This study aimed to develop machine learning models to predict Low Cardiac Output Syndrome (LCOS) in patients following cardiac surgery using machine learning algorithms.The clinical data of cardiac surgery patients in Nanjing First Hospital between June 2019 and November 2020 were retrospectively extracted from the electronic medical records. Six conventional machine learning algorithms, including logistic regression, support vector machine, decision tree, random forest, extreme gradient boosting and light gradient boosting machine, were employed to construct the LCOS predictive models with all predictive features (full models) and selected predictive features (reduced models). The discrimination of these models was evaluated by the area under the receiver operating characteristic curve (AUC) and the calibration of the models was assessed by the calibration curve. Shapley Additive explanation (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) were used to interpret the predictive models.Data from 1,585 patients  were employed to train and validate the LCOS models. Among the full models, the RF model  and the XGB model  exhibited well predictive power for LCOS. Eleven predictive features including left ventricular ejection fraction (LVEF), first post-operative blood lactate (Lac), left ventricular diastolic diameter (LVDd), cumulative time of mean artery blood pressure (MABP) lower than 65 mmHg (MABP < 65 time), hypertension history, platelets level (PLT), age, blood creatinine (Cr), total area under curve above threshold central venous pressure (CVP) 12 mmHg and 16 mmHg, and blood loss during operation were used to build the reduced models. Among the reduced models, RF model  revealed the best performance. SHAP and LIME plot showed that LVEF, Lac, LVDd and MABP < 65 time significantly contributed to the prediction model.In this study, we successfully developed several machine learning models to predict LCOS after surgery, which may avail to risk stratification, early detection and management of LCOS after cardiac surgery. Low Cardiac Output Syndrome (LCOS), a clinical manifestation of insufficient cardiac output and peripheral tissue perfusion, was first proposed by Rao et al. . Previou2 and a systolic blood pressure of < 90 mmHg, in conjunction with signs of tissue malperfusion  in the absence of hypovolemia. Accordingly, it is of necessity to monitor CO by the pulmonary artery catheter (PAC) or pulse indicator continuous cardiac output (PICCO). All these current monitoring technologies, however, are too costly to be routinely applied in the setting of patients undergoing cardiac surgery, which consequently increases the difficulty of early recognition and prevention. Studies showed that significant independent risk factors for LCOS include age, preoperative left ventricular ejection fraction (LVEF), emergency surgery, temperature during cardiopulmonary bypass (CPB), application of cardioprotective drugs and echocardiographic parameters  repair surgery, etc. Exclusion criteria: (1) Patients under 18 years of age. (2) Patients who died or were discharged during or within 48 h after the operation. (3) Patients with incomplete clinical data, such as pre-operation echocardiographic measurements or intraoperative hemodynamic data. Data were collected from electronic medical records (EMR) database, and approval was gained from the Ethics Committee of Nanjing First Hospital (KY20220518-KS-01).2; (2) Patients with systolic blood pressure < 90 mmHg, in conjunction with signs of tissue hypoperfusion ; (3) Patients requiring mechanical circulatory support or inotropic agents (dopamine or dobutamine at least 4 μg/kg.min for a minimum of 12 h and/or epinephrine at least 0.2 μg/kg.min and/or milrinone at least 0.02 μg/kg.min and/or levosimendan at least 0.05 μg/kg.min) to maintain hemodynamics after optimizing preload. Patients who received vasoconstricting medication to increase peripheral vascular resistance in the presence of normal cardiac output were not considered to have LCOS.According to previous reports , 13, the2 (body surface area)  database included demographics: age, sex, height, weight; comorbidities: hypertension, diabetes, myocardial infarction, hyperlipidemia, cerebral vascular disease, atrial fibrillation, chronic obstructive pulmonary disease (COPD), congestive heart failure, renal disease, liver disease; preoperative echocardiographic parameters: left ventricular diastolic diameter (LVDd), left atrial diameter (LAD), interventricular septum thickness in diastole (IVSd), left ventricular posterior wall thickness (LVPWT), pulmonary artery systolic pressure (PASP), left ventricular ejection fraction (LVEF); preoperative laboratory results: white blood cell count (WBC), neutrophil ratio (NEU), lymphocyte ratio (LYM), platelets level (PLT), hemoglobin (Hb), blood creatinine (Cr), blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein (TP), total bilirubin (TB), low density lipoprotein (LDL), creatine kinase-MB (CKMB), triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), brain natriuretic peptide (BNP); operation information: operation time, cardiopulmonary bypass (CPB) time, aortic occlusion (AO) time, Emergency surgery, urine output (UO) during operation, blood loss during operation, operation type; intraoperative hemodynamics: mean arterial blood pressure (MABP), central venous pressure (CVP); postoperative hemodynamics: cardiac output (via pulmonary artery catheter for some patients), systolic artery blood pressure (SABP), CVP, inotropes  usage, urine output and first post-operative blood lactate levels (within 30 min post operation), prognosis variables: mechanical ventilation (MV) time, ICU stay time and hospital stay time. Renal disease was defined as preoperative glomerular filtration rate < 30 ml/min/1.73 mce area) . Hyperlice area) .During operation, MABP and CVP were continuously monitored using invasive peripheral artery, central vein or pulmonary artery catheter and saved as time-series data. Artifactual data were removed according to previously published criteria . ThreshoThe entire dataset was randomly stratified into the training and test sets (7:3), meaning that the ratio of patients with LCOS to those without LCOS was maintained consistent in both subsets. The training set was applied to train the model with 10-fold cross-validation and test set was used later to assess the models’ performance. All variables with a missing rate > = 10% were excluded from the analysis . VariablSix conventional machine learning algorithms were employed to construct the LCOS prediction models will all variables (full models), including logistic regression (LR), support vector machine (SVM), decision tree (DT), random forest (RF), extreme gradient boosting (XGB), and light gradient boosting machine (LGB).Boruta and the least absolute shrinkage and selection operator (LASSO) were used to select the optimal subset of variables. All variables confirmed as important by the Boruta algorithm were entered the LASSO regressing. Finally, variables identified by LASSO regression were included for constructing reduced models using the same six machine learning algorithms.t-test was employed for comparisons. Measurement data that did not conform to a normal distribution were denoted as median [lower quartile-upper quartile]. Wilcoxon rank-sum tests were performed to draw comparisons. The enumeration data were represented as frequency and percentage and compared by performing Pearson χ2 test. Fisher’s exact test was performed under the expected frequencies of one or more cells less than 5. The difference was considered with statistical significance at P < 0.05.Baseline characteristics of patients in the training and test sets were compared. Measurements conforming to a normal distribution were described as mean ± standard deviation. Student’s The discriminations of models were evaluated by the area under curve (AUC) of the receiver operating characteristic (ROC), accuracy, sensitivity, specificity and calibration of the models were assessed by the calibration curve and Brier score. Shapley Additive explanation (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) were used to provide consistent and locally accurate values for each variable within the prediction models. All analyses were conducted in R (version 3.6.3) and Python (version 3.7).P < 0.001), longer ICU stay time  and hospital stay time . There was no significant difference in morbidity between patients with LCOS diagnosed by CI criterion and other criteria , and patients with LCOS diagnosed by different criteria had similar prognoses  male, 18 to 88 years old] were enrolled for analyses. Among them, 386 (24.4%) patients received PAC insertion during the surgery, and the proportion of PAC use varied by surgery types . Among prognoses , indicatWe randomized 70% of these 1,585 patients into the training set and the remaining 30% into the test set. The clinical variables of patients in training and test set are listed in The full models were conducted with all variables, using the six algorithms including LR, DT, SVM, RF, XGB, and LGB for LCOS predicting, and the AUC, accuracy, sensitivity, and specificity of each full model on test set were presented in Feature selection was performed by the following two steps. First, Boruta algorithm was employed and 35 features were confirmed important to the prediction of LCOS . Then, LThe SHAP summary plot  and depeBig data and machine learning are enabling the shift from conventional to customized treatment, which could soon result in the birth of a new health system , 19. To We adopted a dual definition of LCOS, similar to the prior studies , 13, witLow Cardiac Output Syndrome could be corrected by timely and effective intervention and a variety of therapeutic strategies can be applied to the treatment of LCOS, when it is early recognized, including optimization of ventricular preload and afterload; inotropic agents; positive pressure ventilation; heart rhythm and rate control; metabolic and hormonal disorders correction; and in extreme circumstances mechanical circulatory support , 25, 26.The present study showed that LVEF, Lac, LVDd, MABP < 65 time, hypertension, PLT, age, Cr, CVP_AUT_16, CVP_AUT_12, and blood loss significantly contributed to the prediction. The reduced RF model using these features also showed little discrimination loss in the prediction of LCOS (AUC:0.895 vs. 0.909) but it could significantly increase the efficiency and convenience, which may contribute to risk stratification and short-term decision making for LCOS.Traditionally, machine learning models have been less interpretable when compared to traditional regression models. This black-box behavior has hindered their application in clinical settings. To enhance the interpretability of machine learning, we utilized SHAP and LIME interpreter techniques to visualize how features affect the prediction of LCOS, both globally and individually accordingly. SHAP summary plot revealed that LVEF, Lac, LVDd and MABP < 65 time were the most significant predictors of LCOS, with lower LVEF, higher Lac, larger LVDd and longer MABP < 65 time indicating increased possibility of the prospective onset of LCOS. LVEF is the most widely used estimate of left ventricular systolic function and a decreased LVEF is an independent risk factor for LCOS , 28. SerOur study had several advantages when compared to previous studies. Firstly, our study included comprehensive variables including demographics, commodities, echocardiographic and laboratory measurements and operation related information including intraoperative hemodynamic data, which could reflect the patient’s profile in multiple dimensions. Secondly, we incorporated various hemodynamic time-series features that were considered difficult to incorporate in prediction models –34. In oThirdly, we analyzed the predictive value of all features and selected features for LCOS prediction. Some studies made feature selection only based on linear regression or stepwise logistic regression, which may exclude features that were not statistically significant but have causal effects on the output variable due to non-linear relationships or interactions between the variables and outcomes . As a wrThis study was subject to some limitations. First, we did not compare the performance of our models with previous LCOS risk scores because some of the variables required in the risk scores were not available. Second, the models have not been verified in the external validation queue. Third, this is a single center retrospective study. Further multi-center studies with external validation are needed to further verify our findings and prospective studies could be of more importance in assessing the performance of our predictive models.In the present study, we successfully developed several machine learning models to predict LCOS following cardiac surgery, which may avail to risk stratification, early detection and management of LCOS following cardiac surgery.The original contributions presented in this study are included in the article/The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Nanjing First Hospital, Nanjing Medical University (KY20220518-KS-01). Informed consent was not obtained due to the observational and anonymous nature of data collection.LH, HX, CG, DG, and CZ conceived the conception of the study. LH, HX, CG, HT, and XSh acquired the data. XSo, DG, and CZ participated in data analyses. CG and DG constructed the predictive model. LH, HX, CG, and HT prepared the first draft of the manuscript. CZ and DG led the project and supervised the study. All authors were involved in writing or editing the manuscript, read, and approved the final version of the manuscript.


