The stability of molecular T2/non-T2 phenotypes remains uncertain. The objectives of this study were to assess the stability of these phenotypes and the correlation between serum periostin and asthma T2 phenotypes and endotypes.Demographics, clinical data, and blood samples were collected. Patients diagnosed with moderate-to-severe asthma were classified into T2 or non-T2 according to previously defined thresholds of blood eosinophilia and serum total IgE levels. Asthma endotype was also determined. After at least 1 year of follow-up, the stability of T2 phenotypes and endotypes was assessed.P = 0.063). Periostin levels correlated to endotypes (P = 0.001): 45.7 (27.9) ng/mL in allergic asthma (n = 16 patients), 64.7 (24.9) in aspirin-exacerbated respiratory disease (n = 14), 59.0 (27.6) ng/mL in late-onset eosinophilic asthma (n = 4), and 28.3 (13.3) ng/mL in non-eosinophilic asthma (n = 18).A total of 53 patients (72% women), mean age 47 years (range 16–77), were included. In the initial and second evaluations, the T2 phenotype was found in 41.5% and 43.4% of patients and the non-T2 phenotype was found in 58.4% and 56.7%, respectively. The mean  serum periostin level was 52.7  ng/mL in patients with T2 phenotype, and 39.3  ng/mL in non-T2 patients (T2 and non-T2 asthma phenotypes assessed by accessible methods in daily practice are stable over time yet widely heterogeneous. Serum periostin does not discriminate between T2 and non-T2 phenotypes. Nevertheless, its correlation to asthma endotypes may contribute to guide therapies targeting T2 cytokines in a more personalized approach. The development of new biological therapies targeting T2-driven inflammation has aroused great interest and efforts to identify simple, non-invasive biomarkers capable of defining asthma phenotypes in individual patients . These sal blood , 7. Moreal blood . Initialal blood , periostal blood , 11 and al blood .Another important question in clinical practice is the stability of asthma phenotypes over time. Although in the study of Woodruff et al. , phenotyIn a clinical scenario of such heterogeneity and lack of other useful and available biomarkers for patients with uncontrolled moderate-to-severe asthma, the aims of this study were to (1) assess the stability over time of molecular T2 and non-T2 phenotypes, defined according to the simple biomarkers proposed by Woodruff ; (2) assess the correlation of these phenotypes with serum periostin levels; and (3) assess the correlation between serum periostin and asthma endotypes, on the path to personalized medicine in asthma.2.2.1.We designed an ambispective study conducted at the Severe Asthma Unit of the Hospital Universitario 12 de Octubre . Patients previously diagnosed with moderate-to-severe partially or uncontrolled asthma, according to current guidelines , and whoThe study was conducted in accordance with the Declaration of Helsinki  and was approved by the Clinical Research Ethics Committee of the Hospital Universitario 12 de Octubre (N°14/368).2.2.Asthma: Diagnosed according to the Spanish Guidelines  for the Atopy: At least one positive skin prick test/specific IgE to common aeroallergens, independent of the presence or absence of clinical symptoms correlated to the respective sensitization .Allergy: The presence of suggestive clinical symptoms supported by positive skin prick tests and/or positive specific serum IgEs to the suspected allergen .2.3.9/L in peripheral blood. Patients with only one or none of the above criteria met were defined as having a non-T2 phenotype. The initial phenotype was established retrospectively according to data recorded in the patient's medical record. After inclusion in the study, patients were followed prospectively, and analyses of total IgE levels and blood eosinophil count were repeated after a minimum interval of 1 year from the inclusion visit.Patients were assigned to the T2 or non-T2 phenotype group based on serum total IgE and peripheral eosinophil levels established by Woodruff et al. : the T2 2.4.– Allergic asthma: suggestive clinical history, confirmed by concordant positive skin prick tests and/or specific IgEs to the suspected allergens. Allergic asthma, by definition, implies atopy and usually eosinophilia, but the latter is variable.– AERD (aspirin-exacerbated respiratory disease): typically late onset, associates chronic rhinosinusitis with or without nasal polyps, aspirin intolerance confirmed by oral positive challenge with aspirin/other COX-1 inhibitors. It may associate atopy or coexist with a real allergic endotype in the same patient.9/L (– Late-onset eosinophilic asthma: patients who meet eosinophilic asthma criteria (blood eosinophils >0.26 × 109/L  are non-3) or T2 inflammation, without suggestive clinical symptoms of allergic asthma , late-onset eosinophilic asthma, and non-eosinophilic asthma, according to thorough clinical history and the other criteria proposed by Lötvall et al. .– AllerBlood samples were obtained by venipuncture using a serum tube without an anticoagulant. Serum was collected, placed into aliquots, and immediately frozen at −80°C until analysis. Periostin levels were measured using a streptavidin–HRP ELISA commercial kit  according to the manufacturer's instructions. The specificity of the periostin assay is 100%, and the detection limit is 180 pg/mL. In all patients, serum periostin levels were measured in duplicate .2.5.t-test or the Mann–Whitney U-test, according to the normal or not normal distribution of data. McNemar's test was used to compare the percentage of patients with T2 and non-T2 phenotypes at baseline and follow-up. The correlation between serum periostin levels and the study variables, including T2 phenotypes, asthma endotypes, gender, smoking status, age at the onset of asthma, pulmonary function tests, fractional exhaled nitric oxide (FeNO) atopy, serum IgE levels, and eosinophil blood count, was assessed with Pearson's correlation coefficient. Statistical significance was set at P < 0.05.Categorical variables were expressed as frequencies and percentages, and quantitative variables were expressed as means and standard deviations (SDs). Quantitative variables were compared with Student's 3.1)/postbronchodilator forced vital capacity (FVC) ratio was <70% in 44% of the patients. In relation to asthma endotypes, allergic asthma was diagnosed in 16 patients, AERD in 14, late-onset eosinophilic asthma in 4, and non-T2 non-eosinophilic asthma in 19 patients.A total of 53 patients, 38 women and 15 men, with a mean age of 47 years (range 16–77 years), were included in the study. The baseline characteristics of the patients are shown in n = 22) patients and the non-T2 phenotype was found in 58.4% (n = 31). In the second evaluation, at least after 1 year of follow-up, the non-T2 phenotype of only 1 patient changed to a T2 phenotype, thus resulting in 23 patients (43.4%) in the T2 group and 30 (56.7%) in the non-T2 group (P = 0.012). Sixty percent of patients were followed for 3 years prospectively, while retrospective data were available and analyzed for 20% of the patients for 5 years, and for the other 20%, data were available for a variable period between 6 and 20 years. During all these periods, the phenotypes remained stable. One patient was initially misclassified as non-T2 asthma at the beginning of the study; in the follow-up visit, he was correctly diagnosed with occupational asthma due to isocyanates plus probable asthma-COPD overlap.T2 phenotypes were stable: there were no significant differences in the percentage of patients with T2 and non-T2 phenotypes at the initial evaluation and the follow-up visit. At the initial assessment, the T2 phenotype was found in 41.5% (P = 0.063) (see P = 0.001) according to endotypes, with mean values of 45.7 (27.9) ng/mL in allergic asthma, 64.7 (24.9) ng/mL in AERD, 59.0 (27.6) ng/mL in late-onset eosinophilic asthma, and 28.3 (13.3) ng/mL in non-eosinophilic asthma (see Serum periostin levels were higher among patients with the T2 phenotype [mean (SD): 52.7 (26.2) ng/mL] than those with the non-T2 phenotype [mean (SD): 52.7 (26.2) vs. 39.1 (25.6) ng/mL], but the difference was not statistically significant (063) see , Table 2thma see , Table 2P = 0.06). No correlation was found between serum periostin and the other classical T2 biomarkers—total IgE levels, blood eosinophil count, and FeNO  in non-atopic patients  than in those with at least one positive skin prick test  (FeNO see .4.Previous studies on the stability of asthma phenotypes have shown inconsistent results –20. KupcN = 292), in which our group participated, periostin did differentiate between T2 and non-T2 asthmatics/COPD (P = 0.005. With an area under the ROC curve (AUC) of 0.602 (IC: 95 0.528–0.677), periostin did not yield enough sensitivity and specificity to accurately predict T2 and non-T2 molecular phenotypes, with the best cutoff of 35.2 ng/mL , only half of them showed an allergic asthma endotype, and 32.3% (11 out of 34 patients) were diagnosed with non-eosinophilic asthma. Also, a patient with negative skin prick tests to common aeroallergens was diagnosed with allergic occupational asthma to isocyanates (positive specific IgEs in serum). Results of diagnostic tests should always be analyzed and reported with propriety since atopy is not a definitive indicator of allergic asthma and apparently not even of eosinophilic asthma. The results of our study emphasize the heterogeneity within the T2 phenotype and the need for more personalized approaches in asthma. One of the strengths of our study resides precisely in the clear definitions of atopy, allergy, allergic and non-allergic asthma, eosinophilic asthma, and T2 asthma, which are not synonymous terms. Although these traits share some common underlying mechanisms, the genetic and epigenetic interindividual variety, in terms of T2 genes, is probably what makes asthma patients so heterogeneous; therefore, we think these traits and their clinical significance should be analyzed one by one in each patient. Yet, in multiple asthma studies or clinical trials with new drugs, these terms are sometimes inaccurately exchanged and analyzed, inducing more confusion in the already complex decision-making process of choosing the ideal biologic for a real-life patient.In sum, this study shows that T2 and non-T2 asthma phenotypes assessed by accessible methods in daily practice are stable over time. Serum periostin levels were slightly higher (ns) in patients with the T2 phenotype but strongly correlated to asthma endotypes, which may contribute to guide therapies targeting T2 cytokines in a more individualized fashion. Periostin is not an ideal biomarker, but it maintains a certain value when interpreted properly, together with the classical T2 biomarkers. It seems that, as with other biomarkers such as FeNO, clinicians need to learn how to interpret periostin values in the context of the patient's characteristics and comorbid diseases . Also, mFrom a practical point of view, based on the present study, we propose a simple two-step algorithm for approaching biological therapy of severe asthma: step 1—classifying in T2 and non-T2 molecular phenotypes; step 2—endotyping as described, and within the same endotype, individual characterization and interpretation of available biomarkers and their dynamics, including periostin. Further validation is, of course, required to examine the effectiveness of this algorithm, but we consider it would be a practical step forward on the path to personalized medicine in asthma.


