 1.000), the diabetes group (p = 0.497), and the comorbid disease group (p = 0.585) compared with the healthy control group , 63.16 , 63.96 , and 72.56 , respectively. There was no statistically significant difference in the neutralizing antibody GMT post vaccination among groups (ol group .p = 0.185) The incidence of solicited adverse reactions was 10.70%, 13.07%, 10.14%, and 7.71%, respectively, with no statistical significance between groups (p = 0.096)  . However= 0.096) , the 60–= 0.096) .p = 0.757); the symptoms were mainly soreness and swelling. Meanwhile, the incidence of systemic adverse reactions was 8.56%, 10.64%, 7.77%, and 5.42%, respectively, with no statistical significance between groups (p = 0.052); the symptoms were mainly dizziness, fatigue/lethargy, and headache. The severity of adverse reactions was all grade 1 (mild) mainly  mainly , the 60–) mainly .For those with hypertension, blood pressure was measured at nine time points, before vaccination, 30 min after vaccination, and on days 1–7 after vaccination, and the line graph did not show any significant abnormal fluctuations. In the diabetic population, fasting and 2 h postprandial blood glucose was measured at five time points, before and on days 1, 3, 5, and 7 after vaccination, and the line graph did not show any significant abnormal fluctuations .Our study results showed that the COVID-19 vaccine (Vero cell), inactivated, has good immunogenicity and safety in the population aged ≥60 years with hypertension and diabetes mellitus. The seroconversion rates and post-vaccination GMT in the hypertension, diabetes, and combined disease groups were non-inferior compared with the healthy controls. The differences in the seroconversion rates, post-vaccination GMT, and the incidence of adverse reactions among the four groups were not statistically significant. No serious adverse effects were reported during the study. No apparent abnormal fluctuations in blood pressure and blood glucose values were observed after vaccination in participants with hypertension and diabetes. The results of the study also showed that hypertension, diabetes, and combined illnesses did not adversely affect the immune response in the population aged ≥60 years. During the phase Ⅰ/Ⅱ clinical studies of Sinopharm BBIBP-CorV, 24 healthy subjects aged over 60 were included, with a post-vaccination GMT result of 18.9 (95% CI: 13.4–26.6) 28 days after the second dose of vaccine (6.5 U of antigen), relatively lower compared with our result (73.84). Another phase Ⅰ/Ⅱ clinical study of the inactivated COVID-19 vaccine among a healthy elderly population showed a plunge of the GMT (less than 8) six months after two doses of vaccination. The GMT increased rapidly to 342.8 after a booster inoculation . The phaBecause elderly people, especially those with multiple co-morbidities such as hypertension and diabetes, are more susceptible to SARS-CoV-2 infection with a higher likelihood of developing severe disease after infection and a higher hospitalization rate and mortality rate , it is eThe active monitoring of all participants in this study within 21 days after vaccination revealed only dominated systemic reactions, including dizziness, fatigue/lethargy, and headache, all of which resolved, with a grade 1 (mild) severity. No vaccine-related serious adverse events were reported during the study, showing a good safety of the Sinopharm BBIBP-CorV vaccine. It has also shown good immunogenicity and safety in phase III clinical studies in the United Arab Emirates, Bahrain, Egypt, and Jordan . The resOur study is the first ever to report the immunogenicity and safety in a hypertensive and diabetic population aged ≥60 years after COVID-19 inactivated vaccine, as well as the possible short-term influence on their blood pressure and blood glucose. Thus far, there have been no exploratory studies on the effects of COVID-19 vaccination on blood pressure and blood glucose. In this study, we minimized the measurement error by providing the same model of blood glucose and blood pressure monitor to the participants and training them in a standardized way. Blood pressure and blood glucose testing at multiple time points before and after vaccination showed no significant impact among elderly people with hypertension and diabetes. We plan to follow up with these participants with different immunization schedules of booster shots to obtain immunogenicity results to further carry out antibody persistence studies in the hope of providing a more thorough evidence-based basis for further improvement of the immunization schedule of the COVID-19 inactivated vaccine.This study has several limitations. Due to ethical reasons, we did not set up unvaccinated or placebo-vaccinated healthy control groups. Because the study period was right amidst the COVID-19 pandemic, it would have been unethical to leave a portion of the subjects exposed to the threat without vaccination, especially the elderly population with underlying illnesses. In addition, given that most of the healthy population had already been vaccinated against COVID-19 at the time, the number of healthy population controls that could be enrolled was not too large. Another limitation of the study is that antibody duration data after vaccination in this population are still lacking, as well as the lack of long-term blood pressure and glucose results among the hypertension and diabetes population.With a 100% seroconversion rate of the COVID-19 neutralizing antibodies for all participants, the vaccine has showed good immunogenicity in the population aged ≥60 years suffering from hypertension and diabetes mellitus. No serious adverse events were reported during the study, showing the vaccine has satisfying safety. In the future, further studies with larger sample sizes and longer research duration are still necessary.