The role of uric acid levels in the cardiovascular continuum is not clear. Our objective is to analyze the prevalence of hyperuricemia (HU) and its association with cardiovascular risk factors (CVRF), subclinical target organ damage (sTOD), and cardiovascular diseases (CVD). We evaluated the prevalence of HU in 6.927 patients included in the baseline visit of the IBERICAN study. HU was defined as uric acid levels above 6 mg/dL in women, and 7 mg/dL in men. Using adjusted logistic regression models, the odds ratios were estimated according to CVRF, sTOD, and CVD. The prevalence of HU was 16.3%. The risk of HU was higher in patients with pathological glomerular filtration rate (aOR: 2.92), heart failure (HF) (aOR: 1.91), abdominal obesity (aOR: 1.80), hypertension (HTN) (aOR: 1.65), use of thiazides (aOR: 1.54), left ventricular hypertrophy (LVH) (aOR: 1.36), atrial fibrillation (AFIB) (aOR: 1.29), and albuminuria (aOR: 1.27). On the other hand, being female (aOR: 0.82) showed a reduced risk. The prevalence of HU was higher in men, in patients presenting CVRF such as HTN and abdominal obesity, and with co-existence of LVH, atrial fibrillation (AFIB), HF, and any form of kidney injury. These associations raise the possibility that HU forms part of the early stages of the cardiovascular continuum. This may influence its management in Primary Healthcare because the presence of HU could mean an increased CV risk in the patients. Cardiovascular diseases (CVD) are the leading cause of death in Spain, particularly in women , and areAtherosclerosis is the pathophysiological base of CVD, which progresses silently over decades due to the effect of CVRF and of subclinical target organ damages (sTOD) to the development of CVD . This isAmong CVRF, the potential role of uric acid—a product of xanthine oxidase—in the development of CVD has been set forth, since high uric acid levels have been identified in the context of oxidative stress and of CVD, such as ischemic heart disease (IHD) and heart failure (HF) .Hyperuricemia (HU) is associated with a state of oxidative stress that produces endothelial dysfunction, increases oxidation of LDL, and promotes a proinflammatory state which contributes to the development of atherosclerosis and its thrombotic complications ,7,8,9. TAt present, there are studies available that provide solid results on the relationship between HU and CVRF such as hypertension (HTN) , diabeteForming a complete picture about patients and the CVRF, the risk factors needing to be controlled, and the sTOD or CVD rates would allow us to control the confounding effect among all the variables and to further the study of the role of HU in the cardiovascular continuum, as is the case of the IBERICAN study  .The objective of this study is to analyze which CVRF, sTOD, and CVD are associated with HU in patients seen in primary care practices.Cross-sectional HU prevalence study conducted in patients included in the IBERICAN study .https://clinicaltrials.gov with the number NCT02261441 (accessed on 1 November 2022).The study was approved by the Ethics Committee for the investigation with medicinal products (CEIm) of the Hospital Clínico San Carlos of Madrid on 21 February 2013 (C.P. IBERICAN-C.I. 13/047-E) and is registered at Patients aged between 18 and 85 were recruited consecutively in primary care practices with the following inclusion criteria: (1) user of the National Health System, (2) residing in Spain during the last 5 years, (3) registered with the physician researcher, (4) signing the informed consent form. The exclusion criteria were (1) change of habitual residence to another town or country in the next 6 months, (2) terminal illness or reduced life expectancy in the next 5 years, (3) clear difficulty in being followed up in PC, or (4) refusal to form part of the cohort in the first place or to continue to be part of it during the follow-up. The estimated sample size has been detailed in previous publications .Socio-demographic data of each patient were recorded in the entry visit , as well as toxic habits , family history of early CVD and personal history , clinical parameters , information on the presence or absence of each CVRF as well as their treatment. The complementary tests recorded were lab tests  and electrocardiogram, which were considered valid if performed within the last 6 months before the patient’s inclusion. The equation CKD-EPI was used to calculate the glomerular filtration rate (eGFR) .The HU was defined as uric acid levels above 6 mg/dL in women and 7 mg/dL in men, as set out in the guidelines on HTN of the European societies 2018 . All othQualitative variables have been defined as percentages with a 95% confidence interval (95% CI). For quantitative variables, the Shapiro–Wilk test has been used to check the data fitting to normal distribution. If the variable showed normal distribution, it has been described using the arithmetic mean and the standard deviation (SD); otherwise, the median and the interquartile range have been used.The bivariate analysis has been performed using chi-square for qualitative variables, and ANOVA for quantitative variables, comparing patients with HU with patients without HU.p-value < 0.05.Unconditional logistic regression models were used to estimate the odds ratios adjusting (aOR), as the case may be, for socio-demographic variables  or clinical variables. Results are presented with their 95% confidence intervals (95% CI). Finally, a multivariate analysis was carried out to study the relationship of CVRF and demographic variables with HU. All analyses were performed with the program STATA version 16. We consider statistically significant a The study included the 6927 patients with available data on uric acid levels. The prevalence of HU was 16.3% (95% CI: 15.4–17.1). In total, 35.4% (95% CI: 32.6–38.3%) of patients with HU presented some form of sTOD. The sTOD which had the highest risk of HU was left ventricular hypertrophy (LVH) (aOR: 1.36 [95% CI: 1.00–1.83]) .A total of 23.9% of patients with HU presented CVD. A significantly higher prevalence of HU was observed in patients with AFIB (aOR: 1.53 [95% CI: 1.19–1.98]) . The risThe model best-fitting model  includesThe results presented here, from a sample of 6927 patients recruited consecutively in PC, show that the prevalence of HU is 16.3%, and that the risk of HU increases in patients with both forms of kidney disease , HF, AFIB, and in the presence of CVRF such as HTN and abdominal obesity, as well as the use of thiazides. These associations have been described in various studies independently, although this is the first time that all the clinical and epidemiological variables are analyzed at the same time in a contemporary PC cohort. This has allowed us to analyze the risk of HU associated simultaneously with other variables, in order to be able to make the necessary adjustments in a multiple analysis.The HU prevalence (16.3%) found in this study is slightly higher than other works that used the same cut-off points in neighbouring countries (13.9%) , or evenOur results, obtained from a cross-sectional analysis of the entry visit of the patients of the IBERICAN study, do not enable us to establish the causal link of these CVRF and HU. Nevertheless, these results reinforce the association with obesity , HTN 1212,33, DMThis study also allowed us to analyze the simultaneous coexistence of sTOD with CVRF and CVD. It has been observed that both albuminuria and LVH have a higher risk of associated HU. This is important because both lesions are closely linked with HTN ,40,41, bFrom a practical point of view, HU appears to be a risk marker that reflects the oxidative stress associated with a higher CVR, from the first stages to recurrent events, and the development of kidney disease and CVD. In the absence of treatments that improve the CV prognosis with the reduction of uric acid levels, identifying patients with higher levels of uric acid could be useful to identify individuals with a higher associated CVR, and who could benefit from a better control of CVRF, giving priority to obesity, in order to improve the CV prognosis. In parallel, a careful use of thiazides should be considered in patients with HTN, since the results of our multivariate analysis have shown that both affect the risk of HU. So, taking into account that it is a first-line drug for HTN  and a knWe believe that the results presented here are statistically robust and consistent with the available literature on this topic; in addition, they allow for a better understanding of the characteristics of the patients with HU in a contemporary cohort. The sample size is sufficient to analyze which CVRF are associated with HU, as well as the adjustment variables necessary for this study. However, our research also has limitations, some of which have been discussed in previous works ,53, suchMoreover, the cross-sectional design of the study does not allow us to establish causal relationships, although the aim of this study was to describe the patients’ characteristics and, therefore, its design is valid.Lastly, in this research, the uric acid-lowering treatment of the patients was not recorded; therefore, it could not be included in the adjustment models. In this sense, it is possible that some patients classified as normouricemic would actually be HU. Even keeping that in mind, our results show the best situation, and by avoiding this bias, we would obtain more strength associations as we observed. Moreover, our results are similar to those of other authors published before, and they are biologically plausible. For these reasons, authors consider our findings answer our main research question.Given the foregoing findings, it can be concluded that the risk of HU is greater in men, in the presence of CVRF such as HTN and abdominal obesity, and with the coexistence of LVH, AFIB, HF, and any form of kidney injury. These associations raise the possibility that the HU forms part of the early stages of the cardiovascular continuum, but it needs observational studies that confirm this hypothesis. However, it remains to be seen whether it is a cardiovascular risk factor and a possible therapeutic target to modify the CV prognosis, or a reflection of the existence of other metabolic disorders and of the oxidative stress characteristic of abdominal obesity which are mainly responsible for increasing the CV risk in this group of patients. If we can confirm this association, its presence in the early phases of the cardiovascular continuum makes it necessary to pay more attention in primary care to patients classified as low or moderate cardiovascular risk who have increased uric acid levels, since it could lead to reassessment of CVR.


