This study aimed to evaluate the accuracy of oscillometric blood pressure measurement at the ankle in children using invasive blood pressure as reference standard. This prospective observational study included children undergoing noncardiac surgery. Paired radial invasive and ankle non-invasive blood pressure measurements were obtained. Delta blood pressure was calculated as the difference between two consecutive readings. The primary outcome was the mean bias and agreement between the two methods using the Bland-Altman analysis. The ISO standard was fulfilled if the mean bias between the two methods was ≤ 5 ± 8 mmHg. Other outcomes included the trending ability of ankle blood pressure using the four-quadrant plot and the accuracy of ankle measurement to detect hypotension using area under receiver operating characteristic curve (AUC) analysis. We analyzed 683 paired readings from 86 children. The mean bias between the two methods for systolic, diastolic, and mean blood pressure  was − 7.2 ± 10.7, 4.5 ± 12.8, and − 1.8 ± 8.2 mmHg, respectively. The concordance rate of ankle blood pressure was 72%, 71%, and 77% for delta SBP, DBP and MAP, respectively. The AUC  for ankle MAP ability to detect hypotension was 0.91 (0.89–0.93) with negative predictive value of 100% at cut-off value ≤ 70 mmHg, We concluded that in pediatric population undergoing noncardiac surgery, ankle blood pressure was not interchangeable with the corresponding invasive readings with the ankle MAP having the least bias compared to SBP and DBP. An ankle MAP > 70 mmHg can exclude hypotension with negative predictive value of 100%. Blood pressure measurement is a standard practice during anesthesia; and maintaining adequate blood pressure is important to maintain organ perfusion . The golPrevious studies evaluated the accuracy of blood pressure at the ankle using arm non-invasive blood pressure measurement as the reference standard –5 and reThis prospective observational study was conducted in a University Hospital after institutional Ethics Committee approval  from June 2021 to June 2022. Written informed consent was obtained from patient’s guardian before the enrolment.We included children aged 3–14 years, American Society of Anesthesiologist classification of I-III, scheduled for elective non-cardiac surgery under general anesthesia that requires invasive blood pressure monitoring.Children with any of the following morbidities: congenital heart disease, severe valvular disease, coarctation of the aorta, arrhythmias, peripheral vascular diseases, and deep venous thrombosis were excluded from the study. Children with lower limb edema, scarring, or previous operations or fractures at the ankle were also excluded.Upon arrival to the operating room, routine monitors were applied . After induction of general anesthesia, a 22-G radial arterial catheter was inserted, and connected through a fluid filled system to a pressure transducer placed and zeroed at the level of the mid-axillary line. After establishing the invasive blood pressure monitor, the arm cuff was disconnected, and another cuff was applied to the ankle. The ankle cuff size was selected according to the recommendations of the American Heart Association for arm cuff  . The cufAn independent researcher was responsible for collecting the data of invasive and non-invasive blood pressure. The invasive blood pressure measurement was recorded as the reading just after the onset of noninvasive blood pressure cuff inflation. Multiple paired measurements were obtained during the course of the surgery.For evaluation of the trending ability of the ankle blood pressure measurement, the difference between each two successive readings was calculated .All paired blood pressure measurements were obtained while maintaining the ankle at the level of the mid-axillary line using a pillow if needed. Anesthetic and hemodynamic management were according to the discretion of the attending anesthetist.The primary outcome was the mean bias and agreement between invasive- and ankle non-invasive blood pressure measurements .Secondary outcomes were the number of paired readings with difference of ≤ 5, 10, and 15 mmHg between invasive and non-invasive blood pressure. Demographic data namely age, sex, weight, height, and ankle circumference were collected and the effect of age, sex, and ankle circumference on the magnitude of bias between the two methods was reported. The trending ability of non-invasive blood pressure in relation to invasive blood pressure was also reported.The accuracy of ankle MAP to detect hypotension (defined as MAP < 5th percentile for the age) was also calculated. Since MAP 5th percentile in our cohort ranged between 52 and 56 mmHg , we usedThe Universal Standard for the validation of blood pressure measuring devices by the Association for the Advancement of Medical Instrumentation/European Society of hypertension/International Organization for Standardization (AAMI/ESH/ISO) requires at least 85 subjects for validation of a non-invasive blood pressure device. The number was rounded to 100 subjects to account for the risk of non-invasive blood pressure failure [Statistical package for social science (SPSS) software, version 26 for Microsoft Windows , Microsoft Office Excel 365  and MedCalc software V 14  were used for data analysis. Continuous data were tested for normality using the Shapiro-Wilk test and were presented as mean ± standard deviation or median (quartiles) as appropriate. The Bland-Altman analysis, adjusted for multiple measurements per subject, was conducted to calculate the mean bias and 95% limits of agreement between invasive and non-invasive readings. The ISO standard was fulfilled if the mean bias between the two techniques was ≤ 5 mmHg and its standard deviation was ≤ 8 mmHg [The STROBE guidelines were applied when writing this manuscript.One-hundred and thirteen patients were screened for eligibility, 13 patients were excluded  and 100 patients were included for this study. Fourteen patients were excluded from the analysis due to incomplete data and 86 patients with 683 paired readings were available for the calculation of the bias and agreement between the two measurement sites.  age of the participants was 6  years, and 46/86 (54%) of the participants were males. Table  All the The mean bias between the two methods was − 7.2 ± 10.7, 4.5 ± 12.8, and − 1.8 ± 8.2 mmHg for SBP, DBP, and MAP respectively. , 380 (56%), and 556 82%) for SBP, DBP, and MAP, respectively. (Table % for SBPThe magnitude of bias between the two methods was the lowest for MAP (6.5 ± 5.6 mmHg) in comparison to the SBP (9.9 ± 8.0 mmHg) and DBP (10.6 ± 8.5 mmHg), P-value < 0.001 for both comparisons. The generalized estimating equation analysis on the effect of patient’s characteristics on the magnitude of bias between the two methods revealed that only SBP bias is affected by the child age. Table The four-quadrant plot analysis for the trending ability of the ankle non-invasive blood pressure, revealed a concordance rate of 72%, 71%, and 77% for delta SBP, delta DBP, and delta MAP, respectively. Fig. The number of hypotensive readings (MAP < 56 mmHg) was 16 (2%). The AUC  for the ability of ankle MAP to detect hypotension was 0.91 (0.89–0.93), with sensitivity (95% CI) of 88% (62–98%), specificity (95% CI) of 82% (79–85%), positive predictive value (95% CI) of 11% (6–17%) and negative predictive value (95% CI) of 100% (99–100%) at ankle MAP of ≤ 70 mmHg,In this report, we evaluated ankle non-invasive blood pressure using invasive blood pressure measured at the radial artery as the reference standard in children undergoing noncardiac surgery. We found that ankle measurement did not satisfy the ISO standard  as the mThe low accuracy of both SBP and DBP at the ankle is explained by the pulse pressure amplification phenomenon, which is the progressive increase of pulse pressure from central to peripheral arteries, resulting in increased SBP and, to a lesser extent, decreased DBP, while the MAP is the least affected .We evaluated the effect of patient’s characteristics, namely the age, male sex, and ankle circumference, on the magnitude of bias between ankle and invasive measurement and found that the difference between the two methods increased with the child age for SBP only. This could contribute to the inaccuracy of ankle SBP in this cohort. On the other hand, both DBP and MAP were not affected by patient’s characteristics.Previous reports in pediatric population did not support the accuracy of ankle blood pressure , 4; howeHayes et al.  investigWe also report that the ankle measurement underestimated high invasive readings and overestimated low invasive readings. This finding is supported by previous studies that evaluated oscillometric devices . TherefoIntra-arterial measurement is the gold standard for blood pressure measurement; however, using this invasive and expensive technique is usually reserved for patients undergoing major surgery and/or unstable critical patients . Thus, nOur study had some limitations. 1- It was performed in a single center. 2- A single model of blood pressure monitor and non-invasive cuff were used in this study; hence, our findings are limited to this model. 3- We excluded patients with significant cardiac anomalies and arrythmias. More studies needed to evaluate the ankle blood pressure in these populations. 4- We excluded patients less than three years; however, the study’s age range is based on the AAMI/ESH/ISO recommendation of age range when validating noninvasive device in pediatric population . Future In pediatric population undergoing noncardiac surgery, ankle blood pressure was not interchangeable with the corresponding invasive readings with the ankle MAP having the least bias compared to SBP and DBP. An ankle MAP > 70 mmHg can exclude hypotension with negative predictive value of 100%.