Additional RFCA for the trigger site was attempted in 10 patients with AIAF; however, the recurrence rate of atrial arrhythmias was also not different between the groups with and without additional ablation . Conclusions: AIAF after PVI was not clinically associated with recurrence during long-term follow-up. Ablation of the trigger site in AIAF did not improve the clinical outcomes.Background: Adenosine can cause dormant electrical conduction between the pulmonary vein and left atrium after pulmonary vein isolation (PVI). Adenosine can also induce atrial fibrillation (AF) during catheter ablation. However, the clinical outcomes and effects of additional ablation for the trigger sites of adenosine-induced AF (AIAF) are unknown. This study therefore aimed to evaluate the clinical significance of AIAF. Methods: Between January 2010 and September 2019, we analyzed 616 consecutive patients with paroxysmal AF (PAF) who underwent radiofrequency catheter ablation (RFCA), including wide-area circumferential pulmonary vein isolation (PVI) and post-PVI adenosine testing. Results: Among 616 patients, 134 (21.7%) and 34 (5.5%) showed dormant conduction and AIAF, respectively. Eight patients (1.3%) had both dormant conduction and AIAF. The AF recurrence rate was not significantly different between patients with and without AIAF (16.7% vs. 18.6%, log-rank  According to the 2020 European Society of Cardiology (ESC) guidelines, radiofrequency catheter ablation (RFCA) is beneficial for patients with symptoms of atrial fibrillation (AF) and those refractory to medical treatment . It is kRecurrence may also occur during RFCA due to the electrical recovery of the initially isolated PV and atrial arrhythmias originating from causes other than the pulmonary veins. Adenosine injection has been used to confirm non-inducibility or unmask dormant PV-LA conduction. Adenosine may uncover non-PV lesions after antral PVI in >10% of patients . A meta-We retrospectively analyzed all consecutive patients who underwent RFCA for PAF at the Korea University Medical Center between July 2010 and September 2019. The exclusion criteria were as follows: (1) Patients who underwent RFCA for persistent AF, (2) patients who did not receive adenosine administration during the procedure, (3) contraindication to anticoagulation, (4) history of any precious AF ablation, (5) presence of intracardiac thrombus, and (6) pregnancy. The Institutional Review Board of the Korea University Anam Medical Center approved the study protocol. All eligible participants provided written informed consent prior to enrolment. PAF was defined as the documentation of at least one AF episode lasting ≥ 30 s on 12-lead electrocardiography or 24 h Holter monitoring and terminating either spontaneously or by intervention within 7 days of onset [All patients underwent transthoracic echocardiography  prior to RFCA and, if necessary, transesophageal echocardiography or intracardiac echocardiography to rule out left atrial (LA) thrombus.An electrophysiological study was conducted on patients who were sedated by an intravenous injection of midazolam and propofol, and arterial blood gas analysis was performed hourly. Intracardiac electrocardiograms of the coronary sinus (CS) and low right atrium (RA) were mapped with a duodecapolar catheter , and the high RA was mapped with a decapolar catheter . Two transseptal punctures were performed under fluoroscopic guidance using a Brockenbrough needle and two long sheaths . Unfractionated heparin was injected to maintain an activated clotting time within 300–350 s. After two transseptal punctures, an ablation and mapping catheter was inserted, and cardioversion was performed to restore sinus rhythm. Three-dimensional electro anatomical mapping was performed using NavX  and CARTO  and merged with cardiac magnetic resonance imaging and spiralComputed Tomography.All patients underwent wide antral circumferential PVI. Complete PVI was defined as the elimination of antral potentials or dissociation of the PV recorded on a circumferential PV catheter. Additional substrate modifications, defined as additional ablation other than PV isolation, were performed to achieve non-inducibility at the operator’s discretion. The ablation strategy was performed as previously described . We evalFirst, adenosine was administered at 9 or 12 mg and titrated until at least one P wave was blocked or until there was a sinus pause of 3 s or more. Adenosine administration resulted in unmasking of dormant conduction or AIAF between the PV and the LA. Dormant conduction was defined as transient representation of the PV potential recorded on a circumferential PV catheter. AIAF was defined as AF induced after the P wave was blocked or paused after adenosine administration. Adenosine testing was performed until all the PVs