Venoarterial extracorporeal membrane oxygenation (V-A ECMO) with femoral access has gained wide acceptance in the treatment of critically ill patients. Since the patient´s cardiac output (CO) can compete with the retrograde aortic ECMO-flow, the aim of this study was to examine the impact of the inspiratory oxygen fraction on the cardiac function during V-A ECMO therapy.cvO2), CO, stroke volume, left ventricular ejection fraction (LVEF), end diastolic volume, and pressure were measured. Cardiac injury was determined by analyzing the amount of lactate dehydrogenase (LDH).Eighteen male Lewis rats (350–400 g) received V-A ECMO therapy. The inspiratory oxygen fraction on the ventilator was randomly set to 0.5 (group A), 0.21 (group B), or 0 in order to simulate apnea (group C), respectively. Each group consisted of six animals. Arterial blood pressure, central venous saturation (ScvO2 were significantly impaired compared to group A and B. The course of LDH values revealed no significant differences between the groups.During anoxic ventilation the systolic, mean and diastolic arterial pressure, CO, stroke volume, LVEF and SAnoxic ventilation during V-A ECMO with femoral cannulation leads to cardiogenic shock in rats. Therefore, awake V-A ECMO patients might be at risk for hypoxia-induced complications.The online version contains supplementary material available at 10.1186/s12872-022-02613-w. Extracorporeal membrane oxygenation (ECMO) has been widely accepted for the treatment of pulmonary or cardiac failure in critically ill patients, which has led to increased implementation in intensive care medicine over the last decade . While vIn contrast to complete cardiopulmonary bypass (CPB) perfusion with cardioplegic cardiac arrest, during ECMO therapy the heart continues beating . Knowled2), both ECMO and mechanical ventilation affect pCO2 values. During awake ECMO therapy, a decrease of pCO2 might lead to apnea resulting in a severe deoxygenation with consecutive ischemia of the coronary and cerebral tissue caused by the harlequin phenomenon. For this reason, the aim of our study was to examine the impact of the inspiratory oxygen fraction (FiO2) on cardiac function during V-A ECMO therapy with jugolo-femoral access.Recent studies showed the beneficial effects of awake V-A ECMO therapy but especially these patients are at an increased risk for the development of ventilator-associated pneumonia , 14. As All procedures involving animals were conducted in compliance with standards for animal care and the ARRIVE guidelines, and were approved by the responsible single local committee for animal care .iO2 was adjusted at 0.5 , 0.21 , or 0 in order to simulate apnea . Since the measurements of the pressure volume (PV) catheter are influenced by the ventilation, apnea would have affected the results of the PV catheter. Therefore, anoxic ventilation with 100% of nitrogen was performed as a surrogate for simulated apnea.Twenty-two male Lewis rats (350–400 g) obtained from Janvier Labs  were housed at 22 °C, 55% relative humidity, and a day/night cycle of 14/10 h, with access to standard chow and water ad libitum. The rats were randomly divided into three groups. The FFour animals had to be euthanized before the end of the study due to perforation of the draining cannula into the chest cavity during the process of cannulation. These animals were excluded from the study.1.01 × 0.0062; respiratory rate (/minute) = mass (kg)−0.26 × 53.5). The animals were placed on an automated heating pad and a rectal temperature probe was inserted. Monitoring included end-tidal carbon dioxide , continuous electrocardiogram, heart rate (HR), CO, stroke volume (SV), left ventricular end diastolic volume (LVEDV) and pressure (LVEDP), left ventricular ejection fraction (LVEF), and arterial blood pressure . After the percutaneous cannulation of the lateral tail vein  a continuous balanced crystalloid infusion at a rate of 5 ml/kg/h  with fentanyl  was started.After inhalative induction of anesthesia  balanced with 100% oxygen) the rats were intubated endotracheally  and ventilated volume-controlled  in a weight-adjusted manner  = mass (kg)Additionally, midazolam  and pancuronium  were administered for the maintenance of anesthesia.The vascular accesses were placed surgically and consisted of the tail artery cannula for measurement of the arterial blood pressure and intermittent blood gas analysis , the right femoral artery cannula for ECMO return , and the right jugular vein cannula for ECMO drainage  . FurtheriO2 was adjusted to 0.5, 0.21 or 0, accordingly. Sweep gas flow on the membrane was regulated between 20 and 30 ml/minute to adjust the pCO2 levels between 35 and 45 mmHg. The oxygen fraction on the ECMO membrane was set to 1.0. Further, the animals received no vasopressor support. Moreover, the volume of blood sampling was replaced with hydroxy ethyl starch 6%.As previously described, the ECMO circuit consisted of a venous reservoir , a roller-pump , and a membrane oxygenator  . The who0). While a new timepoint was defined every 7.5 min, arterial blood pressure and invasive hemodynamic parameters were recorded up to 120 min (t0–t16). Depending on the procedural injury, the animals in groups A and B were observed for two hours, whereas the observation period of group C was one hour due to animal welfare.Baseline values were captured before commencing the ECMO after implementation of all cannulas and catheters at baseline , and every 30 min after commencing the ECMO till t16. At each observation point the oxygen partial pressure (pO2), pCO2, hemoglobin, hematocrit, pH, bicarbonate, base excess (BE), lactate, glucose, sodium, potassium, calcium, and chloride were measured . In addition, blood samples were centrifuged at 3000 g for 5 min and the plasma samples were stored at −80 °C for further analysis.Blood samples were collected at baseline (tLactate dehydrogenase (LDH) measurements were performed using a commercial enzyme-linked immune sorbent assay (ELISA) according to the manufacturer's instructions . The probes were unfrozen only once.http://www.r-project.org). A group size of ten animals revealed a measurable difference of a twofold standard deviation regarding the LVEF . According to animal welfare regulations, intermittent statistical analyses were performed. Following the regulations of the animal welfare board, the experiments were stopped after six animals of each study group because statistical significance of the results had already been reached. All data are expressed as median with 25th and 75th percentile. Homogeneity of variance was verified with the Levene test. If the test of homogeneity was positive, the ANOVA and post hoc Tukey test were used for comparison of intergroup differences at identical time points, while the Welch and post hoc Games-Howell test were applied during inhomogeneity of variance. Due to the fact that group C ended after t8, groups A and B were compared with Wilcoxon–Mann–Whitney test between t8 and t16. The analysis of variations in LDH levels across different time points within the same group was calculated by the Friedmann test. All statistical analyses were performed using SPSS Version 20 . GraphPad Prism Version 7 was used for data presentation .The sample size calculation was performed using R statistical software version 3.6.2 (iO2 0.5) and B (FiO2 0.21) the systolic, diastolic, and mean arterial pressure were significantly decreased during anoxic ventilation (group C). Contrary, no differences were found between group A and B after commencing the ECMO  at t4 and t8 compared to groups A and B  was significantly reduced in group C during t4 and t8  resulted in severe hemodynamic alterations which was defined by a significant reduction of systolic, diastolic, and mean arterial pressure. Furthermore, a significant impairment of cardiac function determined by a reduction of LVEF and CO was observed during pulmonary hypoxia, which was mainly induced by a decrease of the SV but not the HR indicating cardiac failure.Even though these results seem unsurprisingly, they are the first to describe systemically the relevance of apnea on the cardiac function during ECMO-therapy with femoral cannulation because commonly rat models of CPB are performed under asphyctic cardiac or deep hypothermic circulatory arrest –19. FurtcvO2 and increased lactate level. Next, loss of BE, decreased bicarbonate, and impaired pH demonstrated that the acid–base metabolism was not able to compensate for the lactate induced acidosis. These results are in accordance with the findings of Engels et al. who investigated rats under circulatory arrest. Despite the deep hypothermic circulatory arrest, bicarbonate levels of 13.8 mmol/l and a BE of -12.5 were measured during rewarming [Cardiogenic shock during anoxic ventilation was reflected by the severely impaired Sewarming . In addiewarming .2 and elevated pCO2 are also explainable with the anoxic ventilation within study group C. However, Koning et al. were able to adjust the pO2 between 150 and 250 mmHg within a rat model of CPB with femoral cannulation and apnea before the beginning of CPB [iO2 of 1.0 during ECMO therapy.Lower blood pOg of CPB . These siO2. Therefore, the impaired cardiac function during anoxic ventilation appears to be caused by the low oxygen saturation of the coronary blood. However, to the knowledge of the authors, it is technically not possible to measure the coronary blood flow in rats. Further, it offers the risk of exsanguination due to additional aortic cannulation and probe placement. Last, the measurement of both—coronary blood flow and blood saturation—would have required an open chest cavity, which affects the measurements of the pressure volume catheter. We decided against increasing the ECMO flow because an enhanced ECMO flow might raise the already reduced mean arterial pressure and, thus, aggravate the shock signs by raising the left ventricular afterload. This is shown by Konig et al., even though they used no PV catheter in their model. In the description of their experiments, the blood pressure of the tail artery showed an almost flat line during CPB indicating low CO [Due to the fact that the ventilator driving pressure during ECMO therapy is associated with increased in-hospital mortality, ultraprotective lung ventilation under ECMO-supported oxygenation is widely adopted across ECMO centers , 24, 25.g low CO . Contrarg low CO . In summiO2 of 0, our approach is different from apnea. Compared to apnea without ventilation, we opted for continuous ventilation without oxygen to maintain the ventilation-induced positive intrathoracic pressure. While the reduced intrathoracic pressure during spontaneous breathing could enhance the perfusion of the lungs and thus affect the left ventricular PV measurements, our experimental groups would not have been comparable. Therefore, we also opted for ventilation during V-A ECMO with neuromuscular blocking to avoid spontaneous breathing. Moreover, due to the limited diameter of the venous cannula, only blood flows of 90 ml/kg/minute were achieved. Third, this study was not able to proof cardiac ischemia in terms of increasing LDH blood levels only during anoxic ventilation. Lacking of data on the harlequin effect during V-A ECMO therapy in the rat, we designed this study as a pilot study and performed the sample size calculation on the primary endpoint “LVEF”. To reduce unnecessary harm to the animals, we stopped the inclusion of further rodents after the interim analysis according to the regulations of the local department of animal welfare . As a result, only a limited number of animals were available for the analyses of secondary endpoints such as the measurement of LDH. For this reason, the study is not able to clarify if a higher number of animals would have revealed significant alterations of the plasma LDH. Furthermore, LDH was rising continuously in all study groups indicating the increasing ECMO-induced cell damage. Clements et al. analyzed the time course of LDH and Troponin I levels after isoproterenol-induced myocardial injury in the rat and revealed serum peak levels of LDH after four and troponin I after three hours, respectively [iO2 on the brain during V-A ECMO therapy could be investigated by histological investigations in the future. Last, results from an animal model cannot be directly transferred to humans.Our experiments still have some limitations. First, positive intrathoracic pressures induced by the mechanical ventilation are lacking during awake V-A ECMO with spontaneous breathing. However, it is very difficult to perform good quality left ventricular PV measurements during spontaneous breathing. Furthermore, passive oxygenation with ambient air can occur during apnea. Since no passive oxygenation is possible during ventilation with a Fectively . FollowiiO2 on cardiac function during V-A ECMO with femoral cannulation was investigated. Pulmonary hypoxia led to hypotension and severe cardiac dysfunction determined by a lactate-induced acidosis and severely impaired ScvO2. For this reason, apnea induced pulmonary hypoxia might endanger patients for cardiac ischemia during V-A ECMO with femoral cannulation.In summary, the impact of FAdditional file 1. Supplementary Table S1: Results of the blood gas analysis.