The aim of this study was to investigate the association between estimated glucose disposal rate (eGDR), a proxy for insulin resistance, and retinopathy or kidney disease, i.e. micro-, or macroalbuminuria, in young individuals with type 1 diabetes (T1D).Using data from the Swedish pediatric registry for diabetes (SweDiabKids) and the registry for adults (NDR), all individuals with T1D with a duration of diabetes of less than 10 years between 1998 and 2017 were included. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) for two cohorts: retinopathy cohort or kidney disease cohort, stratified by eGDR categories: < 4, 4 to 5.99, 6 to 7.99, and ≥ 8 mg/kg/min (reference).A total of 22 146  children and adults with T1D  were studied. During a median follow-up of 4.8 years (IQR 2.6–7.7) there were 5040 (24.7%), 1909 (48.1%), 504 (52.3%) and 179 (57.6%) events for retinopathy in individuals with an eGDR ≥ 8, 7.99 to 6, 5.99 to 4, and < 4 mg/kg/min, respectively. Corresponding numbers for kidney disease was 1321 (6.5%), 526 (13.3%), 255 (26.8%) and 145 (46.6%). After multiple adjustments for different covariates, individuals with an eGDR 7.99 to 6, 5.99 to 4 and < 4 mg/kg/min, had an increased risk of retinopathy compared to those with an eGDR ≥ 8 mg/kg/min  1.29 (1.20 to 1.40); 1.50 (1.31 to 1.71) and 1.74 (1.41 to 2.14). Corresponding numbers for kidney disease was  1.30 (1.11 to 1.52); 1.58 (1.25 to 1.99) and 1.33 (0.95 to 1.86), respectively.eGDR, a proxy for insulin resistance, is associated with retinopathy and kidney disease in young adults with T1D. The risk of retinopathy increased with lower eGDR. The risk of kidney disease also increased with lower eGDR; however results show no association between the lowest eGDR and kidney disease. eGDR can be helpful to identify young T1D individuals at risk.The online version contains supplementary material available at 10.1186/s12933-023-01791-x. Individuals with type 1 diabetes (T1D) are at increased risk of macrovascular and cardiac complications, in which microvascular complications may predict the risk , 3. HoweThe term double diabetes, first described in 1991, was initially defined as an individual with T1D with a family history of type 2 diabetes (T2D) . Today, The gold standard for measuring insulin resistance is the euglycemic hyperinsulinemic clamp technique . Since tNot only macrovascular complications are associated with insulin resistance, but also microvascular complications . There iThe study was a nationwide, observational cohort study. The study was approved by the Swedish Ethical Review Authority (Dnr 977-17).st December 2017. Between these time points all children, adolescents and adults in the registries were included if they had a diagnosis of T1D since ten years, or less when first recorded in the registries. The age span in the whole cohort was 0–39 years, i.e., patients were included if they are diagnosed with T1D before 30 years of age and if duration was < 10 years.We used data from the Swedish national diabetes registry for adults (NDR) and the Swedish pediatric registry for diabetes (SweDiabKids), no other registers were used. Participants provided informed consent when entering the registries. NDR defines T1D on the basis of epidemiological data: treatment with insulin and a diagnosis at the age of 30 years or younger, which has shown to be validated in 97% of cases . In chilData extracted from the registers were age, sex, diabetes duration, weight, height, BMI, blood pressure, HbA1c, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, smoking, physical activity, type of diabetes treatment, micro/macroalbuminuria, estimated glomerular filtration rate (eGFR), and result of retinopathy screening. Categorization of the variables from the registers are shown in Tables In the final data set individuals with at least one registration of examination of retinopathy, or kidney disease was included. They also needed at least one registration of eGDR  and at least one registration of each of the covariates that was used in the final model. In total 15 111 individuals were recruited from SweDiabKids and 19 298 individuals were recruited from NDR. 26 786 individuals had T1D with < 10 years duration when entering the registry. After including patients with at least one examination of retinopathy or nephropathy, one eGDR observation and at least one observation for each covariate, 10 289 cases in the retinopathy cohort and 11 857 cases in the nephropathy cohort remained Figure S1  were excluded from retinopathy analysis  and 14 929 individuals (55%) from kidney disease analysis  Figure S1  was calculated as previously described [BMI = 19.02 − (0.22*BMI) − (3.26 * HT) − (0.61*HbA1c) . BMI = body mass index (kg/m2), HT = hypertension (yes = 1/no = 0), and HbA1c = HbA1c (DCCT %).eGDRescribed  based onHypertension was defined as a blood pressure > 140/90 mmHg or current use of any anti-hypertensive agents. For individuals < 18 years old, we used IsoBMI . AnalyseBased on previous studies , 23, we −1, or urinary albumin of 20–200 µg min−1 (20–300 mg/L), or macroalbuminuria defined as an albumin/creatinine ratio > 30 mg mmol−1, or urinary albumin > 200 µg min−1 (> 300 mg L−1) [Endpoints of retinopathy were classified as any retinopathy, preproliferative diabetic retinopathy (PPDR), or proliferative diabetic retinopathy (PDR). Any retinopathy included any signs of retinopathy, i.e. simplex retinopathy, PPDR or PDR. PDR was defined as evidence of current proliferations or any earlier laser photocoagulation. Endpoints of kidney disease were classified as any microalbuminuria defined as two positive test results from three samples taken within one year with an albumin/creatinine ratio of 3–30 mg mmolst of December 2017, whichever came first. Follow up did not end if mild retinopathy, i.e. simplex retinopathy, or microalbuminuria was registered. If more severe forms were registered, milder forms were ignored, and the first diagnosis of the severe form was included.All individuals were followed from the first observation (between 1998 and 2017) when they first appeared in the register, i.e. index date, until the first event of any retinopathy, or any kidney disease , or until the end of the study 31Baseline characteristics  are based on the first available observation (between 1998 and 2017) from index date and after that with no specific time limit, for each individual in the study. Continuous variables are presented as medians with interquartile range (IQR), due to the contribution of data, and categorical variables as proportions. Crude and adjusted hazard ratios (HRs) and confidence intervals (CIs) were estimated using univariable and multivariable Cox regression models with time until endpoints, that is retinopathy or kidney disease, as response variables and time-varying covariates as exposure variables, that is eGDR, and potential confounders. Exposure to risk of retinopathy and kidney disease starts at diabetes onset, but follow-up starts at first eGDR observation. This means that data are left-truncated as well as right-censored handled accordingly.Instead, age at diabetes onset was included as a covariate. All covariates which were adjusted for in the final model were time-varying, but sex. The time-varying variables, i.e. numbers and timespan per patient are shown in Table S2  and 9% were obese (BMI > 30 kg/m2), both cohorts. Finally, 5% of individuals had hypertension. All covariates, multivariable adjusted for in the final model, are shown in Table Baseline characteristics of the study participants in the retinopathy and nephropathy cohorts, respectively, are shown in Table The estimated retinopathy crude cumulative risk curves illustrating the accumulated risk for retinopathy are shown in Fig. We further assigned individuals to different degrees of retinopathy to compare the risk for severe retinopathy with milder degrees: PPDR/PRD/laser photocoagulation vs. non/simplex retinopathy and PRD/laser photocoagulation vs. non/simplex retinopathy/PPDR, respectively, into the same eGDR categories Table .Number of events and event rates was much less for severe retinopathy compared with mild retinopathy. Crude and adjusted for sex and age relative risk for PPDR/PRD/laser photocoagulation vs. non/simplex retinopathy increased in all eGDR categories below 8 mg/kg/min Table . After mThe estimated crude survival curves illustrating the accumulated risk for kidney disease, i.e. microalbuminuria, or macroalbuminuria are shown in Fig. After adjustment for age and sex, and all covariates in Table We further assigned individuals to different degrees of kidney disease, i.e. comparison of microalbuminuria and macroalbuminuria vs. non-albuminuria respectively. Number of events and event rates was much less for macroalbuminuria compared with microalbuminuria Table . Crude aThe reason for using ISO-BMI, instead of BMI, is that this formula “correct” BMI, especially for the youngest children . Since t2 ± SD) for each variable in the eGDR formula for the risk of retinopathy was highest for HbA1c (0.0242 ± 0.0049), followed by BMI (0.0012 ± 0.0011), and hypertension (0.0006 ± 0.0010). Corresponding explained relative risk for kidney disease was for HbA1c (0.0389 ± 0.0103) followed by BMI (0.0163 ± 0.0064), and hypertension (0.0067 ± 0.0059).The estimated explained relative risk (R2) and 9% were obese (BMI ≥ 30 kg/m2) according to the World Health Organization’s definition. The prevalence of obesity in childhood T1D populations is increasing. In the Nordic countries the obesity rate was 18.5% in children with T1D under 15 years of age during the period 2008–2012, which was higher than for the Swedish reference population [This nationwide, observational study shows that eGDR, a proxy for insulin resistance, associates with the risk of retinopathy and kidney disease in young individuals with T1D. The risk of retinopathy increased with lower eGDR. Risks of kidney disease also increased with lower eGDR, however not for the lowest eGDR category (< 4 mg/kg/min).eGDR has been proven a tool for the measurement of insulin resistance in people with T1D  and has pulation . Risk fapulation . We adjupulation , 36.2, in the population in the DCCT/EDIC study increased from 1 to 31% over the course of 12 years [The impact of obesity and microvascular burden in patients with T1D is not fully established . The pre12 years . One pos12 years , 8, 37. 