demonstrated complete PVI. PVs with dormant conduction were considered reconnected, and further ablation was performed in all cases with dormant conduction. Repeated adenosine administrations were performed to determine the trigger site of earliest activation in the CS and RA electrograms and to confirm the trigger sites by repositioning the circular mapping catheter. The triggered site of earliest activation was eliminated until AIAF did not occur. For cases where the vein of Marshall (VOM) was identified to be the trigger, a perimitral isthmus ablation was performed.The patients were discharged within 3 days of RFCA and visited the outpatient clinic 2 weeks after discharge. If the patient was found to have palpitations, we performed an electrocardiogram (ECG), 24-h Holter monitoring, or event recorder to evaluate the cause. All patients had routine follow-up outpatient clinic appointments at 1, 3, 6, and every 6 months thereafter. ECG was performed at each outpatient visit, and 24-h Holter monitoring was performed at 3, 6, 9, and 12 months after RFCA. Atrial arrhythmia lasting more than 30 s during the first 3 months of the blanking period was defined as early recurrence, and atrial arrhythmia lasting more than 3 months after the procedure was defined as late recurrence. Antiarrhythmic medications were taken for 3 months after RFCA and discontinued at the physician’s discretion.t-tests were used to compare continuous variables between the two patient groups. Categorical variables were compared using the chi-squared test or Fisher’s exact test. Kaplan–Meier survival curve analysis was used to delineate the degrees of freedom of recurrence, and log-rank tests were applied to compare differences between groups. Univariate and multivariable Cox regression analyses were performed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each independent variable. Two-tailed p-values were reported, and the results were considered statistically significant at p < 0.05. Statistical analyses were performed using SPSS statistical software .Continuous variables are expressed as mean ± standard deviation, and unpaired In total, 616 patients who received adenosine after PVI were enrolled in this study. The baseline characteristics of two groups of patients with and without AIAF are presented in AIAF was identified in 34 patients (5.5%). Negative dormant conduction was observed in 76.5% of patients with AIAF and 78.4% of patients without AIAF. Among the patients with AIAF, 8 (23.5%) showed dormant conduction. Dormant conduction was observed in 23.5% of patients with AIAF and 21.6% of patients without AIAF, which was not significantly different. Additional ablation for triggers of AIAF was performed in 10 of 34 patients . The trip = 0.827) (p = 0.704) (p = 0.740) (p = 0.011) was associated with an increased risk of recurrence of atrial arrhythmia. However, sex, age, comorbidities, and AIAF were not significantly associated with recurrence after RFCA for PAF. Multivariable analysis showed that LA diameter ≥ 40 mm  was also independently associated with recurrence after adjusting for age, sex, body mass index, congestive heart failure, hypertension, diabetes, history of stroke or TIA, vascular disease, AIAF, LA diameter, and LVEF. A total of 54 (8.8%) patients underwent redo-RFCA during the follow-up period. Among them, 2 (5.9%) AIAF patients underwent redo-RFCA.The recurrence rate was not significantly different between patients with and without AIAF  A during = 0.704) B. The re= 0.740) C. The CoThe main results of this study are as follows. (i) Most of the trigger sites where AIAF occurred were detected in crista terminalis, and all sites except VOM were in RA. (ii) There was no significant difference in the recurrence rate between the AIAF and non-AIAF groups. (iii) In the AIAF group, ablation of the trigger site did not affect AF recurrence. An LA diameter > 40 mm was associated with recurrent AF, whereas AIAF was not significantly associated with recurrence of atrial arrhythmia.A recent study has shown no significant difference in recurrence between patients with and without AIAF . In addiKAdo, formed by G protein-coupled inwardly rectifying potassium channels (GIRK), which shortens the atrial action potential duration (APD) and refractory period [Adenosine is known to cause membrane hyperpolarization in cardiomyocytes through the activation of adenosine A1 receptors (A1R) and activation of the outward potassium current, Iy period ,13. The y period . Thus, sp = 0.014). However, in the Cox regression analysis, there was an association with the recurrence rate when the LA diameter was more than 40 mm. It means that in case of adenosine induced AF electrical properties of atrial myocardium play more important role in AF development than structural changes while in case of recurrent