In the last decades, improvements in the average life expectancy in the world population have been associated with a significant increase in the proportion of elderly people, in parallel with a higher prevalence of non-communicable diseases, such as hypertension and diabetes. As the kidney is a common target organ of a variety of diseases, an adequate evaluation of renal function in the approach of this population is of special relevance. It is also known that the kidneys undergo aging-related changes expressed by a decline in the glomerular filtration rate (GFR), reflecting the loss of kidney function, either by a natural senescence process associated with healthy aging or by the length of exposure to diseases with potential kidney damage. Accurate assessment of renal function in the older population is of particular importance to evaluate the degree of kidney function loss, enabling tailored therapeutic interventions. The present review addresses a relevant topic, which is the effects of aging on renal function. In order to do that, we analyze and discuss age-related structural and functional changes. The text also examines the different options for evaluating GFR, from the use of direct methods to the implementation of several estimating equations. Finally, this manuscript supports clinicians in the interpretation of GFR changes associated with age and the management of the older patients with decreased kidney function. The proportion of older people in the population is increasing worldwide, reflecting profound demographics changes overall. In 2020, there were 727 million elderly individuals aged 65 years or over, representing 9.3% of the world's population—a number expected to double by 2050 . As a re2 , reflecting the loss of kidney function. Anatomical and functional changes become more evident in advanced ages, accounting for the GFR decrease. The loss of kidney function with advancing age indicates a physiological decline in GFR associated with healthy aging as a natural senescence process , a condi2 . However2 in the absence of kidney damage, as defined by structural of functional abnormalities  was proposed and analyzed in a large Canadian cohort, consisted of 127,132 individuals. Using a single, fixed eGFR threshold irrespective of age resulted in a 60% higher incidence of CKD. In this study, it is of note that 75% of individuals classified as CKD according to current fixed eGFR criteria <60 mL/min/1.73 m2 were 65 years or older and had an eGFR of 45–59 mL/min/1.73 m2 without significant albuminuria, raising the concern whether these individuals should be classified as CKD patients. The classification of older patients with age-related eGFR decline as having CKD is of crucial relevance, as it leads to an increase the risk of unnecessary interventions in much of this elderly population with additional implications for clinical practice and health policies  published a new chronic kidney disease (CKD) classification based on five categories of estimated glomerular filtration rate (eGFR), CKD has been defined as GFR <60 mL/min/1.73 mmalities . This ths of age . Althoug elderly . In factpolicies .Accurate assessment of renal function in the older population is of particular clinical significance for the diagnosis and classification of CKD, enabling tailored therapeutic interventions, and avoiding treatments of unnecessary and/or potential risk. GFR measurement can be carried out using conventional approaches through renal or plasma clearances of specific filtration markers, by measuring the marker concentration in plasma and urine or only in plasma, respectively . AlternaThe present review is aimed at understanding the physiology of glomerular filtration in the elderly, highlighting the structural and functional changes associated with normal healthy aging leading to age related loss of kidney function. Also of interest is reviewing the different options to evaluate GFR in the elderly population to provide support to clinicians in the option and interpretation of the most appropriate method to either measure or estimate GFR.The kidneys receive 20–25% of the cardiac output. Appropriate glomerular filtration occurs to excrete waste products of metabolism and to maintain internal homeostasis of water and electrolytes. The most important physiological function of renal hemodynamics is to keep the blood flow and pressure within the glomerular capillary at levels that provide adequate filtration rate with subsequent optimum tubular reabsorption and secretion functions . An adeq2 adjusted to demographic parameters such as gender, race and age  and confirmed a progressive decline with the age of an average of −0.89 ml/min/1.73 m2 per year, corresponding to a Full Age Spectrum (FAS) equation prediction of an average decline rate of −0.92 ml/min/1.73 m2 per year , a robust study including 1,594 healthy individuals from the general population (age 50–62 years) followed for more than 5 years, showed a measured GFR decline rate of 0.95 ± 2.23 ml/min/1.73 mper year . A meta-hy women . Table 12  –37.Structural changes are associated with the senescence kidney process. With aging, the number of nephrons decreases among healthy adults –41. UndeThe loss of nephrons likely reflects a progressive degree of glomerulosclerosis, which increases with normal aging, even in healthy aging , 43–47. Along with the structural and functional impairment changes, an age-related decline in GFR occurs with healthy aging –51. ProgIncreased glomerular volume associated with compensatory hypertrophy can induce podocyte injury and loss. Podocytes are crucial cells for maintaining the normal glomerular architecture and capillary permeability but, due to their terminal differentiation nature, they have a limited capacity to undergo cell division, regeneration, and repair . The degThe pathophysiology of renal mass decrease may be related to several mechanisms, such as a decrease in klotho expression, an increase in telomere shortening, DNA instability, increased oxygen radicals, and overexpression of proteins that induce cell cycle arrest, with induction of p16 and p21 cell cycle inhibitors –59. KlotBesides glomerulosclerosis, other structural changes become more evident in the kidneys of elderly patients, including tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and atherosclerosis that increase with aging . One hypArterial hypertension, a high-sodium diet, the Western lifestyle, and its correlated comorbidities such as obesity and diabetes have already been associated with age-related loss of kidney function, although there is evidence that this process occurs despite the presence of these factors. Studies performed in patients without arterial hypertension or in diabetic patients showed similar declines in renal function rates , 63, sugSeveral studies indicate that renal hemodynamics is impaired with aging due primarily to a vascular process. The altered renovascular tone can be due to structural lesions in the renal vasculature, more evident in older patients with cardiovascular comorbidities, whilst pronounced renal vasoconstriction is also expressed in healthy normotensive elderly subjects, possibly due to functional abnormalities , 64, 65.With the aging process, other changes in kidney function can be observed . The abiRenal regulation of sodium/potassium balance is also impaired in the elderly. Individuals older than 60 years submitted to sodium restriction have a lower capacity to reduce sodium excretion. On the other hand, older individuals submitted to sodium load do not properly excrete sodium, leading to sodium retention and fluid volume expansion . Potassi+ load and ammonium  2D3, and an age-related decrease in the capacity of 1,25-dihydroxyvitamin D3 to promote intestinal absorption of calcium, resulting in increased PTH secretion and higher FGF23 levels .Several studies have addressed the discussion of the accuracy of GFR measurements in the elderly , 74–78. The determination of inulin clearance performed under continuous intravenous infusion and urine collection is considered the most accurate, and still the gold standard method for GFR measurement, but it is cumbersome, expensive and not feasible in daily clinical practice . AlternaA disadvantage of urinary clearances for measuring GFR, particularly in the frail elderly population, is the troublesome related to urine sample collection, which can lead to errors due mainly to urinary losses and incomplete urinary bladder emptying, causing sampling errors that might jeopardize the results. In this setting, the evaluation of plasma clearances for measuring GFR provides more precise results than urinary clearances .Cystatin C is a more reliable endogenous marker for the evaluation of renal function compared to creatinine. Cystatin is a substance constitutively produced by all nucleated cells. As a low molecular weight protein, cystatin is freely filtered by kidneys and catabolized in the tubules, where all metabolites are reabsorbed. Cystatin C is not dependent on muscle conditions  but is i51Cr-EDTA, 99mTc-DTPA, and 125I-iothalamate have also been employed for GFR measurements with different availability in different centers. Determination of plasma clearances comprises intravenous injection of the compound and subsequent blood-sample drawings at different time-points to construct a plasma disappearance curve of the exogenous marker. Although methods based on exogenous markers likely provide higher accuracy in determining GFR, they are usually more expensive and not widely accessible in routine practice. While they have also been considered as gold standard for GFR determination in many studies, it is important to be aware that substances such as iothalamate are secreted by renal tubules and therefore, can overestimate GFR as compared to inulin clearances  equations rather than direct measurement of GFR. eGFR based on equations is a simple and less expensive assessment, recommended by clinical guidelines from the National Kidney Foundation (NKF KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) , 82. Dif2 body surface area (BSA) derived from measured iothalamate-measured GFR , normalized to 1.73 mured GFR . In bothured GFR , 78, 85,ured GFR . Of noteThe Chronic Kidney Disease-Epidemiology Collaboration equation (CKD-EPI) , also deEquations based on serum cystatin C levels