Unscheduled return visits (URVs) to the emergency department (ED) constitute a crucial indicator of patient care quality.We aimed to analyze the clinical characteristics of patients who visited the ED with abdominal pain and to identify the risk of URVs with admission (URVAs) from URVs without admission (URVNAs).This retrospective study included adult patients who visited the ED of Taipei Medical University Hospital because of abdominal pain and revisited in 72 h over a 5-year period . Multivariable logistic regression analysis was employed to identify risk factors for URVAs and receiver operating characteristic (ROC) curve analysis was performed to determine the efficacy of variables predicting URVAs and the optimal cut-off points for the variables. In addition, a classification and regression tree (CART)-based scoring system was used for predicting risk of URVA.Of 702 eligible patients with URVs related to abdominal pain, 249 had URVAs (35.5%). In multivariable analysis, risk factors for URVAs during the index visit included execution of laboratory tests , older age , Level 1–2 triage scores , and use of ≥ 2 analgesics . ROC curve analysis results revealed the combination of these 4 above variables resulted in acceptable performance (area under curve: 0.716). The above 4 variables were used in the CART model to evaluate URVA propensity.Elder patients with abdominal pain who needed laboratory workup, had Level 1–2 triage scores, and received ≥ 2 doses of analgesics during their index visits to the ED had higher risk of URVAs.The online version contains supplementary material available at 10.1186/s40001-023-01256-7. An unscheduled return visit (URV) to the emergency department (ED) can be defined as an unexpected return to the ED after the index visit with similar complaints. URVs constitute an important indicator for monitoring patient care and medical performance . A high Since abdominal pain is a leading cause of ED visits , and alsStudies have analyzed the characteristics of patients with URVs to the ED , 10, 19;We extracted the patient profiles from the administrative database of the Emergency Department of Taipei Medical University Hospital (TMUH-ED), which is a university hospital and level I trauma center. The TMUH-ED database preserves copies of all patients’ medical records in electronic form. This study was approved by the Joint Institutional Review Board of Taipei Medical University . Informed consent was waived because all records were either anonymous or de-identified.We consecutively enrolled patients aged ≥ 20 years who visited the ED and then revisited the ED within 72 h of the index visit during the period between January 1, 2014, and December 31, 2018. To identify a subgroup of patients with URVs related to abdominal pain, we first excluded patients whose diagnoses based on International Classification of Diseases, Tenth Revision (ICD-10) codes during the revisit were not related to abdominal pain. Second, we excluded patients with pelvic diseases such as pelvic inflammatory disease or pregnancy-related problems during the revisit. Subsequently, abdominal-pain-related symptoms and diagnoses made on the basis of ICD-10 codes during the index visit were confirmed by Hui-An Lin and Li-Tsung Lin. Lastly, we excluded patients who were discharged against medical advice or those who had been transferred to the ED from other departments during either the initial or second visits.The selected variables were broadly classified into 2 categories: patient-related and system-related variables. The patient-related variables comprised sex, age , triage score (Levels 1–5), vital signs (body temperature and pulse rate), pain score , blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), tenderness or rebound tenderness, potentially immunocompromised status , or history of abdominal surgery. The system-related variables comprised duration of ED stay , number of analgesics used, performance of initial examination (order of laboratory tests and imaging procedures), and history of TMUH visits.The Taiwan Triage and Acuity Scale , which iU test for continuous variables. Thereafter, univariate and multivariate logistic regression analyses were performed to obtain odds ratios and to identify the significant variables. In the multivariate analysis, we adopted two strategies for the explanatory variables: (1) the first strategy was by putting all clinical meaningful variables which showed statistically significant in univariable analysis (in our models 1 and 2). (2) the second strategy was by selecting the variables through backward elimination (in our models 3 and 4). In addition, the Hosmer–Lemeshow statistics were used to examine the goodness of fit for logistic regression models, and the Akaike information criterion (AIC) was used to determine which model had the best fit for the data. The model with the lowest value of AIC was the most preferred model. We used receiver operating characteristic (ROC) curves to examine the correlation between the identified significant variables and URVAs. The Youden’s index (sensitivity + specificity—1) was used to obtain the optimal cut-off value for age. As a validation analysis, a classification and regression tree (CART)—a predictive model that applies a dichotomous decision process and splits data according to a certain cut-off value—was used to establish clinical guidelines for identifying URVAs. In the CART model, all significant variables in the logistic regression analysis were included and were determined which stratification to conduct at every stage. All statistical analyses were performed using R software 4.1  and SAS 9.4 . The statistical significance was defined as p < 0.05.We compared URVA and URVNA groups by applying the Chi-square test for categorical variables and the Mann–Whitney During the 5-year study period, a total of 6829 patients with URVs were identified in our database; of these patients, 702 met the study inclusion criteria. Among the 702 patients with URVs, 249 (35.5%) and 453 (64.5%) had URVAs and URVNAs, respectively. The flowchart of the study procedures, including the patient enrollment and outcome analysis procedures is displayed in Fig. P < 0.001), had a greater history of prior hospital visits , had a longer ED duration , had higher triage scores , had higher laboratory test execution rates , had higher imaging execution rates , and was prescribed more analgesics . Moreover, a comparison of the URVA and URVNA groups indicated that the URVA group exhibited lower SBP levels  and more comorbidities . The 2 groups did not differ significantly in terms of other variables, namely gender, body temperature, heart rate, DBP, pain score, chronic kidney disease, tenderness (including rebound tenderness), or sonography performance.The characteristics of the study population are shown in Table The results of comparative analyses between the URVA and URVNA groups are presented in Table In model 4, older age , execution of laboratory tests , and administration of multiple analgesics  were associated with increased odds of URVA. Both models 3 and 4 revealed consistent results.P = 0.236), 0.535 (P = 0.122), 0.619 (P < 0.001), and 0.656 (P < 0.001), respectively. Through these 4 risk factors, the model could achieve acceptable discrimination performance  in the prediction of URVAs.The ROC curves of risk factors for URVA are displayed in Fig. P = 0.483).Our logistic regression analysis results indicated that age ( ≥ 40 year), triage score Levels 1–2), execution of laboratory tests, and number of analgesics used (≥ 2) were significant variables predicting URVAs after the index visit to the ED Table . Cutoff , executin = 148) were less likely to have URVAs  compared with other patients. Among patients aged > 40 years, those with a triage score of Levels 1–2 (n = 25) were more likely to have URVAs  compared with other patients. Among patients with a triage score of Levels 3–5 (n = 255), number of analgesics administered was a predictor of subsequent branching. Patients who received 2 or more analgesics (n = 27) were more likely to have URVAs  compared with other patients.To explore influential predictors of URVAs, a CART model was established to predict URVAs and URVNAs Fig. . The 4 vIn this study, we constructed a new scoring system by employing several significant risk factors for URVAs related to abdominal pain. The factors considered in this system are outlined as follows: age (≥ 40 year), triage score (Levels 1–2), execution of laboratory tests, and number of analgesics used (≥ 2). We observed that a score of ≥ 3 in this system indicated a higher risk of URVAs.According to our CART analysis, whether patients had laboratory workup was most related to their URVAs. Similar to our result, Liu and colleagues demonstrated a positive correlation between execution of laboratory tests and readmission within 72 h after discharge from the ED . ConsideTo comply with the National Health Insurance (NHI) System in Taiwan, the physicians must prescribe laboratory and image workup with proper indications. Medical expenses would only be paid by the NHI if they fulfilled the documented clinical indications. Otherwise, the responsibility fell upon medical providers. We considered the reasons for higher use of laboratory tests than imaging studies as follows. In general, imaging studies were performed to confirm the diagnosis, such as ileus, appendicitis, ischemic bowel, etc., rather than an indispensable tool for most clinical conditions after comprehensive history-taking, physical examination, and laboratory tests. In addition, laboratory tests were prescribed in emergency departments for multiple clinical purposes. While these tests assisted in surveying the cause of abdominal pain only, they helped evaluate the complications in other organ systems, such as acute kidney injury, electrolyte imbalance, anemia, etc. A common example was that the creatinine and pregnancy tests were prescribed for a young woman with abdominal pain.Aging is another important risk for revisit. Evaluation of older adult patients in the ED is challenging because of their comorbidities, obscured clinical presentations, and fragile physical conditions , 26–29. Another noteworthy parameter in our study was the triage score, which was used to assess how imperative a patient needs to be managed. Triage consists of 5 acuity levels that indicate severity and enable paramedical staff to effectively prioritize patients . PatientAlthough the degree of pain is subjective, scholars and clinicians had widely supported the importance of pain evaluation and considered pain as the fifth vital sign –43. ApprAccording to our review of the literature, this is the first study to reveal the association between abdominal pain and the risk of URVAs. However, this study has several limitations. First, all data were extracted from a single database of a tertiary teaching hospital, and patients who visited a different hospital within 72 h of the index visit would have been overlooked by this study. Second, indications for admission at the revisit varied between physicians; detailed parameters must be used to conduct a comprehensive analysis of indications for admission. Third, because our study involved a retrospective design, we could not determine the causality of URVAs and its predictors. Therefore, additional prospective or randomized controlled trials should be conducted to confirm this association.In conclusion, our study demonstrated that patients who underwent laboratory tests, were aged ≥ 40 years, had high triage scores, and received multiple analgesics during their index visit to the ED because of abdominal pain were at a relatively high risk of URVAs. Accordingly, on the basis of age (≥ 40 year), triage score (Levels 1–2), execution of laboratory tests, and number of analgesics used (≥ 2), we established a scoring system for screening patients with abdominal pain prior to ED discharge. In this system, a score of > 3 points should alert clinicians to consider additional risks for disease progression or deterioration in patients and the possible need for further inpatient treatment.Additional file 1: ICD-10 diagnosis codes and the Youden's index.Additional file 2:  Optimal cut-off point.