AF vice versa.At baseline characteristics, the LA diameter of patients with AIAF was significantly smaller than that of patients without AIAF (37 ± 4.5 vs.39.0 ± 5.3, Sunny et al., suggested that acute autonomic remodeling induced by the administration of parasympathomimetic agents such as adenosine results in either easily induced or spontaneous sustained AF . After aAnother study showed that when isoproterenol and adenosine were administered to the same patients, isoproterenol mainly induced a PV trigger, whereas adenosine-induced a non-PV trigger, especially in RA. However, the trigger site induced by isoproterenol was correlated with recurrence, whereas the non-PV trigger induced by adenosine did not show a clear correlation with recurrence . In addiIn our study, no significant difference was observed in the recurrence of atrial arrhythmias with or without AIAF. The adenosine-induced non-PV trigger may be caused by adenosine A1R and GIRK current activation in RA, and AF may occur due to vagal response by enhancing the adrenergic effect. Furthermore, there was no significant difference in the recurrence rate between the group in which AF was not induced by adenosine and the group that was induced but not eliminated. Therefore, eliminating AIAF as an endpoint may be unnecessary.This study has several limitations. First, this is a retrospective single center study and the number of patients enrolled in the study was relatively small. Second, the origin of the trigger site could not be identified in approximately half of the AIAF patients. Third, asymptomatic AF may be missed due to its paroxysmal nature. However, similar to previous studies including patients with PAF, all patients had regular Holter monitoring as well as ECGs at each outpatient visit.AIAF most frequently occurred in RA; among these, most occurred in the CT. AIAF was not clinically relevant during long-term follow-up when compared with patients with non-induced AF due to adenosine. Additional ablation of the trigger sites of AIAF did not improve clinical outcomes.


To describe medication adherence to lipid-lowering drugs (LLDs), antihypertensive drugs, and acetylsalicylic acid (ASA) among persons with coronary heart disease (CHD) and explore its association with low-density-lipoprotein (LDL)-cholesterol, and systolic and diastolic blood pressure.Based on record linkage between the seventh wave of the Tromsø Study and the Norwegian Prescription Database, medication adherence was calculated as the proportion of days covered (PDC) for persistent prevalent users in the period of 365 days before the attendance date. Multivariable linear regression models were used to assess the association between systolic and diastolic blood pressure and medication nonadherence to antihypertensive drugs, age, sex, lifestyle, body mass index (BMI), current and previous diabetes, and between LDL-cholesterol and medication nonadherence to LLDs, age, sex, lifestyle, BMI, and current and previous diabetes.Mean PDC was 0.94 for LLDs and antihypertensive drugs and 0.97 for ASA. Among persons with PDC ≥ 0.80 for LLDs, 12.0% had an LDL-cholesterol < 1.8 mmol/L. Blood pressure < 140/90 mmHg (< 140/80 mmHg if diabetes patient) was reached by 55.1% of those with a PDC ≥ 0.80 for antihypertensive drugs. Adherence to LLDs was associated with lower LDL-cholesterol, while neither systolic nor diastolic blood pressure was associated with adherence to antihypertensive drugs.Adherence to antihypertensive drugs, LLDs, and ASA among persons with CHD were high despite low achievement of treatment goals for blood pressure and LDL-cholesterol. There was a statistically significant association between adherence to LLDs and LDL-cholesterol, but not between adherence to antihypertensive drugs and blood pressure.The online version contains supplementary material available at 10.1007/s00228-022-03276-4. Adherence to medications for secondary prevention of coronary heart disease (CHD) is important to achieve the full effect of lipid-lowering drugs (LLDs), antihypertensive drugs, and low-dose acetylsalicylic acid (ASA) and thereby avoid new cardiovascular events –4.Lowering low-density-lipoprotein (LDL)-cholesterol and blood pressure reduce the risk of further morbidity and mortality of coronary heart disease , 6. EuroAdherence to long-term therapies is generally found to be as low as 50% . AlthougThe medication adherence process can be divided into three separate phases: initiation, implementation, and discontinuation. Initiation determines when the first dose is taken, implementation indicates to which extent patients’ actual dose per medication corresponds to the prescribed regimen and is often measured as a proportion, while discontinuation marks the last dose taken and thus the end of treatment . PersistFew studies have assessed the