12 years , 38, as 12 years . However12 years .Hypertension, often coexist with insulin resistance, is a well-known risk factor for micro- and macrovascular complications . In the Hyperglycemia is a well-known risk factor for both macrovascular and microvascular complications , 3. HypeThe main strength of this study is the large nationwide population of individuals with T1D with a long follow up. The results show an association between eGDR and risk of retinopathy and kidney disease. We were able to adjust for several important confounders. However, there are limitations to this study. The eGDR formula, including hypertension, has not entirely been validated in youth . DiffereIn conclusion, the current cohort study shows that young people with T1D with low eGDR have higher risk of developing both retinopathy and kidney disease, which indicates that insulin resistance increases the risk of these complications. Since microvascular complications are predictors for cardiovascular disease, and earlier observation demonstrates the association between eGDR and cardiovascular death and mortality, in individuals with T1D, further studies are much needed to explore insulin resistance as a risk factor for micro-, and macrovascular complications in people with T1D.Additional file 1: Table S1. Baseline characteristics of all patients divided in the retinopathy and kidney disease cohort and excluded patients, respectively. Table S2. Number of measurements and timespan per patient, median and (range). Table S3. Baseline characteristics of all patients according to eGDR categories. Table S4. Interaction analysis between the retinopathy cohort  and the kidney disease cohort  with an overlap of 9575 individuals. Number of events, event rate and relative risks for any retinopathy and kidney disease in children and adults with type 1 diabetes. Table S5. eGDR based only on BMI (ISO-BMI excluded). Number of events, event rate and relative risks for any retinopathy and kidney disease in children and adults with type 1 diabetes. Figure S1. Flowchart for the studied group. The overlap between cohorts included 9575 individuals. Proportion of excluded patients between the registers was for the retinopathy cohort 70% vs. 47% (SwedDiabKid vs. NDR) and for the kidney analysis corresponding proportional numbers were 62% vs. 39% (SwedDiabKid vs. NDR), for the two registers. eGDR, estimated glucose disposal rate; NDR, National Diabetes Register.


Adipokines are associated with several pathological states including, metabolic syndrome, obesity, insulin resistance and type 2 diabetes. One of these adipokines, adiponectin is of particular interest as it has been shown to have numerous anti-inflammatory effects, However, the association between adiponectin and blood pressure remains inconclusive especially in the obese Hispanic adolescent.to investigate the relationship between plasma adiponectin and blood pressure in obese Latino adolescents’ boys with a family history of Type 2 diabetes.395. Blood pressure was assessed using the Dinamap automated blood pressure monitor, and the average of three readings was used in the analysis. Fasting plasma adiponectin was determined using radioimmunoassay.Thirty two obese Latino male adolescents aged 14–17 years with a family history of type 2 diabetes underwent a frequently sampled glucose tolerance test (FSIVGTT) to measure insulin sensitivity. Body composition was assessed using dual energy x-ray absorptiometry. Obesity was defined as having a BMI percentile There was a strong positive significant correlation for adiponectin and Systolic blood pressure(SBP) (p< 0.027) and a moderate, positive significant correction for Diastolic blood pressure(DBP) (p< 0.028). A multivariate liner regression showed that plasma adiponectin could significantly predict 19% of the variance in SBP .In conclusion, adiponectin was positively and significantly correlated to blood pressure in obese Latino adolescent youth. Future studies should investigate this relationship in a large sample of Latino adolescent youth. Pediatric obesity is one of the most pertinent health issues of the last century. In 2019, 340 million children aged 5–19 years are considered overweight/obese , fatty lLow insulin sensitivity (IS) is also a predictor of high blood pressure (BP), particularly in minority youth . In adulThe prevalence of hypertension in children is threefold higher in obese children than in non-obese children . A systeFurthermore, adiponectin, an adipose tissue-derived protein with insulin-sensitizing and antiatherogenic properties, has been associated with the regulation of BP in adults and adolescents , 21. DurN = 43) participants were recruited from the greater Los Angeles County area through medical clinics, advertisements, and local schools to participate in the study . Participants were recruited to the study if they met the following study inclusion criteria: 1) male; 2) grades 9th through 12th (approximately 14–18 years of age); 3) with a BMI ≥95th percentile for age and sex; 4) of Latino ancestry (parents and grandparents descent as determined by self-report); 5) absence of diabetes using established guidelines; 6) absence of comorbid inflammatory disease, secondary hypertension or any condition that would predispose them to type 2 diabetes;7) have a positive family history of type 2 diabetes . The study was conducted in accordance with the guidelines of the Helsinki Declaration. Written informed consent and assent were obtained from the parents and children prior to testing. The Institutional Review Board of the University of Southern California approved the study.Forty-three . Obesity was defined as have a BMI ≥95th percentile for age and sex. A dual-energy X-ray absorptiometry (DEXA) scan  was performed to estimate total fat mass (FM) and total lean tissue mass (LTM).Height was measured with a stadiometer to the nearest 0.1cm. Body mass was measured without shoes and in a hospital gown to the nearest 0.05kg using a beam medical scale. Body mass index (BMI) was calculated; age- and sex-specific BMI percentile were determined using Resting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in the sitting position using a Dinamap automated blood pressure monitor  with the arm supported at heart level. After sitting quietly for 5 minutes, measurements were obtained on each child using an appropriately sized cuff placed on the right arm. Three readings of blood pressure were obtained, and the average was recorded, according to the recommendations of the American Heart Association . SystoliA venous blood sample was taken after 12 hours overnight of fasting for the following measurements, plasma glucose, and insulin as previously described , 27. TheAll data were checked for normality prior to statistical analysis using descriptive statistics, histograms with normal distribution curves, and the Anderson-Darling (AD) normality tests. Data are presented as means and standard deviation unless indicated otherwise. The correlation analyses in N = 32) obese Latino adolescent males were consented into the study. Characteristics of participants are shown in Thirty-two  F  = 6.437, p = 0. 017; see 2 = (0.183) F  = 5.598, p = 0.026). Plasma adiponectin also predicts DPB . Plasma adiponectin predicted 8% of the variance of pulse pressure (R2 = (0.113) F  = 3.441, p = 0. 075). However, plasma adiponectin did not significantly predict pulse pressure .A multivariate linear regression analysis was conducted to investigate whether plasma adiponectin levels could significantly predict SBP and DBP. The results of the regression analysis showed that the model with Adiponectin only could significantly predict 19% of the variance in SBP  this is a cross-sectional study design, which is not an appropriate design to assess cause and effect between adiponectin and blood pressure. However, the strength of our study is 1) the homogeneous sample, 2) the precise techniques; 3) representative sample of the obese Latino adolescent community and 4) as gender differences were not observed in several studies, we chose to focus on males so as not to confound the analysis.In conclusion, adiponectin and blood pressure are closely related in these obese adolescent males with a family history of type 2 diabetes. Future larger studies in the Latino obese adolescent population need to be conducted due to the biological importance of adiponectin.