While chronic kidney disease-associated mineral and bone disorders (CKD-MBD) prevail in the endocrinological assessment of CKD patients, other endocrine abnormalities are usually overlooked. CKD is associated with significant thyroid, adrenal and gonadal dysfunction, while persistent and de novo endocrinological abnormalities are frequent among kidney transplant recipients (KTR). Low T3 levels prior to transplantation may help identify those at risk for delayed graft function and are often found in KTR. Thyroid surveillance after kidney transplantation should be considered due to structural anomalies that may occur. Despite the rapid recovery of gonadal hormonal secretion after renal transplantation, fertility is not completely restored. Testosterone may improve anemia and general symptoms in KTR with persistent hypogonadism. Female KTR may still experience abnormal uterine bleeding, for which estroprogestative administration may be beneficial. Glucocorticoid administration suppresses the hypothalamic-pituitary–adrenal axis in KTR, leading to metabolic syndrome. Patients should be informed about signs and symptoms of hypoadrenalism that may occur after glucocorticoid withdrawal, prompting adrenal function assessment. Clinicians should be more aware of the endocrine abnormalities experienced by their KTR patients, as these may significantly impact the quality of life. In clinical practice, awareness of the specific endocrine dysfunctions experienced by KTR patients ensures the correct management of these complications in a multidisciplinary team, while avoiding unnecessary treatment. More than 10% of the general population worldwide suffers from chronic kidney disease (CKD). In 2017, CKD was reported to be the 12th global cause of death (increasing in the past two decades) and accompanied by an ever-growing ranking among the causes of years of life lost [While the cardiovascular, metabolic, hematologic, neurologic and mineral and bone disorders (CKD-MBD) prevail, CKD-associated endocrine abnormalities other than CKD-MBD are usually overlooked. However, CKD is frequently associated with menstrual disorders, sexual dysfunction, infertility and resistance to the effects of growth hormone (GH), all affecting the quality of life . The litKidney transplantation is generally regarded as the optimal method of renal replacement therapy in most cases of end-stage renal disease . A recenIn practice, the interpretation of frequent hormonal perturbations found in samples from CKD and kidney transplant recipient patients (KTR) is challenging for differentiating compensatory from pathological changes, and yet it is crucial for their optimal care.Hormonal disturbances merit further attention in KTR. Endocrinological investigations in KTR, although readily available, are not routinely performed. Furthermore, result interpretation is cumbersome, as little is known about the specific hormonal changes and the timeline of their occurrence after kidney transplantation compared to the pre-transplantation period.This manuscript aims to review the main thyroid, sex hormones and cortisol abnormalities in KTR compared to CKD, thus drawing attention to an enhanced partnership between the nephrologist and the endocrinologist in this clinical setting. Many endocrinological abnormalities seen in CKD improve in KTR, but they usually do not disappear completely. Therefore, discussing endocrinological abnormalities in CKD and kidney transplantation together can help clinicians gain a better understanding of the pathophysiology, natural evolution, risks and challenges associated with the management of thyroid, gonadal and adrenal disorders after kidney transplantation.We searched the PubMed electronic database for articles published in the past 20 years (from January 2002 to December 2022) using the keywords “thyroid hormones”/“thyroid”, “sex hormones”/“testosterone”/“estrogen”, “cortisol”/“adrenal” and “kidney transplantation”. Original articles that reported thyroid hormone levels and/or thyroid ultrasound features, sex hormone and cortisol levels in KTR were included. Studies evaluating sex hormones in women included only those referring to premenopausal women for accuracy. Studies reporting data in KTR returning to dialysis or following hormonal substitution therapy were excluded.In addition, data regarding similar changes in CKD and dialysis patients were also included, if significant. Relevant references from the selected articles were also searched manually.Thyroid hormones regulate renal structure and hemodynamics, glomerular filtration and water balance . Early aWhile hypothyroidism impacts overall growth in animal models, hyperthyroidism seems to be more selective upon the heart, where it causes cardiac hyperplasia in developing rats . In humaOn the other hand, CKD patients may experience disturbances in the regulation of the hypothalamic–pituitary–thyroid axis and, thus, kidney dysfunction is frequently associated with alterations in thyroid function tests ,15. Adva2 in large cohort studies, such as the Third National Health and Nutritional Examination Survey (NHANES III) [2 was associated with two-fold increased odds of having TSH above the upper limit of normal compared to an eGFR ≥ 90 mL/min/1.73 m2 [2 decrease in the GFR increases the risk of hypothyroidism by 18%, independently of comorbidities [The prevalence of subclinical or overt hypothyroidism increases with advancing CKD. CKD stages 4 and 5 were associated with two-fold and three-fold higher odds, respectively, of having thyroid dysfunction in the study of Khatiwada et al. . The thyNES III)  or more NES III) , and up NES III) . More thNES III) . Additio/1.73 m2 . More sobidities .While TSH is considered the most reliable and specific marker for primary hypothyroidism in the general population, this is not necessarily true in CKD patients. Changes in TSH values are common in CKD and do not always reflect thyroid disease, especially in uremic patients. These changes are mainly due to TSH and TRH diminished clearance, abnormal glycosylation of TSH and a reduced response of the pituitary to TRH stimulation. However, TSH is the last thyroid parameter that changes with progressive kidney dysfunction, and it is still more robust when facing non-thyroidal illness . A recenDialysis is also associated with a higher prevalence of hypothyroidism, thyroid nodules and low T3 levels . The preLow T3 levels were proposed as a predictor of all-cause mortality, but the association was lost after adjusting for hemoglobin, dialysis vintage and history of cardiovascular disease (CVD) in a cohort of 114 HD patients . FT3 levA large cohort study performed by Rhee et al.  also fouLow T3 syndrome was found to be persistent after kidney transplantation. In addition, a low pre-transplantation T3 is associated with poor survival of the graft, probably also related to the previous time spent on dialysis ,30. FuncSchairer et al.  found anA positive association was described between serum creatinine and thyroid volume, with the regression of goiter mirroring improving graft function during the early post-transplantation period ,33; a neOn the other hand, administering T3 early in the course of delayed graft function (DGF) for acute tubular necrosis in KTR had no effect on graft function at a one-year follow-up, despite KTR exhibiting typical “euthyroid sick syndrome” .The early drop in TSH, FT3 and FT4 levels  ) by fine needle aspiration biopsy in 5 out of 44 kidney allograft recipients . A Koreap < 0.05 in the study of Sobki et al. [Serum calcitonin is frequently assessed in clinical practice when facing thyroid nodules, especially if suspicious or the patient is young. The kidneys play a significant role in the degradation of calcitonin, and thus calcitonin increases in kidney dysfunction, with levels above 10 pg/mL being common in dialysis patients . Studiesi et al. ), especii et al. ,45. The Low T3 syndrome may persist after kidney transplantation due to corticosteroid administration, inflammation or prolongation of the uremic milieu.Pre-transplantation FT3 levels may help identify patients at risk for graft failure.Periodical evaluation of thyroid function in KTR is recommended, together with ultrasonographic surveillance, due to chronic immunosuppression and associated risk of malignancy.Primary hypothyroidism should be pronounced only when facing elevated TSH levels accompanied by clearly low free T4 concentrations.Key points:Estrogens exert multiple beneficial renal effects for preventing CKD. Estradiol protects against TGF-β-induced transcription of the type IV collagen gene and also inhibits TGF-β-mediated mesangial cell apoptosis ,47. FurtBy contrast, testosterone activates the RAS system, while dihydrotestosterone upregulates the expression of type 1 angiotensin receptors ,53. TestAs such, women seem more protected against renal disease progression compared to men due to different glomerular hemodynamics, a direct protective effect of estrogens on cellular processes and, finally, less lifestyle risk factors .A disturbed hypothalamic-pituitary–gonadal axis is frequently encountered in CKD. In men, testosterone deficiency is a common issue in advanced CKD and dialysis. GnRH pulses are hampered in CKD due to uremia and hyperprolactinemia, leading to a loss of the physiological secretion of luteinizing hormone (LH) and secondary hypogonadism. The feedback exerted by testosterone upon the gonadotropin secretion in CKD is also lost due to uremia, resulting in elevated basal LH levels. These elevated levels may, however, include abnormal LH isoforms with less bioactivity due to posttranscriptional changes. Furthermore, Leydig cell resistance to LH action may also be encountered ,57.Despite experimental data showing the detrimental effects of testosterone on renal biology, low testosterone concentrations in male CKD patients are paradoxically associated with increased morbidity, mortality risk (mainly due to CVD) and metabolic syndrome, but they are also associated with altered body composition with further loss of muscle mass, osteoporosis and anemia . In a crIn a larger Canadian cohort study, low testosterone levels  was associated with a higher all-cause mortality in adjusted analysis and with a lower quality of life. The trend toward an association between low testosterone and cardiovascular events was lost after adjusting for age . In the The mechanisms involved in secondary hypogonadism in women are similar to those seen in men. Progesterone deficiency is prominent in the second part of the menstrual cycle, while estradiol levels are usually low, partly due to hyperprolactinemia. The absence of cyclic release of GnRH leads to anovulation . As a coA recent meta-analysis raises awareness toward a lack of sufficient data regarding the