association between medication adherence and LDL-cholesterol and systolic and diastolic blood pressure as continuous measures. Adherence to LLDs, antihypertensive drugs, and ASA among persistent prevalent medication users with CHD has also not been properly described.This study aims to describe medication adherence to LLDs, antihypertensive drugs, and ASA among persons with CHD, focusing on the implementation phase of the adherence process, and explore its association with LDL-cholesterol serum concentrations, and systolic and diastolic blood pressure.The data for this study were retrieved from the seventh wave of the Tromsø Study  and the Norwegian Prescription Database (NorPD).n = 32,591). Attendance rate was 65% .The Tromsø Study is a Norwegian population-based epidemiological health study that has been conducted seven times since 1974. The population of the Tromsø Study consists of inhabitants in the municipality of Tromsø in North Norway, a university town with approximately 73,000 inhabitants in 2016. Tromsø 7 invited all inhabitants in the municipality aged 40 years or older , LDL-cholesterol values, and self-reported diseases, lifestyle , and demographic information.Data from Tromsø 7 were linked with NorPD data using the unique national identity number assigned to all citizens in Norway. NorPD contains information on all prescriptions dispensed to individuals from Norwegian pharmacies. Medications given at hospitals, nursing homes, or over-the-counter are not included. We extracted the following variables: date of dispensing and information on medications dispensed, including Anatomical Therapeutic Chemical (ATC) code  and the n = 1483), defined as previous myocardial infarction, present or previous angina pectoris, previous percutaneous coronary intervention, or coronary artery bypass graft surgery.The study population consisted of participants reporting established CHD , and antihypertensive drugs (angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs), thiazides, and other antihypertensives) . ATC codWe calculated adherence to medication use as PDC, calculated as a continuous multiple-interval measure of medication availability (CMA) 7 in the R-package AdhereR . CMA7 isAdherence calculations were done for persistent prevalent users, defined as participants who had used the medications from before the start of the observation window and had supplies available to cover days within 180 days before attendance in Tromsø 7. Incident and nonpersistent users were excluded , then we only used the second measurement. If both the second and third measurements were missing (n = 1), we used the first measurement. Three participants did not have any blood pressure measurements registered and were excluded from the analyses examining blood pressure. Achieving the treatment goal for blood pressure was defined as having a blood pressure < 140/90 mmHg (< 140/80 mmHg in those with diabetes) [In Tromsø 7, blood pressure was measured by trained personnel using a digital automated device . Three measurements were taken with 1-minute intervals and after 2 minutes of seated rest . In the LDL-cholesterol was collected and analysed by trained personnel using enzymatic colorimetric methods with commercial kits on a Cobas 8000 c702  from non-fasting venous blood samples. The analysis was performed at the Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway (ISO certification NS-EN ISO 15189:2012) [Weight and height were measured with light clothing and no shoes to the nearest 0.1 kilogram and 0.1 centimetre using the Jenix DS-102 height and weight scale . We calculated body mass index (BMI) as weight in kilograms divided by height in metres squared.We collected variables concerning current or previous diabetes and lifestyle from questionnaires in Tromsø 7. Having a diagnosis of diabetes was defined as answering “yes, currently” or “previously, not now” when asked “Have you ever had, or do you have diabetes?”  or reporting current use of antidiabetic drugs, either by reporting a brand name of an antidiabetic drug when asked to state the name of all medicines used regularly during the last 4 weeks, or checking off “now” when asked “Do you use or have you used tablets for diabetes/insulin?”