have proved their superiority over creatinine-based formulas in the elderly –88. A meTo provide a more precise and accurate GFR evaluation in the elderly, the Berlin Initiative Study (BIS) analyzed a cohort of subjects aged over 70 years , resultiOther eGFR equations for the elderly population have been described such as the Caucasian, Asian, Pediatric and Adult (CAPA) , the JapMore recently, in 2016, Pottel et al. developed, in European healthy individuals, a new eGFR equation for the elderly population, the FAS , based oCompared to gold standard clearance methods, the currently available equations for determining eGFR have different performances related to bias, precision, and accuracy, which highlights the difficulty in defining an accurate estimation of GFR in older patients. It is important to emphasize that the Cockcroft-Gault equation is not similar to CKD-EPI or other eGFR equations.Schaeffner and coworkers compared performances of the eGFR equations, consisting of the BS1 and BS2 equations, Cockcroft-Gault, MDRD, CKD-EPICr, and CKD-EPICys, with the gold standard iohexol plasma clearance measurement in an elderly population-based cohort [the Berlin Initiative Study (BIS)] . BIS equThe 2017 study of Bjork, a large multicenter cohort of Europeans that enrolled 3,226 individuals 74–93 years of age, validated four creatinine equations  compared to iohexol plasma clearance as a gold-standard method . LMRCr hIn 2018, Björk et al. compared the performance of GFR estimating equations using creatinine and cystatin C in a cohort of elderly patients from Iceland who participated in the AGES-Reykjavik Study . A subgrn = 2,247) aged 65–90 years with various degrees of kidney impairment, tested four different equations  compared to measured GFR using inulin clearance . The analysis of discrepancies between the CKD-EPI, Japanese, and BIS equations showed that eGFRcr was overestimated with CKD-EPI or the Japanese equation. They concluded that estimation of GFR using serum cystatin C provided more accuracy in elderly people  separated into two groups, <75 and y people .It is worth mentioning that measured GFR is considered the gold-standard approach to access GFR. This is important because any equation used to estimate GFR may have an average error as wide as 30% or even larger, even while choosing that with higher accuracy, it has a bias that may reach 30 ml/min of difference from the measured filtration rate . TherefoAccurate determination of GFR in the older population is of crucial importance for the correct evaluation of age-related kidney dysfunction, which implies appropriate management related to the stage of kidney disease.In clinical practice, one of the most important aspects to be considered is the adequate adjustment of the dosage of prescribed drugs to avoid overdosing. Elderly patients have often been submitted to polypharmacy and many of these medications have renal excretion, which requires dose reductions adjusted to the degree of GFR compromised, more easily calculated by the GFR equations. Whether it is a pathological or age-related reduction in GFR, the dosage of renal-eliminating drugs should be adjusted according to the GFR, to avoid potential harm.2  are often prescribed for the management of pain relief in the elderly population. NSAIDs are considered nephrotoxic drugs, with the exposure associated with a high risk of GFR decline of ≥30% in individuals with eGFR <60 ml/min/1.73 m2 . Hence, The use of iodinated contrast media is another potential cause of kidney injury possibly leading to kidney adverse outcomes such as renal dysfunction characterized by abrupt GFR decline and, eventually, the need for dialysis. The use of iodine-based contrast media for diagnostic and interventional radiology for the geriatric population has exponentially increased in the last decades, in oncological settings, cardiovascular imaging examinations, and other clinical situations. Risk factors for developing contrast nephrotoxicity include pre-existing CKD, dehydration, diabetes, and the use of ACE inhibitors, diuretics, and NSAIDs, all common situations in older patients providing high susceptibility to developing worsening kidney function , 107. ThAdjustment of drug dosing in the elderly according to GFR is widely employed in clinical settings important for avoiding harmful complications. In the aging population, type 2 diabetes is a prevalent condition, and for instance, the risk of hypoglycemia can be avoided, at least in part, by the adjustment of oral antidiabetic agents. Older patients are often affected by infections for which antimicrobials are prescribed. Therefore, the knowledge of GFR is crucial in determining the ideal dose adjustment. In situations of a moderate/severe reduction in GFR, attention must be paid to avoid toxicity, and the risk of worsening renal function is needed.In summary, the clinical management of older individuals should be based on “do not harm.” The use of contrast should be leveraged according to each indication. Besides antimicrobials, all prescriptions for older individuals should consider possible the risk of further reduction in GFR. Adjustment according to measured or estimated GFR is advised. All patients should be alert against the use of potential renal-damage drugs.The population is aging. With the natural aging process, all organs, including the kidneys, undergo aging-related changes characterized by a progressively decline in biological functions and anatomical changes. The loss of kidney function due to advancing age is expressed by GFR decline. Accurate assessment of renal function in the elderly is of particular clinical importance for the appropriate evaluation and management of age-related kidney dysfunction.The gold standard methods to measure GFR include inulin clearance and plasma clearances based on clearance of radiolabelled or non-radiolabelled exogenous markers, which are laborious, expensive and not feasible in daily clinical practice. In clinical settings, an alternative to gold standard methods still capable of easily provide reliable evaluation of kidney function in the elderly is the use of estimated GFR (eGFR) equations. Hitherto, no equation precisely mirrors the measured GFR in older patients, and therefore, the results should be meticulously interpreted. The currently available equations for determining eGFR have different performances that lead to important discrepancies even in equations specifically developed for older patients. New techniques to measure GFR should be the target of future studies. The ideal method should be cost-effective and not rely only upon serum creatinine, particularly in the elderly and frail patients with sarcopenia and loss of muscle mass. Until then, equations should be used based on either creatinine or preferentially cystatin C, when available. So far, the CKD-EPI seems to be the best choice.IN planned the review article and drafted the manuscript. GS-C, LA, and RE helped to draft the manuscript. RE, LA, VAC, WJ-F, and IN gave important intellectual contributions. All authors read and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Perindopril is an ACE inhibitor that aids in both blood pressure regulation and homocysteine reduction.  Our study aimed to evaluate the results of controlling blood pressure and blood homocysteine levels by perindopril in patients with primary hypertension.  A cross-sectional descriptive study with a longitudinal follow-up was conducted on 105 primary hypertensive patients treated with perindopril. μmol/L was significantly higher than in the other group (p  <  0.05). Concerning the efficacy of decreasing homocysteine in blood, we discovered that after 6 weeks of treatment with perindopril, the proportion of patients with elevated homocysteine reduced considerably from 74.3% to 40% (p  <  0.05). In addition, the homocysteine concentration was 4.33 mol/L lower after treatment than before treatment (95% CI: 3.69–4.97) (p  <  0.05).  The results of our study showed that after 6 weeks of treatment with perindopril, the proportion of patients with the target blood pressure (BP) level accounted for 70.5%, the rate of grade 1 hypertension decreased from 61.0% to 25.7%, grade 2 blood pressure decreased from 17.1% to 3.8%, and there was no case of grade 3 hypertension. At the same time, we also found that the rate of BP control in the group of patients who controlled Hcy below a threshold of 15  Perindopril helps control blood pressure and reduces blood homocysteine levels in patients with primary hypertension. Hypertension is the cause of 62% of cerebrovascular disease and 49% of ischemic heart disease, according to the World Health Organization . In 2018In addition to classic cardiovascular risk factors, there are additional cardiovascular risk factors such as homocysteine, C-reactive protein, fibrinogen, and lipoprotein (a) that may coexist in patients with hypertension –5. HomocNumerous studies have demonstrated that lowering homocysteine levels in primary prevention improves both blood pressure and cardiovascular events , 8. TherAll patients with primary hypertension visited the examination department of the Can Tho University of Medicine and Pharmacy Hospital during the period from 5/2017 to 5/2018.All patients were newly diagnosed with primary hypertension according to JNC 6 criteria . This crAll patients with primary hypertension had comorbidities that affect homocysteine levels such as history of liver disease, kidney disease, cerebrovascular accident, and chronic comorbidities . Subjects are currently being treated with vitamin B6, B12, and folate drugs. Diabetic patients are currently taking sulfonylurea . PatientA cross-sectional descriptive study with a longitudinal follow-up was conducted.p = 0.36 is the rate of hyperhomocysteine in hypertensive patients according to the study of Minna Cheng et al. [The sample size was calculated based on the one-proportion sample size estimation formula, g et al. . In factμmol/L [All patients who met the JNC 6 criteria for hypertension and had no exclusion criteria were treated for hypertension using JNC 8 strategy A, starting with perindopril 5 mg/day, followed by perindopril 5 mg/day. Then, if blood pressure has reached the target (SBP <140 mmHg and DBP <90 mmHg), we then maintain the dose, and if it does not reach the target, the dose can be increased to 10, 15, and 20 mg/day . The antμmol/L , 18.