relationship between hypogonadism and cardiovascular risk in female CKD patients, since 12 out of the included 17 studies investigated only male patients. A U-type relationship between estradiol levels and all-cause mortality has been reported in HD, with both low and high levels being associated with a high mortality risk and also with CVD mortality risk in some studies .Sex hormone concentrations are restored in both sexes approximately 4–6 months after a successful kidney transplantation ,66. HoweMajzoub et al.  reportedLeydig cell dysfunction is generally rapidly corrected after kidney transplantation, with normal LH concentrations together with prolactin normalization reported three months after kidney transplantation in KTR men treated with tacrolimus, mycophenolate mofetil and steroids . HoweverGonadotrophin secretion is also restored in women after successful kidney transplantation, while prolactin returns to the values seen in healthy controls in some ,73, but In their study, Pietrzak et al.  proposedRestoration of gonadal function takes place soon after successful kidney transplantation.Despite testosterone and estradiol concentrations returning toward the normal range, fertility is not completely restored.Male KTR still exhibit low sperm quality and low inhibin B levels.Female KTR still exhibit abnormal uterine bleeding and anovulatory cycles.Steroid immunosuppressive regimens may partially contribute to infertility on the long-term and should be balanced in female KTR planning pregnancy.Hormonal contraception, preferably offered by the transdermal route, is beneficial for correcting bleeding abnormalities and improving quality of life in female KTR.Testosterone therapy may help improve anemia and hypogonadal symptoms in KTR with low serum testosterone.Clinicians should discuss hypogonadism-related health problems with their KTR patients, as immunosuppressive regimens have a detrimental impact upon gonadal health.Sirolimus has a worse impact upon gonadal function compared to calcineurin inhibitors.Key points:Cortisol levels follow a circadian rhythm and vary significantly throughout the day, with serum concentrations peaking in the morning, declining during the day and reaching a nadir at midnight. The hypothalamic–pituitary–adrenal (HPA) axis is one of the body’s adaptive mechanisms to stress. Morning cortisol may increase in response to various stressors, and thus an increased 8 am plasma cortisol does not always reflect pathological hypercortisolism .Studies reporting morning blood cortisol in CKD patients mainly report the absence of significant changes even in dialysis patients ; howeverDue to the physiology of cortisol secretions, multiple tests are necessary for the screening of true hypercortisolism: late-night cortisol, 24-h urinary free cortisol (UFC) and a low-dose Dexamethasone inhibition test. CKD and ESRD patients have higher evening cortisol levels both in the blood and saliva, suggesting that the decline of cortisol over a 24-h period is attenuated ,90. SaliDespite an increased 24-h exposure to cortisol, UFC does not increase due to reduced renal clearance of cortisol and is not, therefore, a reliable test for hypercortisolism screening in CKD ,92. The Adrenocorticotropin (ACTH) blood concentrations also have the tendency to increase in the more advanced stages of CKD, where metabolic acidosis, inflammation and increased stress related to diminished quality of life become apparent .The high dose 8 mg Dexamethasone was proposed to be more accurate when differentiating tumoral hypercortisolism from non-neoplastic hypercortisolism in CKD. This test is usually used to distinguish between pituitary corticotroph adenoma and ectopic ACTH syndrome in the general population. However, the literature data report adequate suppression to less than 1.8 ug/dL for blood cortisol after the 8 mg dexamethasone test in CKD if Cushing disease is absent. Analyzing the circadian rhythm of both cortisol and ACTH performs better in CKD compared to nadir cortisol levels alone .Cushing syndrome, as well as subclinical hypercortisolism, are associated with increased cardiovascular and metabolic risk in the general population . WhetherOn the other hand, diagnosing adrenal insufficiency in dialysis patients is a difficult task, due to falsely elevated cortisol levels. Ohashi et al.  proposedData reporting the function of the HPA axis in KTR are very scarce, probably mainly due to the fact that these patients are exposed to various glucocorticoid immunosuppressive regimens. Long-standing KTR following chronic corticosteroid treatment show a suppressed HPA axis demonstrated by reduced 24 h UFC concentrations that are independently associated with the presence of metabolic syndrome: hypertension, dyslipidemia, central obesity and diabetes  Table 3Table 3.Chronic low-dose prednisolone treatment (5 mg or 7.5 mg prednisolone/day for six months or more) is associated with a suboptimal response to the 250 µg ACTH test in almost half of the KTR that underwent testing in the study of Valentin et al. .Older studies proposed the 1 µg ACTH test in order to test for various degrees of adrenal insufficiency prior to steroid withdrawal : 60% of In 63 KTR following long-term (mean 36 months) prednisone therapy, one third (31%) tested as suboptimal at the low-dose ACTH stimulation test, while morning cortisol was clearly suppressed in 14% of the patients. Graft function slightly decreased by approximately 5% after step-wise steroid withdrawal and it was more pronounced in symptomatic patients  . This maTherefore, studies evaluating the adrenal reserve in KTR advocate for endocrinological evaluation before steroid withdrawal and the use of rescue glucocorticoid supplementation during stress or acute illness if borderline results are found ,104. AbnAccording to the meta-analysis of Broersen et al. , there iRegarding adrenal reserve testing, recommendations vary: if after withdrawal signs and symptoms occur, and if morning cortisol is between 3 and 15 µg/dL, a short Synacthen test (SST) should be performed ; the samAdrenal insufficiency may occur in KTR despite low-dose prednisolone therapy (5 mg/day): symptomatic  adrenal insufficiency due to cytomegalovirus infection was reported five months after renal transplantation in a patient with basal serum cortisol of 4 µg/dL that remained under 10 µg/dL after stimulation with 1 mg tetracosactide. Symptoms improved when the daily dose was increased to 10 mg/day .Therefore, increased alertness regarding the potential occurrence of adrenal insufficiency after steroid withdrawal in KTR is needed. Patients should be informed about the signs and symptoms of hypoadrenalism. Measuring morning serum cortisol either 24 h after the last glucocorticoid dose, or if specific symptoms occur, may be an option for KTR being treated with steroids for more than four weeks prior to withdrawal, as well.Besides the suppressed HPA axis, the cortisol/cortisone ratio is also reported to be altered in prednisolone-treated KTR. The latter exhibit increased urine cortisol/cortisone ratio, which is inversely related to kidney function, thus suggesting a decreased activity of the type 2 11β-HSD in the kidney. The increased cortisol/cortisone ratio was also linked to an increased mortality risk from infectious causes, independently of the prednisolone daily dose or kidney function . More soHPA axis suppression usually occurs in KTR due to chronic glucocorticoid treatment.The HPA axis may be suppressed even with low-dose glucocorticoid regimens.Patients should be informed about the signs and symptoms of hypoadrenalism that may occur after steroid withdrawal.Measuring morning serum cortisol either 24 h after the last glucocorticoid dose, or if specific symptoms occur, may be an option for KTR. Performing the SST should be taken into consideration if indeterminate 8 am serum cortisol values  are found, according to existing data.Symptomatic adrenal insufficiency may exceptionally occur in KTR due to various conditions despite low-dose glucocorticoid treatment.Chronic glucocorticoid administration increases the risk for metabolic syndrome, while an increased mortality from infection is seen in those with increased cortisol/cortisone ratio.A slight reduction in the eGFR may occur after glucocorticoid withdrawal.Key points:Thyroid, sex hormones and cortisol abnormalities are common in CKD patients, tend to worsen in ESRD and dialysis patients, but are only partially restored after successful kidney transplantation. While the tendency is toward augmented blood levels of the aforementioned hormones, their increase is a mirror of kidney dysfunction rather than a truly pathological process. However, long exposure to these hormonal changes may have a detrimental impact upon the patients’ overall health .Clinicians should be more aware of the gonadal status of their KTR patients, as women still experience abnormal uterine bleeding after successful transplantation, while refractory or persistent anemia, together with specific hypogonadal symptoms in a male KTR, should prompt testosterone measurement and supplementation if needed. A thyroid ultrasound is advisable after a kidney transplantation, as a higher incidence of thyroid nodules and papillary thyroid carcinoma are reported. Finally, evaluating the adrenal function prior to glucocorticoid withdrawal in KTR is prudent.