Under the term cardiorenal syndrome (CRS) falls an increasing number of patients who present with combined heart and kidney dysfunction. Despite the increasing knowledge concerning CRS pathophysiology, diagnosis, and treatment, many of the aforementioned aspects remain obscure in everyday clinical practice. Some of the challenges that clinicians face when they treat CRS nowadays is the need for a patient-centered management with early diagnosis, early intervention, the distinction of true kidney injury from permissive renal function deterioration during decongestion therapy, and the development of therapeutic algorithms to guide therapy. Over the last decades, an increasing number of patients have suffered from combined heart and kidney dysfunction largely known as cardiorenal syndrome (CRS). The term “cardiorenal syndrome” first appeared in November 1913, when Thomas Lewis proposed the presence of a close relationship between the heart and the kidney [CRS often coexists with anemia, which in turn has a negative impact on the heart and renal axis. The cardiorenal anemia syndrome (CRAS) is associated with a higher mortality and morbidity rate. Treatment options for this category of patients are currently restricted to intravenous iron and erythropoiesis-stimulating agents (ESAs).In this review, we pinpoint the fields of CRS that remain poorly understood with an emphasis on CRAS, a relatively new subtype of the syndrome requiring specific management.Following the first mention of the syndrome in 1913 [In 2008, Ronco et al. .Hatamizadeh et al., based on the underlying pathophysiology and the main clinical manifestations, proposed that CRS could be divided into seven subcategories: (1) hemodynamic, (2) uremic, (3) vascular, 4) neurohumoral, (5) anemia- and/or iron-metabolism-related, (6) mineral-metabolism-related, (7) malnutrition–inflammation–cachexia-related [ neurohumThe ADQI classification has some limitations in terms of clinical use. Its main shortcoming is that clinicians cannot distinguish whether a patient has renocardiac or cardiorenal syndrome in the majority of cases. Most patients come with an episode of acute heart failure (AHF) or, more frequently, an acute decompensation on the basis of chronic heart failure (CHF) with associated acute kidney injury (AKI), making a correct classification of the patient into CRS types 1, 2, or 3 challenging. Similarly, in the case of a renocardiac syndrome (CRS type 3 or 4), it can be difficult, if not impossible, to determine if the AKI preceded the occurrence of the cardiac injury. Furthermore, patients are classified in overlapping subcategories during the course of their disease, complicating categorization and care even further.A combined assessment tool that classifies patients as having either a cardiorenal or a renocardiac syndrome would be a more effective classification approach. This classification would be based on the patient’s history and a detailed clinical examination combined with cardiac and renal ultrasound. For example, echogenic small kidneys may indicate a renal predominance for the CRS. In contrast, normal sized kidneys with compromised heart function in a cardiac ultrasound may indicate the heart as the main culprit. The response to the therapeutic approach could be of further help in this classification. For example, a creatinine decline in response to diuretic therapy could be interpreted as cardiorenal syndrome type 1 or 2. On the contrary, a creatinine increase during decongestion therapy could be interpreted as a renocardiac CRS, due to the overestimation of the true GFR and the masked kidney failure due to volume overload.A classification of CRS patients into different hemodynamic profiles based on their clinical phenotype has been proposed . This clKey point 1: It becomes evident that a new classification system of CRS is required to categorize patients early in the course of the disease  in order to deliver the appropriate therapy. A kidney ultrasound, echocardiogram, and the response to decongestion treatment may be helpful.Despite the significant value of an early diagnosis of CRS, it becomes more and more evident that CRS prevention and early identification of the patients at risk have a key role in CRS management because a late diagnosis may be associated with irreversible morbidity and organ damage.Potential predisposing risk factors for CRS development are under investigation. However, the identification of contributing risk factors for either cardiorenal or renocardiac syndrome is difficult because of their convergent mutuality . Male geKey point 2: A prognostic tool that incorporates the presence of risk factors , clinical examination findings, and patient history in conjunction with cardiac and renal biomarkers is crucial in order to properly identify high-risk patients for developing a more severe and progressive form of CRS.CRS is characterized by a plethora of interacting pathophysiologic mechanisms. Each pathophysiologic mechanism impacts discretely on CRS’s natural course. Central venous pressure (CVP) and intra-abdominal pressure (IAP) are of major importance. Each cardiac decompensation episode supposedly leads to increased CVP and reduced blood return from renal veins ultimately causing congestion within the kidneys. Kidney congestion in turn leads to a reduced renal plasma flow, reduced glomerular filtration rate (GFR), enhanced fluid retention, and eventually, reduced urine output and renal dysfunction . Both chA reduced renal plasma flow results from a reduced cardiac output. A decreased renal plasma flow leads to intrarenal renin release, which in turn causes the constriction of renal capillaries, sodium retention, and vascular congestion. The validity of this theory has been weakened after the findings of the ESCAPE trial . No corrThe role of the renin–angiotensin–aldosterone system (RAAS) has been well established in CRS pathophysiology, contributing simultaneously to the progress of HF and the deterioration of kidney function . AngioteOxidative stress and chronic inflammation play a significant role in the development of CRS. The increased production of ROS surpasses the body’s antioxidative capacity and is attributed to inflammation, ischemic injury, and venous congestion . IschemiRecently, sodium chloride has been suggested as a potential cardiorenal biomarker . ChloridKey point 3: The examination of serum chloride may pave the way for new findings in the field of diuretic resistance and CRS. However, it is unclear if chloride is only a marker of the severity and prognosis of CRS or a distinctive therapeutic target.There has been a lot of debate about the clinical significance of WRF, defined as a short-term absolute increase in serum creatinine in patients with ADHF. A major difficulty in the management of CRS is to distinguish between true WRF, due to acute tubular injury, from a rise in creatinine concentration as a result of effective decongestion. Recently, it has been shown that WRF is rather a transient phenomenon attributed to intensive decongestive therapy, not accompanied by true renal injury. Among patients with ADHF and reduced ejection fraction only half of the cases of in-hospital WRF persisted after one month. Moreover, patients experiencing WRF with successful decongestion were not at increased mortality risk at 180 days, whereas, in the case of WRF with persistent congestion, there was a heightened risk for poor clinical outcomes . A JapanIt becomes increasingly clear that WRF should always be assessed in parallel with its clinical context. If adequate diuresis is present, a rise in creatinine is associated with better long-term outcomes as shown by several studies such as a post hoc analysis of the DOSE-AHF trial. Indeed, an aggressive diuresis during admission for AHF with or without WRF was associated with better clinical outcomes whereas a drop in serum creatinine was paradoxically associated with worse clinical outcomes . In the Key point 4: Permissive WRF is not associated with unfavorable renal and overall outcomes when it is accompanied by decongestion and enhanced diuresis.There has been a lot of discussion concerning the controversial role of serum creatinine and eGFR in the timely diagnosis of acute kidney injury. It is clear now that serum creatinine changes become clinically obvious once severe damage has already occurred, although these changes continue to be the final gold standard indicator for renal dysfunction. In view of the known weaknesses of creatinine, researchers have turned their attention to other potential cardiorenal biomarkers.The cardiac troponins, cardiac troponin T (cTnT), and cardiac troponin I (cTnI) are well-studied specific biomarkers of myocardial injury and infarction correlating with ventricular remodeling after HF and increasing with the progression of HF. Therefore, they have a role in risk stratification and prognosis in patients with HF. They also predict cardiovascular and all-cause mortality in patients with CKD .The two preferred biomarkers for HF are B-type natriuretic peptide (BNP) and N-terminal probrain natriuretic peptide (NT-proBNP), released from cardiomyocytes in response to atrial stretching and evoke a natriuretic and cardioprotective role. They both correlate with HF NYHA classification, left ventricular ejection fraction (LVEF), and ventricular pressure, thus contributing to prognosis and risk stratification of patients with HF . MoreoveUntil now, creatinine has remained the principal biomarker of renal function that guides therapeutic decisions and determines the presence of AKI. Despite its wide use, a rise in creatinine levels follows several hours to days  after the initial insult failing to timely diagnose the renal injury. Therefore, the identification of new biomarkers for the early detection of AKI has become an increasing need in clinical practice. Among identified biomarkers associated with kidney function, cystatin-C has been well studied. Cystatin-C is an endogenous cysteine proteinase inhibitor that is freely filtered in the glomerulus, completely reabsorbed by renal tubular epithelial cells and is found in urine only during tubular injury. Plasma cystatin-C can increase earlier than creatinine in early stages of AKI  and can NGAL is a useful early marker for AKI, being able to diagnose the development of AKI up to 48 h prior to a clinical diagnosis, also correlating with AKI severity . The valKidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein markedly expressed by the proximal tubule in response to renal injury, being a reliable predictor of AKI. It