. Participants were considered not having diabetes if they did not reply that they had diabetes and did not report using any antidiabetic drug.Two variables summarizing lifestyle were obtained using multidimensional scaling, computed with the R-package vegan, applied to a multivariate dataset including variables concerning self-reported smoking, alcohol use, diet, and physical activity. For more information about these variables, see Online Resource Descriptive statistics are presented as proportions and means with standard deviation (SD). We applied three multivariable linear regression models to assess the association between systolic and diastolic blood pressure and medication nonadherence to antihypertensive drugs, age, sex, lifestyle, BMI, current and previous diabetes (models i and ii), and between LDL-cholesterol and medication nonadherence to LLDs, age, sex, lifestyle, BMI, and current and previous diabetes (model iii). Medication nonadherence was assessed as the adherence variables had to be reversed and log-transformed (1.1—log(PDC)) in these analyses (skewness in variables). The analyses were done as complete case analyses, hence excluding participants with missing values in the relevant variables. The significance level was set to 5%.https://www.R-project.org/).The analyses were conducted using R (R Core Team (2021), R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL The study was approved by the Regional Committee for Medical and Health Research Ethics of North Norway (2015/1775) and had an approved Data Protection Impact Assessment (DPIA) from UiT The Arctic University of Norway. All participants in the Tromsø Study have given written informed consent for their data to be used in research.Participants defined as persistent prevalent medication users were 1003 for LLDs, 1046 for antihypertensive drugs, and 1042 for ASA  was 55.1% compared to 49.4% among those with PDC < 0.80 (n = 83).Treatment goals for both systolic and diastolic blood pressure  were reached for 54.7% of the antihypertensive drug users. The treatment goal for systolic blood pressure was reached by 56.8%, while 90.9% reached the goal for diastolic blood pressure. The proportion of participants reaching the blood pressure goal among participants with a PDC ≥ 0.80 (n = 884) was 12.0% compared to 5.0% among those with a PDC < 0.80 (n = 119).For the LLD-users, the proportion reaching the treatment goal for LDL-cholesterol (< 1.8 mmol/L or < 70 mg/dL) was 11.2%. The proportion of participants reaching the treatment goal among participants with a PDC ≥ 0.80 , while an increased diastolic blood pressure was significantly associated with lower age , male sex , and lifestyle . None of the blood pressure measurements were significantly associated with adherence to antihypertensive drug use. An increase in LDL cholesterol was significantly associated with nonadherence to LLDs , female sex , lifestyle , and not having current diabetes .The regression models Table  show thaR2 = 0.099, F = 13.91, p < 0.001), 6.3% of the variance in diastolic blood pressure  = 8.84, p < 0.001), and 4.2% of the variance in LDL-cholesterol  = 5.96, p < 0.001).The regression models indicated that the predictors explained 9.9% of the variance in systolic blood pressure , and this would lead us to overestimate the PDC. However, a validation of the self-reported use of these medications in this population showed that a daily dose of one dosage unit a day was a more accurate assumption than one defined daily dose (DDD) a day, which would have been the alternative .As in other studies evaluating refill adherence, we cannot determine that having had the medications dispensed actually means that they have been consumed by the participants. We can however be quite certain that these medications are considered in use by the participants, as previously shown in the validation study .When measuring PDC for combination therapies for either antihypertensive or lipid-lowering treatment, we considered a day to be covered if the participants had at least one medication available. We could therefore not determine if the participants using combination therapies used all the antihypertensive drugs or LLDs prescribed, and this might have led us to overestimate the true adherence.Finally, and perhaps most importantly, the proportions of variance in LDL-cholesterol, and in systolic and diastolic blood pressure, explained by our models were low (4.2–9.9%), indicating that other factors also contribute to the observed variance. As this is an observational study, our results might also have been influenced by unmeasured confounders.Adherence to lipid-lowering drugs, antihypertensive drugs, and acetylsalicylic acid among persons with coronary heart disease was high despite low achievement of treatment goals for blood pressure and LDL-cholesterol. Adherence to lipid-lowering drugs was significantly associated with lower LDL-cholesterol, while adherence to antihypertensive drugs was not significantly associated with either systolic or diastolic blood pressure. This suggests that these participants might not receive optimal medication treatment and that perhaps dosages or numbers or combinations of medications are insufficient. More research is needed to explore this.Supplementary file1 (PDF 12 KB)Supplementary file2 (PDF 39 KB)Supplementary file3 (PDF 203 KB)Below is the link to the electronic supplementary material.