Obesity, especially abdominal obesity, increases the prevalence of metabolic and cardiovascular disease (CVD). Fibroblast growth factor 21 (FGF21) has been identified as a critical regulator playing a therapeutic role in diabetes and its complications. This study aims to evaluate the relationship between serum FGF21 levels and body shape parameters in patients with hypertension (HP) and type 2 diabetes mellitus (T2DM).Serum FGF21 levels were determined in 1,003 subjects, including 745 patients with T2DM, and 258 individuals were selected as a healthy control in this cross-sectional study.p < 0.001], and levels in both of these two groups were significantly increased compared with that of healthy control . These differences were also observed in body shape parameters, including weight, waistline, body mass index (BMI), body shape index (ABSI), and the percentage of abdominal obesity. Serum FGF21 levels in T2DM patients were positively correlated with body shape parameters, including weight, waistline, neck circumference, BMI, ABSI, percent of abdominal obesity, and triglyceride, while negatively with estimated glomerular filtration rate . The significance remained stable when adjusted for age and T2DM duration. In addition, both serum FGF21 concentrations and waistline were independently associated with HP in T2DM patients after the adjustment for risk factors . ROC analysis for FGF21 levels of 745 patients with T2DM identified 411.33 pg/ml as an optimal cut-off point to predict HP, with a sensitivity and specificity of 66.0% and 84.9%, respectively.Serum FGF21 levels were significantly higher in T2DM patients with HP than those without [534.9 (322.6–722.2) vs. 220.65 (142.8–347.55) pg/ml, FGF21 resistance occurs in patients of HP in T2DM, and positively correlates with body shape parameters . High levels of FGF21 may be a compensatory reaction to offset HP. These mRecently, fibroblast growth factor 21(FGF21) has been considered as a novel metabolic risk factor, which is closely associated with a variety of metabolic and CVD , 8. Circβ-blockers, angiotensin-converting enzyme inhibitors, diuretics, etc., FGF21 not only improves blood pressure but also has the function of protecting the cardiovascular system and alleviating vascular injury, showing the potential of FGF21 in the development of drugs for dealing with HP. On the one hand, FGF21 promotes the development of HP, possibly through fluid retention. FGF21 is a critical mediator in PPARγ signal transduction. Mice with FGF21 gene knockout showed PPARγ signal defects and resistance to significant side effects (such as weight gain and edema) of rosiglitazone (PPARγ agonist) . By using FGF21 gene knockout mice and overexpressed mice, we confirmed the effect of FGF21 on lowering blood pressure and protecting the cardiovascular system. FGF21 protects against Ang II-induced HP and vascular impairment by fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels through the activation of the ACE2/Ang-(1–7) axis. It is a medium for multiple organs and systems to resist pathological changes jointly . In addiagonist) . On the s system . HoweverFor the superior efficacy of FGF21in handling metabolic diseases, including HP, thus improving FGF21 resistance is a new idea for the treatment of obesity and related metabolic disease. In the general population, FGF21 level has been confirmed to be closely associated with metabolic syndrome, including obesity, non-alcoholic fatty liver disease, HP, and diabetes . Complex2.2.1.2 (kg/m2), a body shape index (ABSI) was calculated as waistline/(BMI2/3height1/2) (m11/6kg−2/3), overall obesity was defined by BMI ≥ 28 kg/m2, and abdominal obesity was defined by waistline ≥ 90 cm for men and ≥85 cm for women. A complete history and thorough physical examination were obtained in each case. BP was measured using a mercury sphygmomanometer after a 10 min rest. Waistline to hipline ratio (WHR), headline, and neckline was also measured at baseline. In addition, routine laboratory tests were done. This study was performed with the approval of the Human Ethics Committee of Ruian People's Hospital, and written informed consent was obtained from each participant.A total of 745 patients diagnosed with T2DM participated in this cross-sectional study recruited from July 1, 2019–January 28, 2023 from the Diabetes Center of Ruian People's Hospital. T2DM was diagnosed according to the criteria of DM proposed by the World Health Organization in 1999: Symptoms of diabetes, a blood glucose level of 11.1 mmol/L at any time, a fasting blood glucose (FPG) level of 7.0 mmol/L or a 2-hour blood glucose level of 11.1 mmol/L . Serum FGF21 levels and other baseline characteristics were compared between T2DM patients with and without HP. Univariable and multivariable logistic regression analysis was used to identify factors most closely associated with HP. Furthermore, correlation analysis was performed to examine the determinant factors of circulating FGF21 levels in patients with T2DM.Additional laboratory data and detailed history of physician-diagnosed disease, drinking, and smoking histories were obtained and evaluated through questionnaires. Blood was drawn following an 8–12 h period of fasting for determination of FPG, hemoglobin A1c (HbA1c), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c). The chronic kidney disease epidemiology collaboration formula was used to calculate the estimated glomerular filtration rate (eGFR). Serum samples obtained from all participants were stored in −80°C preparing for further detection. Human serum FGF21 levels were quantitatively determined 2.3.t test, one-way ANOVA followed by Tukey's HSD test or the nonparametric Kruskal-Wallis test followed by Dunn's test, and χ2 test was used to determine differences between groups. Variables with statistical significance between groups and variables which were biologically likely to be related to HP were all included to determine independent factors of HP in T2DM, using univariable and multivariable logistic regression analysis. In addition, pearson correlation and partial correlation analysis adjusted for age and T2DM duration were applied to identify the association of FGF21 and body shape parameters or biochemical parameters. The predictive value of FGF21 against HP was determined with ROC curves. Two-sided p values < 0.05 were considered statistically significant.All statistical analyses were performed using Statistical Package for Social Science Version 26.0 . Continuous data were expressed as mean ± standard deviation or median with interquartile range. Categorical data are expressed as percentages. Independent-sample 3.3.1.p < 0.001]. Moreover, T2DM patients with HP expressed at the FGF21level of more than twice as high as those without . There was no statistically significant difference between patients of diabetes with or without HP on height, significant differences were only found when compared with healthy, however, there was a gradual increase in weight in these three groups , so was BMI . WHR was equal to waistline/hipline. The mean hipline of the patients of diabetes with or without HP was nearly equal ; interestingly, however, both waistline  and WHR  were increased in diabetes with HP as compared to those without. Similarly, elevated ABSI (0.082 ± 0.004 vs. 0.08 ± 0.003 m11/6kg−2/3) and neckline (38.29 ± 3.17 vs. 37.40 ± 3.79 cm) were found in these T2DM individuals with HP compared with those without . In addition, the prevalence of abdominal obesity was significantly higher in diabetes with HP  than that of diabetes alone. No significant difference was found in headline between the two groups . Although there was a significant difference in anti-diabetic drugs use . These data suggest FGF21 resistance occurs in diabetes, especially those with HP.In sum, FGF21 is increased, and a worse of body shape parameters, including elevated weight, waistline, neckline, BMI, ABSI, and WHR, was found in these T2DM individuals with HP compared with those without this complication . However, serum FGF21 was negatively correlated with eGFR (p < 0.001). After the adjustment for age, the significance remained stable, with a bit of change in neckline (p < 0.05) and ABSI (p > 0.05). Furthermore, the correlation of serum FGF21 with these parameters, except for ABSI remained significant even after the adjustment for age and T2DM duration . These data suggest that serum FGF21 levels are closely related to body shape and HP in patients with T2DM.The prevalence of abdominal obesity is high, and an increased serum level of FGF21 was observed in HP individuals with diabetes . Is therduration . To clar3.3.p < 0.05 in models 1–2.To investigate whether FGF21 is related to the morbidity of HP in patients with T2DM, we first explored the risk factors of HP in these T2DM subjects. As shown in p < 0.001) in the total sample (p < 0.001), moreover, the sensitivity and specificity of combined detection of FGF21, waistline and age were significantly higher than those of single detection. As an optimal cutoff point, high risk LnFGF21 value of 6.02 pg/ml  was determined with a 66.0% sensitivity and 84.9% specificity. Taken together, serum FGF21 levels (411.33 pg/ml or more), waistline (87.75 cm or more), and age (53.5 year or more) may be good predictors for the incidence of HP in patients with T2DM.In addition, Receiver operating characteristic (ROC) curve analysis and 95% confidence interval (CI) were applied to judge the value of FGF21 on HP high-risk score. In this study, the area under the curve (AUC) was found to be statistically significant (AUC: 0.789, 95% CI: 0.756–0.823, l sample . Further4.Patients with diabetes are most likely to have a high risk of CVD, which is the leading cause of death among patients with T2DM. HP is a cardiovascular syndrome with elevated systemic arterial pressure as the primary clinical manifestation. Our previous animal research demonstrated that FGF21 plays an essential role in regulating blood pressure . HoweverNevertheless, the causal relationship and potential effects between HP and FGF21 need to be better clarified. HP may be related to the improvement of insulin resistance and the influence of FGF21 on the afferent pathway of stress reflex. In fructose-induced hypertensive SD rats, FGF21 could improve the absorption and utilization of glucose, improve insulin resistance, increase the activity of NO synthase, stimulate endothelial cells to release strong vasodilator NO, improve endothelial function, and ultimately significantly reduce the SBP of SD rats . Our preIt was firstly reported that the elevated serum FGF21 level was independently associated with HP in American community residents according to a prospective open cohort study , with thPrevious studies have shown that body shape is closely related to HP , and serBody shape parameters including weight, waistline, neck circumference, BMI, ABSI, WHR, and the proportion of abdominal obesity increased significantly. FGF21, waistline, age, HbA1c, and eGFR are independent risk factors for T2DM complicated with HP, suggesting that elderly individuals with abdominal obesity should pay more attention to weight control, not only blood-sugar control, to prevent the occurrence of HP, thus reduced the risk of cardiovascular death in patients with T2DM at high risk for cardiovascular events.5.This study has several limitations. First, the term “FGF21 resistance” during human obesity, in which circulating FGF21 levels are elevated, has been controversial partly due to difficulty in delineating the physiological and pharmacological mechanisms of FGF21 , weight 6.In this study, we have confirmed that the risk factors of diabetes complicated with HP are closely related to body shape, the frequency of chronic complications of diabetes such as HP is high, and an increased prevalence of abdominal obesity was observed with higher serum level of FGF21, in other words, FGF21 resistance occurs in obesity patients in T2DM with HP. The changes in FGF21 level in different populations showed the protective function of FGF21 on the circulatory system, such drugs targeting FGF21 for treating CVD and metabolic diseases will be an excellent boon for cardiovascular patients.