is also a predictor of disease progression in various cardiovascular diseases such as myocardial infraction and postcardiac surgery .C-type natriuretic peptide (CNP) together with atrial (ANP) and B-type (BNP) natriuretic peptides make up the family of natriuretic peptides, a family of hormones involved in the regulation of blood pressure, electrolyte, and volume homeostasis . Both ANGiven that CRS is a syndrome with various clinical features, correct diagnosis can be extremely challenging in such patients. Artificial intelligence using expert-driven knowledge and specialized machine-based decision trees can help significantly towards this direction. Indeed, this was shown in a paper by Dong-Ju Choi et al., where an artificial intelligence clinical decision support system (AI-CCSS) presented a high diagnostic accuracy for heart failure . FurtherKey point 5: A panel of new biomarkers (in plasma and/or urine) and artificial intelligence support systems could aid in the early identification of CRS patients at risk of developing adverse outcomes.The therapeutic pillars in the management of CRS are decongestion, endogenous vasodilation, inotropic support, inhibition of the neurohormonal axis, and extracorporeal therapy. Intravenous loop diuretics are considered the gold standard of therapy although they have not been shown to improve survival or attenuate disease progression . DespiteThe optimal dose of diuretics administered is dependent on the degree of renal dysfunction. Thus, various algorithms for dose adjustment of loop diuretics and thiazides (if used in conjunction) exist in order to guide decongestion . HoweverIt is very common in clinical practice to combine loop diuretics with thiazide diuretics, carbonic anhydrase inhibitors , metolazone (thiazide like diuretic), or potassium-sparing diuretics in order to achieve sequential nephron blockade and thus overcome diuretic resistance. The addition of acetazolamide to loop diuretic therapy in patients with ADHF resulted in a higher incidence of successful decongestion but no benefit in terms of survival or rehospitalization for heart failure in a recent randomized, placebo-controlled trial  . In the Diuretic resistance frequently arises during the treatment of CRS. Various responsible mechanisms have been recognized, including a reduced oral bioavailability due to intestinal edema, an accumulation of uremic toxins diminishing the secretion of diuretics into the proximal tubule, a decreased glomerular filtration of diuretics with acute reductions of GFR, and a compensatory enhancement of RAAS and SNS . To overThe use of vasodilating agents is an effective way to reduce central venous pressure (CVP) and increase net filtration pressure in the kidney. Nitroglycerin and nitroprusside are both vasodilating agents able to decrease CVP. However, neither nitrates, nitroprusside, nor nesiritide have shown robust evidence for improving clinical outcomes in AHF, except perhaps for early symptom improvement . NesiritInotropic support is critical for maintaining perfusion pressure to vital organs but has also been associated with increased mortality in several trials. Among inotropic agents, milrinone, low-dose dopamine, and dobutamine have not shown any improvement in renal function and mortality rates. One of the most promising inotropic agents, levosimendan, has shown contradictory results. On one hand, it was associated with hemodynamic improvement and a lower mortality at 1 and 6 months but on the other hand, according to the SURVIVE and the REVIVE I and II trials, levosimendan did not improve mortality and displayed an increased risk of hypotension, cardiac arrhythmias, and death at 90 days ,80.Neurohormonal axis inhibition with the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are one of the cornerstones in the therapy of AHF. These agents improve mortality even in cases of severe renal insufficiency and/or severe CHF. Although they can acutely cause WRF, in most cases, renal function returns to baseline with the additional benefit of the long-term stabilization of kidney function . Therefo2, when uremic symptoms are present or volume management and nutritional status are difficult to maintain [Ultrafiltration (UF) is a potential useful method in parallel with diuretic therapy especially in those patients presenting with diuretic resistance and severe renal insufficiency. The CARRESS-HF study evaluated the utility of UF in ADHF with worsening renal function. The trial was terminated prematurely due to a lack of efficacy of UF and a higher prevalence of adverse events . Howevermaintain .The scientific world has largely recognized SGLT2i as an effective treatment not only for type 2 diabetes mellitus, but also for HF and CKD patients. Several trials have demonstrated its combined cardio- and renal-protective role in patients with and without type 2 diabetes mellitus. SGLT2i has been postulated to have several pleiotropic effects, including the restoration of autophagy, which may be important in the reversal of HF pathogenesis. Additional processes include the modulation of inflammatory, oxidative, and fibrotic pathways, as well as improved endothelial function and decreased epicardial adipose tissue ,91.Inhibiting SGLT2 in the proximal tubule lowers plasma glucose and hemoglobin A1C (HbA1C), while improving insulin sensitivity and beta-cell activity. A net calorie loss results in a loss of body weight. Aside from the effects on glucose, the combination of osmotic diuresis and natriuresis results in a decreased plasma volume  and, as a result, a decreased blood pressure. The effect of SGLT2i on tubuloglomerular feedback has also been shown to restore excess glomerular pressure and filtration ,93,94,95They also improve renal function by both preventing and delaying the course of chronic kidney disease. SGLT2i usage has been linked to a lower glomerular pressure, a lower activity of the intrarenal renin angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS), lower inflammatory and fibrotic indicators, and an increase in hematocrit, hence reducing renal hypoxia. These effects manifest clinically as a stabilization of the estimated glomerular filtration rate (eGFR), a decreased blood pressure, and decreased albuminuria and ischemic injury ,93.A large body of evidence from randomized clinical studies has established SGLT2i’s effectiveness in diabetic and nondiabetic renal disease, independently of glycemic status and baseline renal function. The rise of this therapeutic class, together with the recently developed new-generation mineralocorticoid receptor antagonist finerenone, has the potential to reduce the excess burden of CKD .Key point 6: In the clinical setting of CRS, a multimodal therapeutic approach involves diuretic usage, neurohormonal activation inhibition, inotropic support, and extracorporeal volume management. Due to their pleiotropic effects, SGLT2i are ideal candidates to prevent or even ameliorate combined cardiac and renal dysfunction.CRAS is considered to be a pathological triangle in which the dysfunctional interplay between the kidney and the heart may lead to the development of anemia. When anemia appears, a vicious cycle commences, where HF and renal dysfunction cause anemia, which in turn will worsen the first two conditions and will unfavorably affect morbidity and mortality . Anemia According to the optimize-HF registry, anemia is associated with a 30% increase in all-cause mortality and morbidity . The comThe development of CRAS is multifactorial and several contributing risk factors have been recognized. Advanced age, a low body mass index, diabetes mellitus, a reduced left ventricular ejection fraction (LVEF), the omission of renin–angiotensin system inhibitors, and the use of intravenous loop diuretics are independently associated with CRAS ,103. FurAnemia of CKD has several underlying mechanisms. Among the most important ones are an inadequate synthesis of EPO, a limited availability of iron for erythropoiesis, increased hepcidin, reduced EPO receptors, and finally, the use of ACE inhibitors and ARBs ,104,105.Currently, there are no evidence-based recommendations for managing patients with CRAS. The treatment of these patients is multifaceted as a concomitant control of anemia, renal dysfunction, and heart failure is needed. Kidney Disease Improving Global Outcomes (KDIGO) organized an international conference and concluded that erythropoiesis-stimulating agents (ESAs) had no impact on the prevention or treatment of HF in patients with CKD ,109. On Intravenous iron and ESAs are the cornerstone therapy for anemia treatment in patients with CKD . HoweverESA therapy has been associated with reductions in LV mass and wall thickness and an improvement in renal parameters . HoweverHypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) represent a novel class of drugs for the management of anemia in CKD and CRAS. These inhibitors promote physiological EPO production by inhibiting the prolyl hydroxylase enzymes that are responsible for the degradation of the hypoxia-inducible factors (HIF), the transcription factors that induce expression of EPO in the kidneys and the liver. Apart from their impact on EPO, HIFs drive a coordinated response resulting in increased iron uptake and decreased hepcidin levels, leading to a more effective mobilization and usage of iron. Clinical trials with HIF-PHIs have shown a decrease in hepcidin and ferritin levels and increase in total iron binding capacity and usage of iron for erythropoiesis . There hKey point 7: Given the limited therapeutic approaches available, CRAS poses a clinical difficulty. A fraction of CRS patients with severe CKD may benefit from tight anemia management with ESAs. Iron store replenishment may be beneficial in the majority of CRAS patients.A CRS classification system that assesses the underlying organ damage and its temporal sequence will assist clinicians in providing appropriate therapy to the proper patient. Furthermore, a combination of several biomarkers  must be established in order to identify patients who are at higher risk of developing a more severe form of CRS. Serum chloride and CNP appear to be potential indicators, but additional research is needed before they can be used in clinical practice. CRS management is still complicated due to the intricacies of decongestive therapy and inotrope selection, the management of diuretic resistance, and the best timing and dose of ultrafiltration therapy. Anemia in the context of cardiac and renal failure comprises a complex triad that should always be addressed.