μmol/L, defined as increased as ≥15 μmol/L [μmol/L [The mean fasting total Hcy concentration (X ® + SD) has a normal range of 5-<15 5 μmol/L , 20. Hyp5 μmol/L , such as5 μmol/L . Control5 μmol/L . Control [μmol/L , 18.Blood pressure was measured using a Japanese ALPK2 watch and stethoscope. During the measurement, the patient rested for 15 minutes and refrained from using stimulants and talking. SBP corresponds to the first pulse sound (phase I Korotkoff), and DBP corresponds to its disappearance (phase V Kororkoff). Three measurements of blood pressure were taken 2–5 minutes apart, and the average of the three readings was obtained . Using pt-test are binary, we use the McNemar test to evaluate the difference between the two groups. To compare the difference between the mean concentration of homocysteine before and after treatment, we used the paired t-test. A p value of less than 0.05 was considered statistically significant.Computerized data processing was conducted using SPSS 20.0 software. Frequencies and percentages (%) are used to represent qualitative variables (%). To compare the difference between qualitative variables, we utilized the chi-squared test and adjusted according to Fisher's exact test for tables with more than 25 percent expected value <5. In case the measured variables in the paired The study included 105 newly diagnosed primary hypertensive patients with an average age of 63.07 ± 9.32 and a mean Hcy concentration of 17.88 ± 6.03. In which, the prevalence of grade 1 hypertension was 60.9%, grade 2 hypertension was 17.1% and grade 3 hypertension was 21.9%, the rate of raised blood Hcy levels was 74.3%, men represented for 27.6%, age ≥60 represented for 68.6%, and diabetes represented for 46.7% .p  >  0.05). However, the rate of BP control in the group of patients with controlled Hcy concentration was higher than in the group of patients without controlled Hcy concentration, and this difference was statistically significant (p  <  0.05) (The proportion of patients with BP control below 140/90 mmHg after 6 weeks of treatment with perindopril was 70.5% . After t<  0.05) .μmol/L after treatment was 60% (p  >  0.05) (p < 0.001). Similarly, when conducting stratified analysis by sex, age groups, and diabetes, we found that the rate of control of blood Hcy levels after treatment rose, and the difference was statistically significant compared to before treatment (p  <  0.05) (p  <  0.001). Similarly, when conducting stratified analysis by sex, age groups, and diabetes, we found that the rate of control of blood Hcy levels after treatment rose, and the difference was statistically significant compared to before treatment (p  <  0.05) (The rate of blood Hcy levels below 15  was 60% . The dif>  0.05) . At the <  0.05) . At the <  0.05) .Our study was conducted on 105 subjects with primary hypertension at the hospital of the Can Tho University of Medicine and Pharmacy. The average age of study participants was 63.07 ± 9.32 years, with the youngest individual being 40 years old and the oldest being 83 years old. The majority of the study participants (68.6%) aged 60. This is the age with a high risk of cardiovascular diseases in general and hypertension in particular , 27.The proportion of women in our study was 2.6 times higher than that of men (72.4% versus 27.6%). According to the 2018 Canadian Hypertension Society analysis, the difference in the sex ratio in hypertension is related to genes and the physiology of sex. Especially after the 5th decade of life, the proportion of women with hypertension tends to increase due to the menopause process . This maIn our study, the prevalence of diabetes was 46.7%. Multiple research projects from throughout the world have suggested that hypertension and diabetes are interrelated. Insulin resistance in people with type 2 diabetes causes elevated cholesterol and triglyceride levels, disrupts cell-to-cell communication, including signals that regulate blood pressure, stimulates the sympathetic nervous system, and makes the heartbeat faster and the arteries constrict. In addition, it also creates an imbalance between sodium and potassium (thereby causing an increase in blood volume) and calcium and magnesium  and simultaneously induces atherosclerosis of the blood arteries, leading to hypertension , 29, 30.μmol/L, accounting for 74.3%. This result shows a relatively close relationship between hypertension and blood Hcy levels. Many studies have shown that the Hcy concentration is an independent risk factor for cardiovascular disease, which can act as a promoter of hypertension through mechanisms such as smooth muscle hypertrophy, decreased function of smooth muscle cells, damaged endothelial cells, and vasomotor dysregulation leading to hardening of the vessel wall [Among 105 hypertensive patients participating in the study, up to 78 people had elevated blood Hcy levels ≥15 sel wall , 32.p  <  0.05). However, we found that the rate of BP control in the group of patients who controlled Hcy <15 μmol/L was higher than in the other group with statistical significance (p  <  0.05). Initially, these data indicate that Hcy-controlled hypertensive patients had a better rate of BP-targeted control than hypertensive patients with uncontrolled Hcy. These data enable us to hypothesize that if hypertension individuals are accompanied by a rise in Hcy, it will be more challenging to attain desired blood pressure management. In other words, high blood Hcy levels influence the outcome of each patient's hypertension treatment. Perhaps, additional scientific studies with larger sample sizes and sufficient follow-up time are required to clarify this relationship.Recent years have seen an increase in the number of studies examining the influence of antihypertensive medications on blood Hcy levels used to prevent cardiovascular disease , 33, 34.p  <  0.05). The difference in the rate of Hcy control following treatment by gender, age groups, and patients with and without diabetes did not reach statistical significance (p  >  0.05). Stratified analyses by gender, age groups, and between groups of diabetic and nondiabetic patients revealed statistically significant differences (p  <  0.001) in the rate of control of blood Hcy concentration <15 μmol/L before and after treatment. The mean blood Hcy concentration after treatment was 4.33 μmol/L, which was lower than before treatment, with a 95% confidence interval of 3.69–4.97. The difference was statistically significant at p  <  0.001. For each sex, each age group, and between groups of patients with and without diabetes, these differences in concentrations were also significant at p  <  0.05.Perindopril or ACE inhibitors inhibit ACE activity, resulting in a decrease in angiotensin II. These medicines may also inhibit the breakdown of bradykinin, resulting in a rise in plasma bradykinin, and increase bradykinin-induced vasodilation, resulting in vasodilation and a reduction in vascular pressure . It has β-blockers dramatically decreased plasma Hcy concentrations, but hydrochlorothiazide considerably increased plasma Hcy concentrations. In this investigation, the Hcy levels before and after 6 weeks of treatment with 5 mg of ramipril were 19.12 ± 6.94 and 14.39 ± 5.75 μmol/L, respectively, with a p value less than 0.01. Consequently, their findings imply that ACE inhibitors, particularly ramipril, may be useful in treating hypertension individuals by lowering Hcy levels [Poduri et al. also conducted a case-control research study with 273 hypertension patients and 103 control people in order to examine the effect of the medication on plasma Hcy levels. In hypertensive individuals, ACE inhibitors and n = 7) treated with conventional therapy (diuretics/β-blockers). The results showed that the Hcy concentration remained unaffected [μmol/L had a significant increase in plasma Hcy levels (p = 0.02) [In addition, several studies examining the effect of ACE inhibitors on various Hcy levels have yielded contradictory results. Šebeková et al. observed the antioxidant effects of ACE inhibitors in patients with nondiabetic kidney disease on short-term use of ramipril, where Hcy was used as a parameter to evaluate oxidative stress. Ramipril (2.5–5.0 mg/day) was administered to 12 newly diagnosed patients for two months, and the data were compared with those of a group of patients (affected . Fan et  = 0.02) . These iμmol/L and 14.39 ± 5.75 μmol/L, respectively [p  <  0.001 and more pronounced in the enalapril + folic acid combination treatment group than in the enalapril monotherapy group [p  <  0.01 [μmol/L and Hcy <15 μmol/L after 6 weeks of treatment with perindopril, there was a significant reduction in blood Hcy levels (p  <  0.001). Perindopril leads to the reduction of homocysteine, a risk factor for hypertension in particular and cardiovascular disease in general, as demonstrated by our findings. Our findings corroborate the efficacy and role of perindopril in achieving the goal of cardiovascular protection via the Hcy lowering pathway.It is probable that the effect of ACE inhibitors on blood Hcy levels has not been demonstrated due to the small sample sizes in the aforementioned research. However, as indicated, in the study by Poduri et al., hypertension individuals treated with ramipril (5 mg/day) for six weeks experienced a significant reduction in Hcy levels. Hcy levels before and after ramipril treatment were 19.12 ± 6.94 ectively . Similarpy group . Fu et a <  0.01 . In our Despite the fact that our study demonstrated the efficacy of perindopril in lowering blood pressure and homocysteine levels, there are some limitations. This is a cross-sectional study using a single center. It has not yet been demonstrated that lowering homocysteine in the blood improves cardiovascular outcomes and mortality in hypertension patients, as the follow-up duration is still short. We lacked sufficient samples to evaluate the effect of each dose group of perindopril on homocysteine levels in blood. Therefore, additional research with bigger sample sizes, longer follow-up periods, and multicenter, double-blind designs is required to better elucidate the study's limitations and results.Perindopril has the ability to lower blood homocysteine levels and regulate blood pressure in patients with primary hypertension.