Cardiovascular diseases, such as stroke and ischemic heart disease attributable to hypertension, are major causes of premature death in Japan and worldwide. Nevertheless, a low rate of blood pressure control among hypertensive patients has been observed in most countries. No previous studies have explored the effectiveness of physician visits among hypertensive patients in Japan.To quantify the effects of persistence in physician visits among hypertensive patients, we evaluated the causal effect of physician visits on the health of hypertensive patients. We used 16 waves of nationally representative longitudinal data drawn from the Longitudinal Survey of Middle-aged and Elderly Persons in Japan (2005–2020). To examine the causal effect of physician visits on patients’ health outcomes, we used inverse probability treatment weights and doubly robust estimation and obtained the estimates of the average treatment effects on the treated (ATETs).Covariates were well balanced among patients who had physician visits during the past two consecutive years . The estimated ATETs suggest that three consecutive years of physician visits had a negative impact on poor subjective health. Furthermore, patients without habitual exercise tended to not continue physician visits and perceived poor subjective health.Although the impact of frequent physician visits on blood pressure stability remains uncertain, regular appointments every 30 days can be effective for individuals with hypertension, particularly if they receive continuous instruction from their family physician. Because it is important for physicians to strengthen hypertensive patients' blood pressure control, promoting consecutive physician visits to hypertensive patients with diabetes, lower educational attainment, or smoking habits is needed. Cardiovascular diseases (CVDs), such as stroke and ischemic heart disease attributable to hypertension, lead to premature death in Japan and worldwide –3. HyperThe control rate of hypertension among hypertensive patients taking antihypertensive medication had an upward trend from 1980 to 2016 in Japan , 8, a reAs no prior studies have explored the effectiveness of physician visits among hypertensive patients in Japan, we must pay attention to patients whose hypertension are poorly controlled and evaluate the causal effect of physician visits on hypertensive patients’ health. Increased continuity of care (COC) with doctors was associated with lower mortality rates . The quaIn general, those with a higher family income have a higher life expectancy and better self-assessed health (SAH). Measures of socioeconomic status (SES), such as income, education, and occupation, are known to correlate with mortality and morbidity , 17. A pWe used longitudinal data over 16 consecutive years (2005–2020) obtained from the Longitudinal Survey of Middle and Elderly Persons (LSMEP) by the Japanese Ministry of Health, Labor and Welfare (MHLW). The LSMEP takes a nationally representative sample of the near elderly in Japan. The samples for this survey were randomly selected through a two-stage sampling procedure. First, 2,515 districts in 2005 were randomly selected from all 5,280 districts covered by another nationwide survey called “Comprehensive Survey of Living Conditions” conducted by the MHLW in 2004. Second, 40,877 respondents aged 50–59 years as of October 30, 2005 were randomly chosen from each selected district. A total of 34,240 individuals responded to the first survey wave (response rate: 83.8%), whereas 32,285 participants returned the questionnaires for the second wave (response rate: 92.2%). Data were collected through a combination of interviews and self-administered questionnaires. The LSMEP collects information about family situations, health status, and employment status. In the second-wave survey, the LSMEP asked about the educational attainment of both the respondents and their spouses.When examining the causal relationships between treatment and outcome and obtaining an unbiased assessment of the average treatment effect (ATE), researchers must pay attention to the differences in baseline characteristics between treated and untreated individuals. To account for such differences, propensity score analysis can be used. Propensity score matching is used to estimate the average treatment effects on the treated (ATETs) because the propensity score defined by  is the pRobins and Ritov proposed the doubly robust estimation that combines two approaches to estimate the causal effect of treatment on an outcome . As longith individual (wi) is defined asi denotes whether the ith individual was treated (= 1) or not (= 0) and ei denotes the propensity score. Here, using ei as the propensity score in the weighting estimator leads to an estimator of the average treatment effect [i is 1 for a treated participant and (1 − Ti)/(1 − ei) for a control participant.To derive the doubly robust estimator, we followed the three-step approach. First, inverse probability treatment weights (IPTW) were calculated as the inverse of the conditional probability. The IPTW creates a synthetic sample in which the distribution of the measured covariates is independent of the treatment assignment. In Eq. , the weit effect . By restSecond, we used the IPTW in multivariate analysis and estimated the weighted regression models of the outcome for each treatment level. Third, the means of the treatment-specific predicted outcomes were computed.c denote the proportions of dichotomous variables in the treated and control groups, respectively.To evaluate the propensity score distribution, the standardized difference was used to compare the mean of the continuous and binary variables between the treatment and control groups. In Eq. , the staA standardized difference < 0.1 indicates a negligible difference in the mean or proportion of a covariate between the treatment and control groups . When thThe proportion of the total sum of 16 consecutive respondents to the subjects who responded to the second-wave survey in 2006 was approximately 53%. This implies that almost half of the respondents in the 2006 survey dropped out.The samples in this study were classified as having hypertension based on a doctor’s diagnosis. Hypertension was defined as a systolic blood pressure (BP) ≥ 140 mmHg, a diastolic BP ≥ 90 mmHg, or use of antihypertensive medication. The control rate of hypertension was defined as the proportion of those with a systolic BP < 140 mmHg and a diastolic BP < 90 mmHg among hypertensive patients taking antihypertensive medication .Table The mean SAH among the hypertensive patients who continued physician visits during the past two consecutive years (HPCPV) was approximately 3.948, which was larger than that of the comparison group (3.882). In contrast, the prevalence of poor SAH  in HPCPV was lower than that in hypertensive patients without continuing physician visits 0.058 < 0.072). The proportion of having cancer, diabetes, heart diseases, lipidemia, and stroke among elderly with hypertension was larger than that in the comparison group . However, the mean SAH among the elderly with both diabetes and lipidemia was < 3.5 . Thus, we must pay attention to diabetes and lipidemia when splitting hypertensive patients.Table To identify the determinants or potential confounders of physician visits among hypertensive patients, assuming the dependent variable distributed as Bernoulli, we estimated three generalized linear models with a logit link function by classification. Table We used patients who had physician visits during the past two consecutive years  and estimated the SAH function. Because variables that were present after treatment assignment should not be included in the propensity score model, we used lagged lifestyle variables. This specification satisfied the balance test after matching. Table Table Noncommunicable chronic diseases (NCDs) with hypertension and diabetes as prominent example, continue to shape entire morbidity landscape in industrialized aging nations ranging from Japan to Europe , 30. IncThe estimated ATETs suggest that three consecutive years of physician visits had a negative impact on poor subjective health. The results also showed that (1) patients without habitual exercise tended not to continue physician visits and perceived poor subjective health; (2) having diabetes or lipidemia had negative effects on physician visits among the patients who had physician visits during the past two consecutive years. The former result coincides with evidence that individuals with regular physical activities (RPA) exhibit greater persistence of latent health stock (LHS) than individuals without RPA . BecauseAlthough the impact of frequent physician visits on blood pressure stability remains unclear, it appears that physician visits that occur less frequently than twice a month or with intervals longer than 40 days may not be effective for hypertensive patients. To maintain stable blood pressure in hypertensive patients, receiving continual instruction from their family physician is important. The relatively larger impact of the patients' heterogeneity may be attributed to their physician visits . To ensuIn Japan, the duration of doctor consultations over the past year was found to be positively associated with PSAH among middle-aged individuals, regardless of gender . HoweverWhen comparing two groups of hypertensive patients, it is important to consider that selection bias could be associated with imbalanced covariates among those who did not continue physician visits in the past two years. Lower continuity of care might be a result of complications from lifestyle diseases, such as neurological symptoms in hypertensive patients with diabetes or other chronic conditions. As a result, there could be significant heterogeneity in the selection of physician visits among hypertensive patients. Researchers should account for the magnitude of selection bias when measuring the true positive treatment effect . In futuHigh COC with doctors had a negative impact on poor subjective health of hypertensive patients. Although the impact of frequent physician visits on blood pressure stability remains uncertain, regular appointments every 30 days have shown effectiveness for hypertensive patients when accompanied by continual instruction from their family physician. In order to enhance blood pressure control in hypertensive patients, it is crucial for physicians to promote consecutive physician visits, particularly for those with comorbidities such as diabetes, lower educational attainment, or smoking habits.


Minoritized communities including refugees are at an increased risk of poorly controlled hypertension. Evidence indicates that self-measured blood pressure monitoring (SMBP) is an effective method to improve blood pressure control in patients with hypertension. However, it has not been studied among refugee populations. The objective of this study is to examine barriers and facilitators to SMBP among Arab refugees resettled in the United States (US) with diagnosed hypertension.A total of 109 participants were recruited through a Federally Qualified Health Center system that is a major provider of healthcare to refugees in San Diego, California. Participants completed a questionnaire and were interviewed using in-depth, semi-structured interviews. Interviews were transcribed and translated, and data were coded using inductive thematic analysis and organized based on the theory of care-seeking behavior.Several barriers to engaging in effective SMBP monitoring were identified. Clinical and sociodemographic barriers included reliance on public monitors and poor hypertension literacy. Psychosocial barriers of affect, norms, and habits included fear and anxiety from hypertension, cultural stigma of illness, and conditional SMBP with symptoms, respectively. Utility psychosocial barriers included lack of SMBP prioritization in treatment and perceived inaccuracy of home monitors. Family members’ support with home monitoring served as an important facilitator to SMBP.There are several barriers to effective SMBP among the US-resettled Arab refugee population that may reflect unique cultural and care-seeking behaviors. Tailored public health and clinical interventions are needed to support refugee patients and providers to improve hypertension self-management behaviors for this unique population. Hypertension is one of the leading preventable risk factors for all-cause mortality and one of the most important modifiable risk factors for coronary heart disease and stroke –3. GlobaRacial and ethnic disparities in hypertension rates and outcomes in the US have been well documented in the literature, however, such studies rarely analyze Arab Americans as a distinct racial/ethnic group of interest –10. VeryRisk for cardiovascular disease increases with even small increases in blood pressure , thus, eMultiple studies have demonstrated SMBP leads to therapeutic compliance and improved blood pressure control –25. For With increasing forced displacement and resettlement of refugees in the US, it is imperative to understand this population’s chronic disease self-managements, particularly among refugees from Iraq and Syria since the Centers of Disease Control and Prevention list hypertension as a priority health condition for these populations –31. Due This study is part of a larger investigation into refugee patients’ barriers to hypertension care and opportunities to improve self-management . The investigation was comprised of three sequential parts: (1) an initial interview with participants regarding their hypertension and self-management; (2) collection of home blood pressure readings after participants were provided a free Withings BPM Connect, an FDA-approved, cellular-connected home blood pressure monitor, and were instructed to maintain a blood pressure diary; (3) a follow-up interview regarding participants’ experience with the home monitoring. Our current study stems from part one of our larger investigation. Here, we employed an exploratory qualitative investigation into the beliefs, attitudes, and behaviors that facilitate or prevent SMPB among Arab refugees with hypertension. Applied thematic analysis was used in this study because of its inductive procedure that presents participants’ experiences as comprehensively and accurately as possible . This stParticipants were Syrian and Iraqi refugee patients with a diagnosis of hypertension at the Family Health Centers of San Diego (FHCSD), a Federally Qualified Health Center system that is a major provider for refugees in San Diego, CA. Inclusion criteria were: (1) having been diagnosed with hypertension ; (2) having a present or former refugee status; (3) being from Iraq or Syria; (4) living in San Diego for 3 months after recruitment date. Exclusion criteria were: (1) anyone under 21 years old; (2) those unable to provide informed consent.Recruitment occurred between April 2021 and April 2022. Our native Arabic-speaking investigators, including authors LB and BA, were trained to follow a standard operating procedure for recruitment and consenting processes in Arabic. They randomly selected potential participants to contact via phone from a list of eligible patients procured by the FHCSD. Interested participants were screened for inclusion and exclusion criteria over the phone and consented. A total of 109 participants completed this study.Data was collected through semi-structured, in-depth interviews and a questionnaire for demographics data . All invInductive thematic analysis was used to analyze the translated transcripts. Investigator triangulation was implemented by authors LB, BA, DAB, and NB who completed the analysis. LB and DAB trained BA and NB on qualitative analysis techniques. Using ATLAS.ti software, LB and BA independently reviewed and open coded a set of transcripts (n = 5) and met regularly to establish a codebook through an iterative process. The coders used the subjective assessment method to establish intercoder agreements . AnalysiOur study involved the following strategies to ensure trustworthiness: prolonged engagement, investigator triangulation, and thick description . We achiInformed consent was obtained by all participants. Participants had the right to withdraw from the study without penalty or loss of benefits to which they are entitled, and their data would be destroyed and not included in this study. The Institutional Review Board (IRB) at the University of California, San Diego approved this research .This study adopted the theory of care-seeking behavior developed by Lauver to explore factors that influence Arab refugees’ SMBP practices . This thAffect refers to emotions associated