Background: Erectile dysfunction (ED) affects the great majority of people undergoing dialysis and also the majority of patients undergoing kidney transplantation. In this study, we investigated the degree of erectile dysfunction (ED), as well as its prevalence, contributory variables, and overall impact after renal transplant.Methods: Adult male kidney transplant patients were the subject of an observational, non-interventional study that was conducted at a single center. Age, time and type of dialysis before transplantation, comorbidities, factors associated with cardiovascular risk, data on sexual history, physical examination, and laboratory results were among the clinical data we examined. In addition to gathering clinical and demographic characteristics, the International Index of Erectile Function (IIEF) questionnaire was used to evaluate sexual function.Results: A total of 170 renal transplanted patients between 20 and 70 years old (mean age: 45.40±11.5) were included in this study. All of the patients had immunosuppressive treatment with a calcineurin inhibitor (cyclosporine or tacrolimus) and had a normal glomerular filtration rate (GFR). The prevalence of sexual dysfunction increased with age . Mild, moderate, and severe ED was noted in 33.5%, 20.6%, and 10.6% of cases, respectively, and 51 (30%) patients reported having a normal sexual function. While calcium channel blockers (122 cases) were the most commonly used antihypertensive medication and chronic glomerulosclerosis (55.3%) was the most common cause of chronic kidney disease (CKD) before transplantation, none of these variables appear to have affected the severity of erectile dysfunction. The only medications associated with sexual dysfunction were alpha-blockers and aspirin (75 mg) .Conclusions: Although kidney transplantation has positive impacts on the quality of life, erectile dysfunction is a frequent condition among patients with renal transplants, and it has an increased frequency with age. In our study, it has been observed that only a small percentage of the research group had a normal sexual function, although most of the patients were young, and that alpha-blockers and aspirin (75 mg) are associated with erectile dysfunction. Chronic kidney disease (CKD) considerably burdens a person’s quality of life. Several comorbidities, including diabetes, hypertension with secondary cardiovascular comorbidities, metabolic syndrome, endocrinological disorders, cognitive and psychiatric diseases, and a prolonged uremic environment, are related to CKD . These dSome research has demonstrated that erectile dysfunction improves after renal transplant surgery ,4, whileQuality of life, including erectile function, became a significant aspect for both patients and doctors in the modern era of healthcare as graft survival and patient survival with graft increased. There is a lack of data regarding sexual function in transplant recipients; consequently, additional information is required to determine the prevalence, risk factors, and severity of the association between post-kidney transplantation status and erectile dysfunction. The aim of our research was to assess the prevalence of erectile dysfunction among patients with kidney transplants and the frequency of risk factors associated with sexual dysfunction.We carried out a retrospective observational research study on male adult patients with chronic kidney disease who underwent a kidney transplant between 1995 and 2021 and were being monitored at the renal transplant unit of “Dr. C.I. Parhon” Hospital in Iaşi. All of the participants provided written consent, and the hospital’s ethics committee authorized the study. Surgical history, the presence of comorbidities, the type of renal impairment, the initial cause of kidney failure, and demographic and clinical data including blood and urine laboratory tests were gathered. In terms of laboratory results, data were gathered and compared for urea (mg/dL), creatinine (mg/dL), hemoglobin (g/dL), hematocrit (%), cholesterol (mg/dL), triglycerides (mg/dL), and uric acid (mg/dL) at the first evaluation following hospital discharge, the evaluation after 12 months, and at the time of study inclusion. All of these data were collected at the start of 2022.The International Index for Erectile Function (IIEF), a validated assessment of sexual function, was given to patients. To determine the diagnosis of erectile dysfunction, the questionnaire was completed by the patients at the time of study inclusion, and severity scores were established together with additional patient data. Individuals with acute or chronic graft rejection and patients with genital abnormalities incompatible with sexual activity were excluded from the study. Patients who underwent surgery less than six months before the study began were also excluded, as were individuals who refused to fill out the questionnaire.The diagnostic criteria established by Rosen et al.  and CappData on patients and completed questionnaires were processed using the Statistical Package for the Social Sciences (SPSS) version 27.0 . Student’s t-test was used for the statistical examination of the means and continuous variables when the data were regularly distributed. Statistically significant differences were those with p-values < 0.05.The study included 170 adult male patients who fulfilled the inclusion requirements, 20-70 years old (mean age: 45.40±11.5). They responded to the IIEF questionnaire at the start of 2022, having received a kidney transplant between 1995 and 2021.2, highest BMI: 37.44 kg/m2). The majority of the recipients (83.5%) underwent dialysis before the renal transplant; 124 patients had hemodialysis and 18 had peritoneal dialysis. The lengths of renal impairment by dialysis ranged from one month to 25 years (mean: 3.36±4.66 years); 19 patients had been dialyzed for more than 10 years until the kidney transplantation, while 53 patients had been on dialysis for less than 12 months. Regarding the donors, there were either live donors  or cadaveric donors . Most cases (70.58%) had been performed 1-10 years before the research, while six patients (3.35%) had their renal transplants more than 20 years before the study. Before they entered the study, 46 (27.1%) patients had undergone one or more reversible rejection events, and 17 (10%) patients had graft biopsies.The clinical details of these 170 patients are shown in Table The distribution of erectile dysfunction severity levels is shown in Figure When looking at the cause of chronic kidney disease before transplantation, chronic glomerulosclerosis (55.3%) was the most frequent cause of chronic kidney disease, followed by hypertensive nephropathy (9.4%), autosomal dominant polycystic kidney disease (ADPK) (7.6%), and urological congenital abnormalities (6.5%), vasculitis (3.9%), and diabetic nephropathy (2.4%).In addition to taking immunosuppressive medications, the majority of patients  also received different therapy for comorbidities. Calcium channel blockers 122 cases), beta-blockers (36 cases), and angiotensin-converting enzyme inhibitors (31 cases) were the most frequently used antihypertensives. Alpha-blockers and aspirin (75 mg)  were shown to be statistically significantly related to the existence of sexual dysfunction, not only with the overall IIEF score but also with each of the five domains. The associations between medication and erectile function of the study group are shown in Table 2 cases, The laboratory characteristics at the first evaluation following hospital discharge and at 12 months after renal transplant are shown in Table The laboratory tests and analyses performed at the time of the study’s inclusion are shown in Table The high prevalence of erectile dysfunction among patients with chronic renal failure has long been recognized for years. Research from the 1970s showed how crucial it was to improve quality of life through transplant and recover one’s normal level of erectile function . SalvatiIt is debatable and possibly multifactorial what induces sexual dysfunction in renal transplant patients. Some of the factors that have been recognized as related to persistent ED include age, anxiety, drug side effects, interference with penile vascularization, failure to adjust hormonal imbalances, or an underlying pathological process .Before starting hemodialysis, patients with chronic kidney disease had a high prevalence of sexual dysfunction (90%), and it remained elevated (60%-70%) during the hemodialysis period, with a range of clinical manifestations, from a lack of sexual desire to the inability to maintain an erection, from reduced sex hormone levels to infertility, from low self-esteem to depressive episodes . In a prAlthough higher than that observed in Spain , in the Age is a widely accepted risk factor for sexual dysfunction, and many studies have demonstrated the importance of age on the occurrence of ED among transplant patients ,17,18. IThere are several well-known sexual dysfunction causes, including high blood pressure, diabetes mellitus, hyperlipidemia, and uremic toxins. Despite potential benefits following renal transplantation, endothelial dysfunction persists . These fAs calcineurin inhibitors such as tacrolimus and cyclosporine, which are gonadotoxic medications, constitute the basis for immunosuppression in transplant patients, additional research explores a variety of immunosuppressive treatment regimens that may have a detrimental impact on sexual function ,23. AlthHemoglobin level is one factor that affects erectile dysfunction in renal transplant recipients, and patients who are anemic have two times higher risk of getting ED than those who are not anemic . While sThere are some limitations to our study. First, patients did not complete the IIEF questionnaire at least six months after the kidney transplant but rather at various intervals thereafter. The study’s observational design, lack of hormonal characteristics that could affect sexual function, absence of clinical manifestations related to the severity of the disease, lack of a control group, and the fact that it was conducted in a single medical facility are additional flaws that should be taken into consideration.In our view, this group of patients is growing annually, appears to be younger, and requires counseling and, where appropriate, therapy. Additional research is required to understand the incidence, risk factors, and severity of erectile dysfunction among those who underwent a kidney transplant.Due to its incidence and risk factors, sexual dysfunction is a significant problem for kidney transplant patients, and its frequency rises with age. The etiology is complex and may be due to a combination of variables; however, the two medical conditions may share many risk factors. Although most of the patients were young, only a small percentage of the study group had a normal sexual function. Among the several medications that this group of patients needed to take, alpha-blockers and aspirin (75 mg) are associated with sexual dysfunction, but these findings need to be validated in a prospective trial. Further research is needed to fully understand the complex interplay of these factors in the development of these disorders.