The management of diabetes and renal failure is changing thanks to the appearance of new drugs such as glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i) that have benefits in terms of survival and cardiorenal protection. Based on the potential mechanisms of GLP1-RA, kidney transplant recipients (KTRs) could benefit from their effects. However, high-quality studies are needed to demonstrate these benefits, in the transplant population, especially those related to cardiovascular benefits and renal protection. Studies with SGLT2i performed in KTRs are much less potent than in the general population and therefore no benefits in terms of patient or graft survival have been clearly demonstrated in this population to date. Additionally, the most frequently observed side effects could be potentially harmful to this population profile, including severe or recurrent urinary tract infections and impaired kidney function. However, benefits demonstrated in KTRs are in line with a known potential effects in cardiovascular and renal protection, which may be essential for the outcome of transplant recipients. Better studies are still needed to confirm the benefits of these new oral antidiabetics in the renal transplant population. Understanding the characteristics of these drugs may be critical for KTRs to be able to benefit from their effects without being damaged. This review discusses the results of the most important published studies on KTRs with GLP1-RA and SGLT2i as well as the potential beneficial effects of these drugs. Based on these results, approximate suggestions for the management of diabetes in KTRs were developed. Chronic kidney disease (CKD) is a common and serious health problem that affects millions of people worldwide. According to epidemiological data, CKD is becoming more prevalent, with an estimated 10% of the global population affected . The maiKidney transplantation is a life-saving treatment for patients with end-stage kidney disease. According to the latest data report of the US transplant registry, almost 47% of patients on the kidney transplant waiting list had diabetes mellitus and trend forecast that this proportion will increase . This siPTDM is a common and serious complication that occurs in a significant proportion of KTRs. According to a 5-year follow-up multicenter cohort study of KTRs who received deceased donor kidneys, PTDM was often observed with a cumulative prevalence of close to 30% . The firIn 2014, an international consensus meeting defined the term PTDM and clarified the definition of the term “new-onset diabetes after transplantation (NODAT)” with the outcome of rectifying the mistake to include patients who may have had undiagnosed diabetes before transplantation ,9. As soRisk factors for PTDM include older age, a family history of diabetes, obesity, and pre-existing diabetes or impaired glucose tolerance ,11,12,13The principal risk factors specifically associated with transplantation are viral infections and immunosuppressive therapy. It is generally recognized that corticosteroids can lead to hyperglycemia and increase the risk of developing diabetes. Impaired insulin sensitivity, increased hepatic gluconeogenesis, and hunger stimulation with consequent weight gain are some of the factors driving corticosteroid-induced diabetes . TacroliPTDM is associated with increased morbidity and mortality, and it can also contribute to the development of cardiovascular disease and other complications ,16,17. TIn this narrative review, we summarize the published literature about the management of diabetes in renal transplants and the use of new agents, namely glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i), in the kidney transplant field. The most relevant case series, retrospective and prospective studies, as well as clinical trials published to date were included, with the main objective of evaluating the impact of these drugs in the renal transplant population.Recommendations for the management of hyperglycemia and diabetes in KTRs are based on guidelines and expert consensus ,22,23,24Insulin therapy is currently considered the first-line treatment in hyperglycemia immediately following transplantation , given t2 and BMI ≥ 25 kg/m2.Metformin remains a fundamental pillar for the management of diabetes in the general population, and its use is increasingly encouraged in the kidney transplant population . SeveralGliptins inhibit the degradation of incretin hormones, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, by inhibiting dipeptidyl peptidase-4 (DDP-4) enzymes. This results in increased insulin synthesis and secretion, the suppression of glucagon secretion, the inhibition of gastric emptying, and the suppression of appetite and dietary intake . Some faHowever, it has been shown that diabetic nephropathy can occur after kidney transplantation, despite intensive glycemic control ,34. MoreGLP-1 is a natural incretin hormone that is swiftly produced after the intake into the bloodstream by enteroendocrine L-cells in the colon and distal small intestine. The many effects of GLP1-RA include increased insulin secretion and sensitivity, decreased hepatic gluconeogenesis, delayed stomach emptying, and reduced central appetite centers . SeveralIn relation to kidney outcomes, the AWARD-7 trial was the first to demonstrate that dulaglutide delays the decline in rate eGFR compared to insulin glargine in patients with type 2 diabetes mellitus and moderate to severe CKD at 52 weeks follow-up . Both thThe evidence of the use of GLP1-RA in KTRs to date is limited as the published studies include few patients and show limited statistical power in demonstrating the benefits. p < 0.0001) was observed. Singh et al., in a retrospective study that included 81 KTRs, compared the action of liraglutide and dulaglutide [p < 0.03) and HbA1C .Sweiss et al. led the largest study in terms of the number of cases, including 83 KTRs treated with GLP1-RA  . A statiaglutide . The resp < 0.0001) [p < 0.3) [Regarding kidney function, most studies have failed to demonstrate benefits after the start of GLP1-RA ,49,51 ex 0.0001)  and VigaThe potential interactions between GLP1-RA and tacrolimus were investigated. Cytochrome P450 enzymes and transporter-mediated drug–drug interactions are not involved in the metabolism of GLP1-RA, as this was eliminated by proteolytic degradation . Hence, The most frequent side effects of GLP1-RA described in SOT recipients are gastrointestinal, including nausea, diarrhea, vomiting, and abdominal pain. However, Kim et al. found an improvement in gastrointestinal problems in 42.9% of patients who developed any symptom after 3 months . DespiteFinally, GLP1-RA could associate hypoglycemia, as demonstrated in the general population, in approximately 12.3% with dulaglutide . In studThere are several mechanisms attributed to GLP1-RA that could be renal and kidney graft-protective, such as the reduction in intraglomerular pressure, the induction of natriuresis, as well as the regulation of the immune system, inflammation, and Redox system . MoreoveThe mechanisms of action of GLP-1RA in the kidney are not completely understood but may involve both neural and nonneural pathways. A gut–renal axis is possible, with regulatory linkages through the gastrointestinal tract, central nervous system, and kidney. The main physiological effect of GLP1-RA on the kidney may be to reduce prandial intraglomerular pressure to reduce the macronutrient  loss in the glomerular filtrate. This would allow increased time for macronutrient uptake by other tissues without having to expend energy to transport macronutrients back into the body through the proximal tubule or overwhelming the proximal tubule reuptake system for macronutrients. It may do so by decreasing the sympathetic activity at the glomerulus through the central nervous system or by direct effects on the mesangium and renal interstitium ,57.Another one of the most important effects is that of GLP1-RA-induced natriuresis. GLP-1 and GLP1-RA have also been shown to reduce NHE3 (sodium-hydrogen antiporter 3) dependent proximal tubule sodium reabsorption in both animals and humans . The inhAdditionally, GLP1-RA could exhibit a specific contribution to regulating the immune system and inflammation . SeveralMoreover, GLP1-RA has been shown to have anti-atherogenic properties, also presumably via indirect effects on lipids, glucose, weight, and blood pressure as well as indirect effects on inflammation and ischemia . The preRegarding the specific benefits of these drugs in KTRs, a protective effect of GLP1-RA against toxicity caused by the most common immunosuppressant has been described. Tacrolimus and sirolimus treatment are toxic to pancreatic cells. A study performed by Dai et al. with human islets transplanted into immunodeficient mice treated with tacrolimus or sirolimus demonstrated that the treatment with both drugs reduced beta-cell granules, increased islet amyloid deposition, increase beta-cell apoptosis, and autophagy in the pancreatic islet cell . AdditioInterestingly, GLP1-RA could have therapeutic effects on tacrolimus and sirolimus-induced pancreatic beta-cell injury. In this regard, Lim et al. observed that rats with tacrolimus-induced diabetes mellitus exhibited increased autophagy-associated protein expression and autophagic vacuole numbers in pancreatic beta cells . GLP1-RABased on the potential mechanisms of these drugs, kidney transplant patients could benefit from their effects. However, high-quality studies are needed to demonstrate these benefits, especially analyzing cardiovascular outcomes in the transplant population, and particularly those related to cardiovascular benefits and renal protection.SGLT2i were originally developed to treat type 2 diabetes, and have demonstrated protective cardiorenal benefits in the general population with diabetes and patients with known kidney disease ,65,66,67The beneficial effects of these drugs related to renal function consist of decreasing proteinuria, slowing the rate of development of end-stage renal disease, and the need to initiate renal replacement therapy. In addition, it has also been shown that the use of these drugs can reduce cardiovascular events and cardiovascular mortality in patients with CKD ,70,71, rStudies with SGLT2i performed in KTRs are much less potent  in termsp = 0.006) [p 0.040) and the progression of creatinine deterioration . Mortality outcomes were less conclusive , as the results were not statistically significant in all the models used [Small studies were initially conducted, consistently in case series ,87,88,89= 0.006) . In addiels used . TherefoRegarding the adverse effects, urinary tract infections were the most frequent (14–20%) ,91,92,93Acute renal failure could be another disadvantage of these drugs, which in some cases forces their withdrawal and in others could delay or discourage their initiation . Some stIn the case of measures aiming to minimize the renal failure associated with the onset of SGLT2i it will probably be interesting to identify those patients at risk of being eGFR- dippers, because this condition probably could be reversible, such as volume depletion, ischemic grafts, high levels of CIN, tendency towards hypotension, septicemia, and other conditions that promote impaired renal function ,76,82,94The benefits demonstrated for the use of SGLT2i have to date been related to the control of the metabolic syndrome  , but it The main potential mechanisms attributed to SGLT2i to achieve the observed reno-protective effects are summarized in terms of their capacity to reduce glomerular hyperfiltration, renal hypoxia, oxidative stress, and autophagy, as well as stimulate erythropoiesis. The minimization of these processes would lead to the reduction in inflammation and consequently, to the reduction in fibrosis  Figure . In factOne of the most important effects of SGLT2i is the regulation of tubuloglomerular feedback mitigating hyperfiltration through the inhibition of glucose and sodium reabsorption in the proximal tubule via the SGLT2 transporter. This effect decreases glomerular hyperfiltration, thus potentially slowing the progression of glomerulosclerosis ,97. RenaThe REDOX equilibrium system is necessary for normal cell function as they modulate cell-signaling pathways and cellular processes . HoweverAnother possible mechanism of glomerular protection, in which SGLT2i has been implicated, consists of the activation of cellular autophagy. It would seem that SGLT2i activates autophagy in podocytes, which might prevent mesangial expansion and reduce albuminuria . AlthougThe stimulation of erythropoiesis is also among the described benefits of SGLT2, which occurs through increased levels of bone marrow-derived hematopoietic cells and the suppression of hepcidin levels . These aAll of the previously described mechanisms ultimately contribute to inflammation and then to renal fibrosis. Therefore, the use of SGLT2i could contribute to alleviating these mechanisms of lesion contributing to CKD ,102. In Based on findings in the general population and studies in KTRs, the use of SGLT2i can be of great benefit to this population. It seems essential to fully understand these medications to be able to use them in most patients, but their condition must be optimized to minimize risks and avoid their removal. However, it is also essential to identify those patients in whom its use may be harmful and, therefore, discard its initiation. It is also important to note that SGLT2i are associated with a profile of benefits that are especially important in KTRs , such as the decrease in uric acid ,90 or thBased on the potential effects and mechanisms, it is important to highlight that the combination of SGLT2i and GLP1-RA could be of interest in diabetic renal transplant patients, since this combination would exploit the beneficial effects of both drugs. GLP1-RA increases insulin secretion and glucagon inhibition and thus decreases endogenous glucose secretion, counteracting the increase that SGLT2i could produce. In addition, the hypoglycemic effect of SGLT2i is discrete and the concomitant use of GLP1-RA could enhance the effects of glycemic control and cardiorenal protection, since the mechanisms are different and complementary . Figure In the last decade, the management of diabetes and renal failure has changed thanks to the appearance of new drugs that have benefits in terms of survival and cardiorenal protection. Renal transplant patients are a population that could greatly benefit from the advantages of new antidiabetic oral drugs such as SGLT2i and GLP1-RA. Therefore, it is important to understand the characteristics of these drugs in order to select those appropriate for the patient to benefit from these drugs without being negatively affected by adverse side-effects. In addition, it would be interesting to adapt other concomitant treatments so that patients can improve their condition and safely receive these drugs and thus benefit from their effects in the medium term . The com