with care seeking including fear of a diagnosis or treatment. Utility encompasses the expectations and values about a certain outcome, reflecting the individual’s perception of the overall worth of care seeking. Norms include both social norms and personal norms. Habits refer to how an individual typically reacts to symptoms. Facilitating conditions are specific external variables that enable an individual to engage in care-seeking behaviors, for example, access to medications.The theory of care-seeking behavior claims that psychosocial variables can influence behavior either directly or in interaction with facilitating conditions. It also acknowledges that variables extrinsic to the theory such as clinical and sociodemographic factors can influence behavior, however, only through the identified psychosocial variables.This study used the theory of care-seeking behavior to organize the themes extracted from participant interviews to exhibit the interrelationships between the themes and their influence on SMBP.Data on demographics and blood pressure monitoring practices of participants is provided in Table Some participants shared that they do not own or have access to a blood pressure monitor at home. To overcome this barrier, they would access the public blood pressure monitor available at their local pharmacies. Although public devices were able to facilitate SMBP for some participants, others shared that measuring through public devices was not as feasible:There are always long waiting lines [at the pharmacy] and I feel like my blood pressure increases more just by waiting in line. .There is no privacy when measuring your blood pressure at the pharmacy; everyone is staring at your reading. .Sometimes I used to go to [a pharmacy] and use their public device. After the pandemic, they stopped so I had to stop. .Importantly, some participants shared how the COVID-19 pandemic impacted their public device use and SMBP:Before the pandemic, I used to use the pharmacy’s device to measure my blood pressure, but now I bought a device. .Many participants revealed that they do not know how to engage in SMBP and/or interpret their blood pressure readings. For participants who are motivated to monitor their hypertension through SMBP, most overcome this barrier by relying on family members and friends with stronger health literacy to aid them:My daughter is the one that helps me and measures [my blood pressure] for me. I do not know how to use the device. .I genuinely do not know how to use [my home device] and turn it on. I need to learn how. I am being transparent with you because I really want to learn since I can’t keep relying on my son to come and help me with it, he has his own busy life and schedule. .My neighbor helps me out when I need to measure my blood pressure since I do not know how to read the measurements… I do not measure it if she is not home to help me. [This bothers me] because [hypertension] is serious. I need to know when my blood pressure is high in case I need to be hospitalized as mentioned by my doctor. .For participants who depend on their social networks for overcoming this barrier to SMBP, some acknowledged the frustration in being unable to immediately measure their blood pressure when urgently needed:[Hypertension does worry me], of course. I heard that hypertension can cause heart attacks and other diseases. Therefore, I always measure my blood pressure and make sure I am managing it. And recently I have developed anxiety and I talked to my doctor about it. This anxiety stems from my fear of something happening to me and leaving my kids on their own. .A majority of participants shared that hypertension, and its consequences, are a source of worry. Most were specifically concerned about cardiovascular disease, hospitalizations, and death. Additionally, some of these worries were particularly concerned about the disease’s impact on family:These fears appear to be heightened among participants with a family history of hypertension or cardiovascular disease. Although this fear associated with hypertension is a negative affect, for some participants, this motivates SMBP:Yes, [hypertension] worries me a lot, especially when I go to the doctor’s appointment and I have already taken my medication, eaten well and still see that my blood pressure is high. It really surprises me. Then I go home and check it and it is still high. I keep checking and after 24 hours, it is still high. .For others, it can have the opposite effect:When I see that my blood pressure is high, this triggers my anxiety and then this anxiety causes my blood pressure to increase… So, I try my best not to increase my blood pressure, thus, I decided not to measure my blood pressure regularly. I get so scared to see a high reading, so I avoid measuring. .Usually, [I measure my blood pressure] once a month or once every three weeks, but when I see it is higher, I start drinking a lot of water and drinking lemons. After one hour, I measure it… or every two to three hours until it decreases all the way to normal. .This SMBP-associated anxiety can alternatively manifest as compulsive monitoring behaviors which can serve as a barrier to SMBP:I heard and read a lot about the disease and how people manage it; I have a friend who was diagnosed with hypertension, yet she never believed it and felt fine. I heard about how pharmaceuticals capitalize on hypertension medications and emphasize the selling of medications. So, I guess with all these conflicting ideas my worry about hypertension fluctuates if it ever existed in the first place. I even do my own research and I never find a solid answer about how to manage hypertension. Same thing goes for the discrepancies in doctors’ opinions. Every time a different doctor gives a different opinion about hypertension… I am not convinced with the disease. .On the contrary, a few participants were not worried about their hypertension, did not believe that they have hypertension, or did not believe in the disease itself. For example, one participant described their understanding of the disease:Most participants interpreted the variability in SMBP readings as a sign that the device is not accurate:Sometimes [my home device is inaccurate]. When I measure three times, I get different readings. .I am not fully convinced with the accuracy of my home device. However, when I am at the clinic and measuring my blood pressure over there, I always find discrepancies between my clinic readings and home readings. Usually, the clinic’s device gives higher readings. .There is a difference between the clinic’s reading and home reading. At the clinic, [my blood pressure] is usually higher, so I don’t know. Maybe it is because I get more anxious at the clinic. .A few participants attributed this variability in blood pressure measurements to a stressful clinical space:I do not [monitor my blood pressure] regularly… As I told you my home device is old, maybe with a new device I will start measuring more regularly. .The belief in the inaccuracy of their home devices serves as a barrier to SMBP:Others implemented different methods to circumvent the perceived inaccuracy of their home monitors:No [I do not measure regularly], only every two months because I have to go to the pharmacy to measure it. My home device is not accurate. .At this point, I know that my device is within two degrees of error from the clinic’s device, however, I still measure my blood pressure using my device and then I estimate my actual blood pressure by subtracting two points from my device’s reading. .Many participants do not find significant value from engaging in regular SMBP for their hypertension management. Compared to medication regimens or visits with providers, monitoring blood pressure at home is not as prioritized:I am not that invested in my blood pressure. I am already preoccupied with my diabetes and insulin shots. .I used to measure my blood pressure regularly, but when I started taking my medications, I stopped and started measuring my blood pressure every 15–20 days… [I used to keep a journal for my blood pressure] for about a month… Now I do not really [worry about checking my blood pressure]. .Whenever I am measuring [my blood pressure], it is mostly for reassurance. I count more on my medications [for my hypertension management]. .I was never [prescribed a device]. My husband had open heart surgery so that is why he was given one. [My doctor did not advise me to measure my blood pressure regularly]. .One reason for the low prioritization of home monitoring is a lack of encouragement from providers. When a participant revealed they did not measure their blood pressure regularly, investigators probed if their provider discussed their blood pressure monitoring:If my doctor tells me to measure my blood pressure I would do it, however my doctor does not tell me, and I feel normal. If I ever feel dizzy or have any other symptoms, I will definitely measure my blood pressure. .Others shared similar experiences:Some participants cited Arab cultural norms and its stigmatization of illness as a barrier to engaging in SMBP. Participants shared how they feel a social pressure to hide their illness and, consequently, neglect their health:Culturally as Arabs, we refuse to admit that we are sick, so we tend to neglect our health. .The fear comes from the cultural and social stigma perpetuated by our family members and friends. They might make you more anxious about your health and well-being by trivializing the importance of keeping up with one’s own health. I can commit to this intervention and the next day I will find my family and friends questioning my health and telling me undesirable jokes about being fixated with my own health. .The idea of taking my blood pressure in front of my kids and showing them that I am sick makes me feel uncomfortable. .This stigma of illness from Arab culture impacts even close familial relationships:Many participants described how they do not have an established SMBP routine. They only engage in SMBP when they experience symptoms they associate with hypertension, for example, headaches and dizziness:When I feel frustrated, or heating up, or agitated, I know that my blood pressure is high. This immediately prompts me to measure my blood pressure and take medications to manage it. .When [I sense my blood pressure] gets high, I start measuring it every three minutes and more frequently. .I do not [monitor my blood pressure regularly], just when I feel extra tired. Sometimes I check three to four times a day on the days when my symptoms are extreme. .This conditional SMBP appeared to increase in frequency proportionally to the severity of symptoms:For participants who do not engage in SMBP on a regular schedule, if they do not experience any hypertension symptoms, they are not motivated to monitor their blood pressure:When I feel better, I tend to forget to measure my blood pressure. .Participants shared how their family members play a role in their hypertension management as caretakers, providing help with blood pressure monitoring and medication adherence:Yes, [I need help measuring my blood pressure]. [My husband and I] alternate in helping each other measure our blood pressure. .When I get migraines, I ask my husband to measure my blood pressure at home. This prompts him to give me my hypertension medications. .My wife [reminds me to measure my blood pressure]. We also use the same device. .I do not [measure my blood pressure regularly], only when my wife pressures me to measure it. .Some participants revealed how encouragement from their loved ones results in SMBP:This study qualitatively examined barriers and facilitators to SMBP among Arab refugees who have resettled in the US. Analysis of the data yielded eight pertinent themes that were classified according to Lauver’s theory of care-seeking behavior . ClinicaFrom the themes on clinical and sociodemographic variables, it is evident that refugees might not have access to the tools needed to engage in SMBP . It is clear from this study’s demographics data – 61.5% have an annual income of less than $15,000 – and previous research that refugees settled in the US face many socioeconomic challenges, therefore securing monitors can be very challenging Table  46]. Ho. Ho46]. Results revealed anxiety and fear of hypertension as important psychosocial barriers to SMBP. Previous qualitative studies revealed conflicting results on SMBP-associated anxiety. In a study on SMBP among pregnant women, the researchers found that SMBP helped to manage the participants’ anxiety regarding their health during pregnancy . HoweverIn contrast to participants that are extremely worried about their hypertension, a significant proportion of participants  did not believe/did not know they have hypertension despite having a diagnosis from their providers Table . This laMany participants in this study were not interested in engaging in SMBP due to their belief in the inaccuracy of their home monitors. This finding supports previous research that found patients were concerned about the reliability of their home blood pressure devices when asked about SMBP . The conLearnings from this study highlight the importance of understanding the culture of minoritized communities in the clinical space. Many participants reported a cultural stigma that presents a barrier to effective SMBP and overall hypertension self-management. Similar findings are also cited in previous literature , 64. In Many of our participants reported not receiving the proper education or training to engage in effective SMBP. These findings confirm prior studies that found inadequate counseling and education from providers is a significant barrier to SMBP and overall hypertension self-management –69. ProvIt is important to investigate facilitators and barriers of SMBP among refugee patients from the providers’ perspectives. Current research shows that providers serving a refugee patient population feel they lack the proper education and tools – especially training on culturally appropriate and trauma-informed care – to support this minoritized group –74. A quWhile this study was not designed to focus on SMBP during a pandemic, it is important to note that data revealed how the COVID-19 pandemic negatively impacted SMBP for participants relying on public monitors. Clinicians, researchers, and leaders discussed similar findings on the exacerbation of blood pressure control inequities by COVID-19 . COVID-1To the best of the authors’ knowledge, this is the first study to investigate SMBP among the refugee population. The large sample size of 109 participants provides strength to this study. While this research has many strengths, there are a few limitations. There is the possibility of social desirability bias in the data collected from participants. However, participants were consistently encouraged by trained data collectors to share their authentic ideas and experiences in an attempt to reduce this bias. Additionally, there is a possibility of self-selection bias as this study was part of a larger investigation into refugee patients’ barriers to hypertension care and opportunities to improve self-management  where participants were provided a free home blood pressure monitor. Since participation was voluntary, it is possible that patients who face more barriers to SMBP may be more motivated to participate to receive a new device. It is also important to recognize that the participant group was limited to refugees in San Diego, CA, a region that may not be representative of refugee experiences in other US resettlement cities. However, the goal of this qualitative study is not to be representative of all refugee experiences; rather, this study seeks to capture and elevate the narratives of the participant population. Further research is needed to comprehensively investigate the diversity of the refugee population.The present study examines the barriers and facilitators to SMBP among US-resettled Arab refugees with hypertension in San Diego, CA. The data revealed this refugee population faces many challenges to engaging in effective SMBP practices including poor hypertension literacy and lack of encouragement from providers. This research confirmed prior studies that revealed similar barriers to hypertension self-management, especially among minoritized and medically underserved communities. Improved patient education and interventions to support self-management of hypertension are necessary for this refugee community. Additionally, further research engaging providers is needed to develop care models that foster strong patient-provider collaborations and improve health outcomes for refugee patients with hypertension.