The relationship between pulse pressure and mortality in acute stroke hemorrhage patients is a subject of debate. To investigate this relationship in the Indonesian context, a study was conducted due to the increasing prevalence of stroke in the country.  The study sample consisted of 111 patients with acute stroke hemorrhage admitted to the hospital between January 1, 2016, and December 31, 2019. Patients with sepsis, cancer, or other hematology disorders were excluded, as were those who were lost to follow-up. Statistical analysis was performed using SPSS 22, and correlations were evaluated between various patient characteristics and laboratory values.  It was revealed that patients with a wider pulse pressure were more likely to die  than those with a normal or constricted pulse pressure.  Pulse pressure had an impact on the mortality of patients with acute hemorrhagic stroke. Stroke is the second highest cause of mortality and third highest cause of disability globally . Over thThe participants in this study were patients with acute stroke hemorrhage who were admitted to Cileungsi district hospital between January 1st, 2016, and December 31st, 2019. Patients with sepsis, cancer, other hematological disorders, or those who were lost to follow-up were excluded. The sample size was determined using the Lemeshow 2 proportion hypothesis and nonprobability consecutive sampling method.Upon admission, the patients' laboratory values and characteristics such as sex, GCS, and systolic and diastolic blood pressure were recorded. Patients were considered to have hypertension if they had a history of hypertension or if their average SBP was greater than 140 mmHg or their DBP was greater than 90 mmHg. Patients were considered to have diabetes mellitus if their fasting blood glucose level was greater than 120 mg/dL or if they were taking oral antidiabetic medication or insulin.The nurses recorded the patients' BP upon admission to the emergency ward. After the patients had been resting for more than 5 minutes, their SBP and DBP were measured using a blood pressure monitor. The difference between SBP and DBP is known as pulse pressure (PP). A PP of more than 60 mmHg is considered high, while a PP of 60 mmHg or less is considered normal or low. Mortality was defined as patients who passed away while in the hospital. Ethical approval came from the UPN Veteran Jakarta Ethical Committee under 153/III/2021/KEPK.The patient data include the total number of patients as a percentage and their mean value with standard deviation. The unfavorable outcomes for hemorrhagic stroke in patients with different pulse pressures are represented as percentages on a histogram in the univariable analysis. Statistical analysis was conducted using SPSS 22, and correlations between age, sex, risk factors, GCS, mean HR, SBP max, DBP max, pulse pressure, mean glucose, leucocyte, platelet, and creatinine were analyzed using the chi square test. A significance level of 0.05 was used.From 2016 to 2019, Cileungsi district hospital admitted 123 patients with stroke hemorrhage, excluding 12 respondents . The majority of patients were aged 65 years, with more males than females. Most of the patients had grade 2 hypertension with intracerebral hemorrhage but no intraventricular hemorrhage. Their Glasgow Coma Scale (GCS) ranged between 3 and 8, and their heart rates were between 60 and 100 beats per minute, with a mean arterial pressure (MAP) greater than 100 mmHg. Out of 123 patients, 61 individuals (48.4%) survived over the study period .Pulse pressure is the difference between systolic and diastolic blood pressure. It reflects factors such as stroke volume, arterial compliance, blood velocity, and the distance between the reflexive point and the heart. Research suggests that higher pulse pressure is associated with an increased risk of cardiovascular diseases, including myocardial infarction, stroke, and congestive heart failure . Based oOur findings indicate that individuals with a poor prognosis had higher pulse pressure levels 74.2 mmHg) compared with those who survived. Similarly, Chang et al. discovered that individuals with a bad prognosis had higher pulse pressure levels (68.5 16.4 mm Hg) than those with an excellent prognosis (65.4 12.4 mm Hg) as well [.2 mmHg cP value of 0.028) [According to our research, there is a significant connection between pulse pressure and mortality rates in patients with acute hemorrhagic stroke. The odds ratio value of 3 indicates that those with an elevated pulse pressure are three times more likely to experience a fatal outcome than those with a normal or reduced pulse pressure. The results of this study align with Ayyagari et al.'s 2014 research, which emphasized the lasting impact of dilated pulse pressure. Ayyagari concluded that pulse pressure dilation is a significant indicator of an increased stroke risk . Based of 0.028) .Recent findings suggest that a higher pulse pressure during the initial phase of a stroke is associated with a 39% greater chance of mortality within a year. This finding is consistent with the study conducted by Chang and his team in 2017, indicating a significant impact of pulse pressure on mortality and the highest probability of death, even after accounting for other factors. Chang argues that increased pulse pressure is an independent predictor of mortality among ICH patients .A study conducted by Liu et al. in 2020 found similar results to the ones presented here. They concluded that pulse pressure is a significant predictor of mortality in hospitalized ICH patients. Patients with pulse pressures over 101 had 11.0 percent case fatality rate, while those with pulse pressures below 60 had a much lower rate of 1.4 percent . NumerouP 0.0001) [According to a study by Mustanoja et al. in 2018, there was no correlation between pulse pressure and mortality in patients with intracerebral hemorrhage (ICH). However, a systolic blood pressure of 160 mmHg during the acute phase was found to be independently associated with higher mortality rates. In addition, at the time of hospital admission, a majority of patients had elevated blood pressure, with 70% having higher systolic blood pressure levels that were linked to increased short-term mortality and long-term mortality. Patients with the highest systolic blood pressure levels had shorter lifespans, highlighting the significance of this measure as a predictor for mortality. A systolic blood pressure of 160 mmHg was found to be associated with both short-term mortality and long-term mortality, while a mean arterial pressure (MAP) of 115 mmHg was linked to long-term mortality. On the other hand, diastolic blood pressure at the time of admission was normal and not independently related to death. Furthermore, there was no observed connection between pulse pressure and mortality. Another study by Mustanoja and Tang found that a pulse pressure of 50 mm Hg was linked to an unfavorable outcome , such as stress, pain, elevated intracranial pressure, reduced autoregulation, heightened systemic vascular resistance, and cerebral endothelial injury, particularly in younger individuals .It is currently unclear whether there is a link between dilated pulse pressure and mortality and how dynamic changes in the acute phase process relate to the chronic characteristics of systemic atherosclerosis. During the acute phase, reduced vascular compliance can cause an increase in pulse pressure to maintain arterial blood flow. This increase in pulse pressure is a dynamic process that may indicate a higher stroke volume or systemic resistance, which can lead to greater bleeding volume and a worse functional outcome .One possible factor is a malfunction in the body's ability to regulate blood flow, which can cause the need to maintain a healthy stroke volume to increase. In cases where this regulation is impaired due to intracerebral hemorrhage (ICH), the pulse pressure may rise to ensure that the brain receives adequate blood flow, resulting in a higher stroke volume and dilated pulse pressure due to an increase in systolic blood pressure. Therefore, it is thought that a sudden and drastic drop in systolic blood pressure, especially in cases of larger ICH bleeding volumes, can decrease cerebral perfusion pressure . HoweverWhen there is an increase in pulse pressure, there may also be a higher risk of cerebral edema. The exact reason why pulse pressure is linked to vasogenic edema is still unclear, but previous studies suggest that it may be due to a breach in the blood-brain barrier. This type of edema occurs when there is a breakdown in the barrier that separates blood vessels from brain tissue, allowing fluid and proteins such as albumin to leak into the brain. This can cause swelling and pressure inside the skull. To prevent this from happening, the blood vessels in the brain are uniquely designed to keep harmful substances out. Brain endothelial cells create tight junctions, while astrocytes and pericytes form the blood-brain barrier. However, if the blood-brain barrier is damaged, vasogenic edema can occur. This can happen as a result of brain injury, which can cause mitochondrial failure, excitotoxicity, and oxidative stress. These events can damage the cells that make up the blood-brain barrier, leading to a breach and the development of edema .Moreover, long-term high blood pressure can lead to a gradual decline in the flexibility of blood vessels, causing an increase in pulse pressure and a decrease in diastolic blood pressure. If widened pulse pressure is a symptom of this chronic vascular disease, it is wise to prioritize diagnostic measures and prevention of intracerebral hemorrhage .It is important to highlight that we did not measure intracranial pressure, which is a direct indicator of brain pressure, nor did we record any ICH clots, which are known to increase intracranial pressure and lead to high mortality. We also did not record the usage of anticoagulant and antiplatelet medications. Both types of medication speed up the development of an ICH clot more.Research has shown a correlation between wider gaps in pulse pressure and increased mortality rates, with gaps of larger magnitude tripling the chances of death.