To identify the determinants of systolic blood pressure variability (SBPV) among Ghanaians.We undertook a secondary analysis of data collected in a prospective studyThe study involved patients with hypertension and or diabetes receiving care in five hospitals in GhanaWe assessed determinants of SBPV among 2,785 Ghanaian patients. We calculated the standard deviation (SD) of systolic BP recordings of 3 to 10 visits per patient over 18 months as a measure of SBPV. A multivariate linear regression analysis was fitted to identify factors independently associated with risk visit-to-visit SBP standard deviation.The mean SD of individual patient visit-to-visit SBP overall was 14.8± 6.3 mm Hg. Those with hypertension and diabetes had the highest SD of 15.4 ±6.2 mm Hg followed by 15.2 ±6.5 mm Hg among those with hypertension only and then 12.0 ± 5.2 mm Hg among those with diabetes only, p<0.0001. Factors independently associated with SBPV with adjusted β coefficients (95% CI) included age: 0.06 (0.03 – 0.08) for each year rise in age, eGFR -0.03 (-0.05 - -0.02) for each ml/min rise, low monthly income of <210 Ghana cedis 1.45 (0.43-2.46), and secondary level of education -1.10 . Antihypertensive classes were associated with SBPV, the strongest associations being hydralazine 2.35 (0.03 – 4.68) and Methyldopa 3.08 (2.39 – 3.77).Several socio-demographic and clinical factors are associated with SBPV. Future studies should assess the contribution of SBPV to CVD outcomes among indigenous Africans and identify actionable targets.Funding for this study was provided by MSD, Novartis, Pfizer, Sanofi (each a Participant Company) and the Bill and Melinda Gates Foundation  through the New Venture Fund (NVF). FSS and BO are also supported by funding from the National Heart, Lung, and Blood Institute (R01HL152188). The global burden of hypertension is enormous, with a staggering 1.4 billion individuals affected.4An inherent characteristic of blood pressure is its variability. This variability is recognisable beat-by-beat within 24 hours monitoring and over long-term observation  among indigenous Africans. This is partly due to a paucity of studies on the determinants of BP control from prospective cohort studies in sub-Saharan Africa (SSA).This is a secondary analysis of data collected in a prospective cohort of patients with hypertension and diabetes receiving care in Ghanaian hospitals. The Committee on Human Research Publications and Ethics (CHRPE) of the Kwame Nkrumah University of Science and Technology gave approval (CHRPE/LPI/006/22) for secondary analysis of the data of an earlier study whose protocol has been published elsewhere.Participants were eligible if they were 18 years or older with a known diagnosis of hypertension and/or type II diabetes presenting for routine care. Participants were excluded if they had hypertensive urgency or emergency or had glycemic complications at initial contact for enrollment. Consecutive participants meeting eligibility criteria were enrolled at each site. Informed consent was obtained from all consecutively enrolled participants.Trained Research Assistants interviewed study participants and collected demographic information such as age, gender, educational attainment, employment status, number of dependents on monthly income and health expenditures. Information on lifestyle behaviours such as alcohol use, cigarette smoking, level of physical activities, frequency and daily quantities of fruits and vegetable consumption and table-added salt were also recorded. The duration of hypertension or diabetes diagnosis was noted. Compliance with hypertension treatment was assessed using the 14-item version of the Hill-Bone compliance to the high blood pressure therapy scale.An International Organization for Standardization (ISO)-certified laboratory was contracted to analyse serum creatinine to calculate the estimated glomerular filtration rate using the CKD-EPI equation.Study participants visited study sites every two months to have clinic BP measured for 18 months.We calculated systolic blood pressure recordings' standard deviation (SD) of 3 to 10 visits per patient over 18 months of follow-up. Blood pressure measurements of study participants were obtained using an automated blood pressure monitor across all study sites (Omron HEM-907XL). Two consecutive systolic BP readings from the same arm taken 2 minutes apart were recorded and averaged for the present analysis.Participants' socio-demographic characteristics, vascular risk factors, medications, medical history and adherence were first compared by tertiles of the standard deviation of the systolic blood pressure. Means were compared using Analysis of Variance (ANOVA), and proportions were compared using Chi-squared tests. We investigated a host of potential factors for associations with visit-by-visit systolic BP variability (SBPV) based on a literature search, our understanding of the epidemiology of BP control and empirical evidence from our data. A multivariate linear regression analysis was fitted to identify factors independently associated with the risk visit-to-visit systolic BP standard deviation as the dependent variable.Independent variables evaluated within domains and included the following socio-demographic factors: age (continuous variable), gender, location of residence, educational attainment, employment status, and monthly income were all categorical variables; lifestyle/behavioural factors: cigarette smoking, current alcohol use, and table added salt , physical activity, fruit intake, vegetable intake, and antihypertensive therapy adherence (continuous); patho-biologic factors: co-morbid diabetes, diagnoses of stroke, cardiac failure, classes of antihypertensive or antiglycemic agents  with a duration of hypertension diagnosis, number of antihypertensive medications, estimated glomerular filtration rate, waist circumference being continuous variables; and finally health system factors: availability of all prescribed antihypertensives on NHIS. In all analyses, two-tailed p-values <0.05 were considered statistically significant. Secondary analysis considering those with hypertension history only vs those with diabetes with or without hypertension was also performed using linear regression modeling. Model diagnosis and fit were assessed using residual plots analysis. Statistical analysis was performed using SAS 9.4.We included 2,785 patients with follow-up blood pressure recordings in our analysis. The mean (SD) age of the entire cohort was 57.8 (12.2) years, with more females (77.7%) than males. The mean (SD) of systolic blood pressure standard deviation was 14.8 (6.3). Those with hypertension and diabetes had the highest SD of 15.4 (6.2) mm Hg followed by 15.2 (6.5) mm Hg among those with hypertension only and then 12.0 (5.2) mm Hg among those with diabetes only, p<0.0001.The mean age (SD) increased with increasing tertile of SBPV being 54.8 (12) years for the lower tertile, 58.6 (11.8) years for the middle tertile and 60.1 (12.3) years for the upper tertile, p<0.0001. Other demographic characteristics with significant differences across the three tiers were educational attainment, employment status, and monthly income, as shown in In bivariate linear regression, we identified 24 variables with significant associations with SD of visit-by-visit systolic BP . Upon ad(a) Factors associated with SBP variability among hypertensives only: Seven (7) out of 16 factors identified in bivariate analyses remained independently associated with SBPV. These include increasing age, educational attainment, eGFR, ACE-I use, beta-blocker, methyldopa, and antiplatelet use (elet use .(b) Factors associated with SBP variability among diabetics: Among diabetics (including those with or without hypertension diagnosis) five out of 20 factors identified in bivariate analyses remained significantly associated with SBPV after adjustment in a multivariate linear regression model. These include increasing age, monthly income, duration of hypertension diagnosis, ARB use, and methyldopa use (not shown).Long-term blood pressure variability assessed using visit-to-visit BP measures has emerged to be strongly and independently associated with subclinical organ damage, cardiovascular events, all-cause mortality, and chronic kidney disease progression.For instance, the SD among a cohort of Japanese with hypertension was 13.7 mm Hg 29Meta-analytic data suggest that each 1-mmHg rise in systolic BP standard deviation is associated with a 3% [95% CI: 2-4%] rise in hazard of all-cause mortality, a 10% [95% CI: 2-17%] rise in hazard of cardiovascular mortality and 2% [95% CI: 1-3%] rise in hazard of stroke.We identified 11 socio-demographic, clinical and medication-related factors independently associated with SBPV in this sample of Ghanaians with hypertension and/or diabetes. Among the socio-demographic covariates, age demonstrated a strong and consistent association with the SD of SBP. This association between increasing age and high SBP variability is thought to be mediated by arterial stiffness exacerbated by ageing.A dose-dependent correlation between the estimated glomerular filtration rate and systolic BPV was noted in the present study. The eGFR declined with the rising tertile of SBPV such that eGFR at the lower tertile was 80.1 ml/min, the middle tertile was 76.2 ml/min, and the higher tertile was 74ml/min, p<0.0001. A previous study among nearly 16,500 Spaniards with hypertension with and without chronic kidney disease showed an increase in short-term SBP variability across all the stages of kidney disease.38As expected, all antihypertensive drug classes were significantly associated with SBPV, with calcium channel blockers exerting the least variability, while alpha methyldopa had the most profound effect on SBPV in the entire cohort. Among those with hypertension alone on therapy, using calcium channel blockers  non-loop diuretics, and angiotensin receptor blockers (ARBs) had non-significant associations with SBPV. A meta-analysis of 398 trials performed by Webb and colleagues demonstrated that CCBs and thiazide-like diuretics attenuated interindividual BPV, whilst ACE inhibitors, ARBs, and beta blockers tended to increase BPV over the long term.43®) to be deployed across all sites, and study nurses were trained on a protocol for BP measurements with quality checks. This study lacks associations between SBPV and outcomes such as incident stroke or mortality due to the relatively short follow-up and lack of data on mortality. Although stroke was associated with SBPV on bivariate analysis, this association attenuated into non-significance upon adjustment for covariates. We have, however, previously reported on determinants of incident stroke in this cohort.There are limitations to this study worth noting. Blood pressure recordings were taken every two months at five medical centres for 18 months of follow-up with a potential for measurement errors. To mitigate this, we procured a validated automated BP monitor (OMRONAn array of socio-demographic factors, namely increasing age, educational attainment, monthly income and clinical factors, including renal function and antihypertensive medications, exerted a differential effect on inter-individual systolic blood pressure variability among a sample of Ghanaians with hypertension and or diabetes mellitus. Further studies are required to assess the impact on CVD outcomes of this emerging hypertension phenotype among indigenous Africans.