To investigate whether extensive renal artery isolation during robotic-assisted partial nephrectomy (RAPN) for renal cell carcinoma (RCC) affects blood pressure (BP) of patients with poorly controlled hypertension.We included 60 patients diagnosed with poorly controlled hypertension who underwent RAPN by an experienced surgeon. The renal artery of the treated kidney was sufficiently isolated. Systolic BP (SBP), diastolic BP (DBP) and antihypertensive medication information were obtained at baseline and 3- and 6-month follow-up after surgery. Primary endpoints were changes in BP, and medications. Predictors of SBP reduction at 3 months were assessed by multivariable logistic regression.P < 0.001; DBP, −4.2 ± 6.4 mmHg, P = 0.01). SBP and DBP did not differ between 3- and 6-month follow-up. The mean number of BP medications prescribed was lower at 3 months than baseline . The only significant predictor of SBP reduction at 3 months was baseline SBP.All 60 RAPN procedures were successful, with no major intra- or postoperative complications. Mean SBP and DBP decreased significantly at 3 months after surgery (SBP, −7.8 ± 6.3 mmHg, Renal denervation with extensive renal artery isolation during RAPN may improve BP control among patients with poorly controlled hypertension in short term. Renal cell carcinoma (RCC) represents approximately 90% of all kidney malignancies. The incidence has shown an increasing trend worldwide . The incHypertension is an important global health issue because of its high prevalence and is a pivotal risk factor of cardiovascular disease and chronic kidney disease . MoreoveDuring RAPN, the renal hilum is identified and exposed and the renal artery is isolated to prepare for temporary clamping. Then the kidney is separated to expose the tumor margin fully for tumor resection and reconstruction. On the basis of the effect of RDN, we hypothesized that thorough peri-arterial tissue stripping may affect RSNs and lead to altered BP. The aim of the present study was to investigate the effect of RAPN with relatively complete isolation of the renal artery on BP in patients with poorly controlled hypertension.We prospectively investigated consecutive patients with kidney neoplasms and poorly controlled hypertension who underwent RAPN in our center between June 2018 and March 2020. The inclusion criteria were age between 25 and 85 years, indication for RAPN, and a history of hypertension and taking antihypertensive medications but with poor BP control [systolic BP (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg] at hospital admission. We excluded patients with bilateral renal tumors, tumors larger than 7 cm and severe atherosclerosis. Eligible patients underwent comprehensive assessments, which ruled out secondary hypertension  and afternoon (16:00). Daily BP was the average of the two results. At least 2 days of BP measurements were obtained. The final BP value was calculated as the mean of the daily BPs.Detailed information on medication was recorded. If necessary, we invited cardiologists to adjust the background BP-lowering medications before surgery. The prescription after adjustment was considered the baseline medication, and baseline BP was calculated after the medication adjustment. Participants were instructed to maintain their medications at the adjusted doses from hospital discharge to the first visit at 3 months.At 3 months, cardiologists in the cardiovascular specialist outpatient clinic of our center reconciled the medication, with blinding to the study. Changes in number of antihypertensive medications or dosage adjustment were obtained and documented. Furthermore, the re-modified prescription was maintained until the 6-month follow-up.Drug enhancement was defined as upregulated number, dose or class of BP medication to improve BP control. Drug mitigation was defined as downregulated number, dose or class of medication intending to weaken the suppression effect.Preoperative urinary CT angiography was performed as routine and 3-D reconstructions of renal arteries were produced. Additional arteries  were noted. Surgical videos were all archived and reviewed to record the number of arteries isolated.Other data collected included patient demographics, personal history, nephrometry score, clinical data, surgical procedures, intraoperative or postoperative complications, perioperative outcomes and pathology. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Diseases equation . Plasma t test was used to analyze continuous variables and chi-square test for categorical variables. Mean BP and other paired data at follow-up were compared with those at baseline by paired t test as appropriate. Univariable and multivariable stepwise logistic regression was used to explore potential factors relating to reduced BP. Variables with P < 0.15 on univariable analysis were included in multivariable models. Two-sided P < 0.05 was considered statistically significant. Statistical analysis was performed with SPSS v17.0 .Data are presented as mean ± SD, median and interquartile range (IQR) for continuous variables or number (%) for categorical variables. Student 2 and median duration of hypertension 9.5 (IQR 5–14) years : median age was 61 (IQR 52–66) years, median body mass index 25.5 (IQR 23.4–27.7) kg/mTable P < 0.05) , respectively  or DBP  .For all patients, mean baseline SBP/DBP was 146.3 ± 8.3/88.5 ± 8.6 mmHg, and 48 (80%) had high baseline SBP (≥ 140 mmHg) despite medication adjustment; the proportion of high SBP significantly decreased at the two follow-up visits (41.7% and 38.3%) (P = 0.0006)  patients had accessory renal arteries or aberrant branches supplying the treated kidneys or tumors. However, additional arteries were not all isolated in 15 cases (Table P = 0.064) or eGFR  . Mean angiotensin II level was reduced by −11.3 pg/ml  and mean aldosterone level by −3.5 pg/ml   (Table P = 0.145), ‘Tumor side’ , ‘Baseline-SBP’ (P < 0.05) and ‘Additional artery’ (P < 0.05) in the multivariable logistic regression model. On multivariable analysis, the only independent predictor of SBP reduction was high baseline SBP .On univariable logistic regression, SBP reduction at 3 months was associated with baseline SBP [odds ratio (OR) 1.249, 95% CI 1.081–1.444, We wondered whether RAPN for RCC after extensive renal artery isolation affects BP in patients with poorly controlled hypertension. In this study, mean SBP and DBP decreased significantly at 3 months after surgery along with reduced requirement for antihypertensive medication. Extensive renal artery isolation during RAPN may improve BP control among patients with poorly controlled hypertension.The effect of PN for renal masses on postoperative BP is inconsistent among several observational studies. Novick et al. evaluated the effect of PN for solitary kidneys in 14 patients, finding no changes in BP during a mean follow-up of 7.7 years . In anotRSNs to the kidneys terminate in the blood vessels, juxtaglomerular apparatus, and renal tubules. Stimulation of RSNs increases renin release and sodium reabsorption and reduces renal blood flow . RDN wasThe laparoscopic approach has been proposed to overcome the limitations of the catheter approach. Gerber et al. found that the approach was capable of removing nerves that are typically not removed by radiofrequency-based catheter ablation . In a beLaparoscopic RDN with no ablation also shows promise in the treatment of carefully selected patients with resistant hypertension. Keisuke reported two cases of unilateral radical nephroureterectomy for renal pelvic cancer, during which the peri-arterial tissues containing RSNs were stripped to expose the vessel and ligated after cauterization; the patients showed reduced BP after surgery . In our Unilateral treatment might reduce BP if complete RDN could be achieved. One case showed that even unilateral RDN can be fully successful and decrease BP to a remarkable extent in a 12-month period . Gao et Measurements of PRA, norepinephrine spillover, or both may help in estimating the activity of the efferent RSNs. In our study, patients not on drugs antagonizing the renin–angiotensin system showed reduced PRA and angiotensin and aldosterone levels, suggesting an effect on RSNs, which was also reported in RDN studies . We evalIt should be noted that the present study has some limitations. This study was terminated prematurely because most enrolled patients were lost to follow-up about 9 months postoperatively as they became reluctant, making this study a preliminary report with relatively small sample size and short follow-up time. Therefore, the finding of the present study should be interpreted carefully, and further investigations are urgently needed. In addition, there could have been a bias due to heightened self-awareness of hypertensive patients in managing blood pressure. The lack of a control arm is another drawback. Besides, we did not quantify the specific degree of RDN, for example the length of renal arterial adventitia surface, nor we took into account drug adherence, the effect of nerve fiber recovery or neuronal regeneration . MoreoveOur short-term findings suggest that RAPN with extensive renal artery isolation may benefit the BP of patients with poorly controlled hypertension. The removal of RSNs may play a role, but the exact mechanism and long-term effects need further investigation.