The clinical efficacy and safety of SGLT2i in treating patients with type 2 diabetes mellitus and hypertension lack immense data support.To systematically evaluate the clinical efficacy and safety of SGLT2i in patients with type 2 diabetes mellitus and hypertension by collecting the previously published randomized controlled trials on SGLT2i to provide data support for SGLT2i as an adjuvant in the first-line antihypertensive regimen in patients with type 2 diabetes mellitus and hypertension.Randomized controlled trials comparing SGLT2i with a placebo in treating type 2 diabetes with hypertension were screened strictly according to inclusion and exclusion criteria. The primary efficacy endpoints included 24H systolic blood pressure, 24H diastolic blood pressure, office systolic blood pressure, and office diastolic blood pressure. The secondary efficacy endpoints included HbA1c. The safety indicators were hypoglycemia, urinary tract infection, genital infection, and renal impairment.MD was the combined effect size for continuous variables, and RR was the combined effect size for dichotomous variables.10 RCTs with 9913 participants (6293 in the SGLT2i group and 3620 in the control group) were included for analysis.SGLT2i is effective in reducing blood pressure compared with placebo in patients with type 2 diabetes and hypertension, 24HSBP , 24HDBP , Office SBP , Office DBP . HbA1c decreased significantly . SGLT2i did not increase hypoglycemia compared to placebo , urinary tract infection , risk of renal injury , but the risk of genital tract infection increased by 2.32 times .SGLT2i can effectively control blood pressure and blood glucose and generally has high safety. For patients with type 2 diabetes mellitus and hypertension with a low risk of genital infection, SGLT2i should be considered as an adjuvant drug for a first-line antihypertensive regimen. Hypertension and diabetes mellitus are independent risk factors for cardiovascular disease . The risAccording to the latest China guidelines, the blood pressure reduction target for patients with type 2 diabetes mellitus and hypertension is < 130/80 mmHg . This reIn summary, finding the ideal drug to achieve both blood pressure and glycemic goals, avoid the side effects of multiple drugs, and achieve optimal efficacy is daunting. The use of SGLT2i could be beneficial to achieve this goal, and this study was conducted with this aim in mind.This study was conducted strictly with PRISMA reporting principles and registered in the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42023400975). The Chinese and English databases of Pubmed, Embase, Cochrane Library, web of science, SinoMed, CNKI, VIP, and Wanfang were searched with diabetes, hypertension, and SGLT2i as the subject words in the mode of “subject words + free words” from the establishment of the database to December 2022. Further full-text assessments are obtained for relevant citations that appear in the literature.(1) Comparative analysis of the efficacy of SGLT2i (any dose) and control group (placebo or no SGLT2i) in patients with type 2 diabetes mellitus and hypertension, efficacy measures including blood pressure (24HSBP/DBP or average office SBP/DBP). (2) The study type is a randomized controlled intervention study. (3) The shortest follow-up time was 4 weeks. (4) The research data are accurate and complete, and the research subjects are at least 18 years old and above, regardless of region, country, nationality, and language.(1) Non-randomized controlled trials. (2) Conference documents and other data are incomplete. (3) The same experimental data were published repeatedly. (4) The sample size is less than 60 cases. (5) The loss to follow-up rate during follow-up is more than 20%.The literature quality evaluation scale provided by Cochrane Collaboration was used to evaluate the quality of the included literature, mainly including the generation of random sequence, concealment of the allocation scheme, double-blind of investigators and subjects, blind evaluation of study conclusion, the integrity of outcome data, selective reporting of study results and bias from other sources.From literature screening to data extraction, two researchers of this specialty independently completed the study according to the inclusion and exclusion criteria. For the literature with disagreement, the third investigator of this specialty will participate in the adjudication. The literature was preliminarily screened by titles and abstracts, and the literature irrelevant to the study content and study type was excluded. The integrity and usability of the study data were further examined by reading the full text. The extraction contents include (1) the authors, years, basic information of subjects, disease severity, sample size, intervention measures, course of treatment, outcome indicators, etc. of the included literature; (2) key factors of document quality evaluation; (3) specific values of outcome indicators.Primary outcome measures included 24H systolic and diastolic blood pressure, mean office systolic and diastolic blood pressure; Secondary outcome measures included HbA1c. Safety indicators included hypoglycemia, urinary tract infection, genital tract infection, and renal injury.2 is an indicator for evaluating heterogeneity, and I2 < 25% is considered as slight heterogeneity; I2 < 50%, moderate heterogeneity; I2 > 50%, highly heterogeneous. The random effect model is preferred for meta-analysis, and the fixed effect model is selected for the results with small I2. The preferential random effect model is based on the interference between different studies, especially the factors such as subject age, disease severity, and primary treatment regimen. Further sensitivity analysis and star plot were performed to analyze the sources of heterogeneity. All analyses were performed using software version Stata14.0.Continuous variables were expressed as mean ± SD, with a mean difference (MD) as the final effect size and a 95% confidence interval (95% CI). Categorical variables were expressed as frequencies and percentages, and the final effect size was assessed as risk ratio (RR) and 95% confidence interval (95% CI). All p-values were 2-tailed, and 0.05 was considered statistically significant. IA total of 947 pieces of literature were retrieved, and ten pieces of literature , 9–17 weTable The Cochrane Collaboration’s risk of bias tool was used Fig. .Fig. 2Li2 = 83.4%, P < 0.1, showing strong heterogeneity among literature .In the initial treatment, any two of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs), diuretics (thiazide or thiazide-like) and long-acting dihydropyridine calcium channel blockers (CCBs) can be selected for combination therapy. Compared with CCBs and β-blockers, ACEIs/ARBs can better reduce the risks of MACE, heart failure, cardiovascular death, and all-cause death and are the first drugs of choice for treating hypertension in patients with diabetes mellitus and coronary artery disease . For patAs a new oral antidiabetic drug, SGLT2i reduces renal reabsorption of glucose and sodium by inhibiting sodium-glucose co-transporter 2, thus exerting hypoglycemic and antihypertensive effects , 24. RecSystolic blood pressure is more clinically significant than diastolic blood pressure in patients with hypertension. The former is a more robust indicator of the risk of cardiovascular disease, which has led to an increasing emphasis on systolic blood pressure control in recent guidelines. This study preliminarily confirmed that SGLT2i can reduce 24-h systolic blood pressure and office systolic blood pressure in patients with type 2 diabetes and hypertension. SGLT2 reduced 24H systolic blood pressure by 5.06 mmHg and office systolic blood pressure by 4.53 mmHg, on average, compared with the equivalent dose of placebo. For 24H and mean office diastolic blood pressure, SGLT2i also showed a certain antihypertensive effect. The antihypertensive efficacy of SGLT2i is partly influenced by choice of first-line antihypertensive agents. Because SGLT2i lowers blood pressure by increasing urine volume, Dapagliflozin’s blood pressure lowering properties are especially beneficial in patients who are already taking beta-blockers or calcium channel blockers, and the addition of Dapagliflozin may result in slightly more tremendous blood pressure lowering than in patients who are already taking thiazide diuretics . The anaOur study confirmed that SGLT2i could effectively reduce HbA1c in patients with type 2 diabetes mellitus and hypertension. Sensitivity analysis showed that this literature  was high2 = 16.9, RR = 2.32, 95% CI , z = 4.23, p = 0.00, and the conclusion has a certain reference value and needs to be further confirmed by expanding the research sample. Sensitivity analysis suggested that this literature [Controversial risk of serious adverse events (SAEs) such as genital infections, urinary tract infections (UTIs), and hypotension associated with SGLT2i has limited its clinical use. Younes  found a Although some studies have reported a higher frequency of serum creatinine increase or glomerular filtration rate (eGFR) decrease in the dapagliflozin group . HoweverLimitations of this study: (1) the included studies were few, and it was not possible to study the effect of SGLT2i on blood pressure control based on baseline blood pressure and the impact of cardiovascular risk factors. (2) The number of studies included was minimal, and the screening criteria for the literature were too wide, failing to analyze subgroups by geography, disease duration, gender, age, concomitant underlying condition, ethnicity, blood pressure, and underlying antihypertensive drug status. (3) The results of this study are somewhat biased due to the tiny study base, diverse location, ethnicity, and sample size. (4) The majority of research times ranged from 4 to 12 weeks, and SGLT2i’s long-term antihypertensive effectiveness is uncertain. (5) To further address these issues, additional clinical studies with sizable sample sizes, multicenter, prolonged study periods, and thorough study methods must be added.There is a considerable risk of cardiovascular events in patients with type 2 diabetes mellitus and hypertension, and antihypertensive management strategies for this high-risk population are particularly important. In our study, the efficacy and safety of SGLT2i in patients with type 2 diabetes mellitus and hypertension were verified. SGLT2i has dual efficacy in lowering blood pressure and blood glucose and has a protective effect on cardiovascular, cerebrovascular, renal, and other composite outcomes and mortality. We can try to employ SGLT2i as an adjuvant medication in the first-line antihypertensive regimen for patients with type 2 diabetes and hypertension because this conclusion has some therapeutic work-guiding significance.