The Lancet in 2008 described the global challenge of diabetes as the biggest epidemic of the 21st century due to the increased percentage of type 2 DM (T2DM) and gestational DM cases and the number of young patients with T2DM  [Diabetes mellitus (DM) is a metabolic systemic disease with a high rate of morbidity and mortality. An editorial article in The disease burden of DM is expected to increase in the next few years and decades. The Atlas of the International DM Federation  estimateIn parallel with the IDF data, the number of publications related to DM on PubMed.gov is constantly increasing. As of the 3rd of April 2023, there were 419,974 relevant publications. There were 59,185 references to DM cardiovascular (CV) complications, 34,299 for diabetic nephropathy (DN) and 33,414 for diabetic kidney disease (DKD).Age-standardized rates of DM-related complications, acute myocardial infarction, stroke and amputations have decreased in the last 15 years, but there has not been a corresponding reduction in the incidence of advanced chronic kidney disease (CKD) requiring renal replacement therapy (RRT). DKD continues to be the primary cause of end-stage renal disease (ESRD) worldwide.The definition and the epidemiology of DN have evolved substantially. The classical presentation includes a progressive rise in albuminuria and subsequently proteinuria . However2.Novel instruments different from albuminuria or the eGFR, such as urinary proteomics, are necessary for better early detection of DKD in individuals with a baseline eGFR above 60 mL/min/1.73 mFour decades ago, patients with DM attending nephrology outpatient clinics usually presented with advanced CKD, severe CV complications, advanced retinopathy or amaurosis or lower extremity amputations. However, DM patients frequently died due to uraemia or CV complications before reaching nephrology care.Multidisciplinary and multifactorial care has dramatically changed the panorama this ancient, catastrophic disease. The pillars of an integrated approach for the management of patients with DM and CKD are based on five classes of drugs:RAAS inhibitors are maintained as the first step of treatment for DM patients with hypertension and/or albuminuria or proteinuria.(1) The Angiotensin-Converting-Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (AIIRBs), such as captopril, irbesartan or losartan. These were offered in some studies  exploring the possibility of reducing albuminuria and the progression of renal damage. Thus, Sodium-glucose-transporter 2 (SGLT2) inhibitors. Their discovery led to the introduction of these drugs to the usual hypoglycaemic therapy for adequate control in subjects with DM. They also offer a safe nephro and CV protection profile. The studies of Zinneman et al. and Wanner et al. with empagliflozin, the CANVAS programme with canagliflozin and many others have showed the possibility of achieving an optimal hypoglycaemic management while allowing CV and renal protection.(2) The meta-analysis by Toyama et al.  gathered2 and a urinary albumin-to-creatinine ratio (UACR) of 200 to 5000 mg/g. These patients received dapagliflozin (10 mg once daily) or a placebo. After a median of 2.4 years of follow-up, a primary outcome event of a composite of a sustained decline in the eGFR of at least 50%, end-stage kidney disease or death from renal or cardiovascular causes occurred in 197 (9.2%) of patients (n = 2152) in the dapagliflozin group and 312 (14.5%) of patients (n = 2152) in the placebo group .The primary end-point was reduced in 44% (p < 0.001), and a composite of death from CV causes or hospitalization for heart failure was reduced in 29% (p = 0.009); 101 participants (4.7%) died in the dapagliflozin group and 146 participants (6.8%) died in the placebo group . The effects of dapagliflozin were similar in patients with and without DM.In a randomized clinical trial (RCT), Heerspink HL et al.  studied Glucagon-like peptide-1 receptor agonists (GLP-1RAs). This is a class of incretin drugs that can improve CV and renal events in DKD. These hypoglycaemic agents can be safely used without an increased risk of hypoglycaemia in various CKD stages in patients with an eGFR above 15 mL/min/1.73 m2. These agents are also able to prevent the onset of albuminuria and retard the decline in GFR in diabetic patients, allowing weight reduction and CV benefits.(3) Some RCTs considering exenatide, liragluide, lixixenatide, dulaglutide, albiglutide and semaglutide showed positive results in the prevention of new-onset proteinuria, (ELIXA with lixisenatide or LEADER with liraglutide), persistent proteinuria (SUSTAIN-6 with semaglutide) or REWIND (with dulaglutide).2 and UACR > 300 to <5000 mg/g or eGFR ≥ 25 to <50 mL/min/1.73 m2 and UACR > 100 to <5000 mg/g. The primary objectives of the FLOW study are renal end-points, and this RCT is projected to be finished by the end of 2024 [Semaglutide OW (1 mg vs. placebo) combined with RAAS inhibitors will be administered in an RCT to 3534 patients with DM meeting the following criteria: eGFR ≥ 50 to ≤75 mL/min/1.73 m of 2024 .Antagonists of Endothelin-1 (ET-1s). Some, but not all studies on ET-1s have proved their ability to reduce albuminuria and proteinuria. Atrasentan has been shown to be able to reduce the risk of kidney failure but at the expense of increasing patients’ risk for edema and heart failure. Proteinuria can be reduced in patients with severe CKD, but the risk of heart failure may be increased. Waijer SW et al. [p > 0.21). Patients in the highest UACR and lowest eGFR subgroups obtained the maximal benefit (p < 0.01). The risk of hospitalization due to heart failure was higher in the atrasentan group (HR 1.39). The relative and absolute risks of heart failure hospitalization were similar across baseline UACR and eGFR subgroups.(4) W et al.  assessedMineralocorticoid Receptor (MCR) antagonist, finerenone. Very recently, finerenone was used in a RCT as an antifibrotic agent. The phase III studies FIDELIO-DKD and FIGARO-DKD [p = 0.0018). The composite kidney outcome occurred in 5.5% (n = 360) of patients receiving finerenone and 7.1% (n = 465) of those receiving the placebo . Hyperkalaemia as the cause of treatment discontinuation was more frequently observed in patients receiving finerenone (1.7%) than those given the placebo (0.6%) [(5) The GARO-DKD  examinedo (0.6%) .2 or a UACR of 300 to 5000 mg/g and an eGFR ≥ 60 mL/min/1.73 m2. If we consider a decrease of >40% in the eGFR, a lower nonsignificant incidence rate was observed with finerenone compared with the placebo . However, if we take into account a reduction in eGFR of >57%, a decrease in HR of 23% was obtained (p = 0.041).In a post hoc analysis of FIGARO-DKD, Ruilope LM et al.  observedA more intense effect of finerenone was observed in patients with severely increased albuminuria. Improvements in UACR, eGFR slope and CV risk were evident in both subgroups provided with finerenone.The risk for kidney failure, atherosclerotic CV disease, heart failure and premature mortality is very high in patients with DM and CKD. As we previously established, recent clinical trials support new approaches to treating DM and CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 and the 2022 American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease both provide evidence-based recommendations. A joint group of ADA and KDIGO representatives reviewed and developed consensus statements using both guidelines to guide clinical care.On the basis of promoting a healthy lifestyle, consensus statements provide specific guidance on the use of RAAS inhibitors, metformin, SGLT2 inhibitors, GLP 1 RA and nonsteroidal MCR antagonists. The consensus provides clear recommendations for improving the clinical outcomes of people with diabetes and CKD .If we take into consideration all these achievements, in my opinion, we are situated in a new era with regard to the integrated management of patients with DM and CKD. The future is not coming; the future is already here. The standards for management and clinical practice guidelines are precise. We can combine many new molecules for an adequate management of patients with DM and CKD. All these measures require a multidisciplinary approach that includes different specialists, patients and health providers in multidisciplinary teams and the establishment of educational programmes. These combined measures may aid the early diagnosis of both DM and CKD. Early referral of patients with DM and renal involvement to nephrology care is necessary to coordinate integrated multifactorial management and halt its progression to ESRD and CV damage .