Cardiovascular autonomic dysfunction, which leads to hemodynamic disorders, is commonly observed in patients with Parkinson's disease (PD). Central aortic pressure (CAP) is the systolic blood pressure (SBP) at the root of the aorta. In young people, CAP is lower than peripheral arterial blood pressure. In older people, the difference between CAP and peripheral arterial blood pressure decreases depending on the extent of arterial stiffness (AS). In patients with AS, CAP increases. CAP is thus regarded as an indicator of AS.  To compare CAP and other hemodynamic parameters for AS between patients with Parkinson's disease and control group. We also aimed to evaluate changes in these hemodynamic parameters after the levodopa (LD) intake.  We included 82 patients with PD and 76 healthy controls. Age, sex, disease duration, disease subtype, Hoehn–Yahr stage (H&Y), and nonmotor symptoms (NMS) were documented. TensioMed Software v.3.0.0.1 was used to measure CAP, peripheral arterial blood pressure, pulse pressure (PP), heart rate (HR), mean arterial pressure (MAP), augmentation index (AI), pulse wave velocity, and ejection time. All patients were being treated with LD, and measurements were performed 1 h before and 1 h after LD intake. p < 0.001 and p=0.02, respectively). Most cardiac hemodynamic parameters, including peripheral arterial blood pressure and CAP, decreased significantly  after LD intake in the PD group. Disease subtype, duration, and severity did not affect any of the hemodynamic parameters. When NMS were evaluated, patients with psychosis and dementia showed higher baseline parameters.  Baseline peripheral arterial blood pressure and CAP values were significantly higher in the PD group than in the control group ( Loss of postganglionic noradrenergic innervation is well-known with PD. Several cardiac hemodynamic parameters were affected, suggesting cardiac autonomic dysfunction in these patients. The data obtained were independent of disease severity, duration, and subtype. After LD intake, most of these parameters decreased, which might have a positive effect on the vascular burden. Over the past two decades, strong evidence has identified loss of cardiac noradrenergic neurons in patients with Parkinson's disease (PD). Cardiac sympathetic neuroimaging has demonstrated a loss of postganglionic noradrenergic innervation in patients with PD. Accumulating data have drawn attention to the cardiac autonomic involvement of the disease, and studies have multiplied in the succeeding years , 2.Nonmotor symptoms (NMS) are common during the progression of PD. Cardiovascular autonomic dysfunction such as orthostatic hypotension (OH), labile tension, nocturnal hypertension, and reduced heart rate (HR) variability can be observed in patients with PD. Cardiovascular autonomic dysfunction in patients with PD can lead to microvascular disorders that contribute to cerebral perfusion defects . VasculaCAP is the systolic blood pressure (SBP) at the root of the aorta. In young people, CAP is lower than peripheral blood pressure owing to the elasticity of the aorta. In older adults, the difference between CAP and peripheral arterial blood pressure decreases, and values become closer to each other . SeveralCardiovascular autonomic changes in patients with PD and the effect of levodopa (LD) have been evaluated in several studies , 5–8. ThPrevious studies have shown that central hemodynamic disorders lead to AS in patients with PD , 18. We This comparative study was conducted at the Movement Disorders Unit of the Çukurova University Neurology Department. Informed consent was obtained from all participants, and the study was approved by the local ethics committee. One hundred and fifty-eight participants (82 patients and 76 controls) were included in the study. The 82 patients had been diagnosed with idiopathic PD according to the United Kingdom Brain Bank criteria. Patients with Parkinson's plus syndromes, secondary parkinsonism, and PD who were not on LD treatment were excluded. The control group consisted of 76-age- and sex-matched healthy controls. Those with hypertension, heart disease, diabetes mellitus, and those who smoked or used any antihypertensive drugs were not included in either group. Age, sex, and body mass index (BMI) were recorded for both groups. Patients were grouped according to disease duration into those with five or fewer years and those with more than five years. For disease severity, patients were divided into two groups: those with a Hoehn and Yahr score (H&Y) < 3 and those with a H&Y score ≥ 3. The presence of other NMS  was assessed in each patient. Patients were also separated into akinetic rigid (ARP) and tremor dominant subtypes (TDP).An arteriograph  was used to record hemodynamic data, including CAP, SBP, DBP, PP, AI, HR, and mean arterial pressure (MAP). The device used in this study automatically measures and records hemodynamic parameters. Participants were informed of the study and the procedures involved. The hemodynamic parameters of all participants were measured on their right arm. The size of the cuff was 15 × 55 cm. All measurements in both groups were made at eight o'clock in the morning. Measurements were performed in a quiet room. Postrest measurements were performed in both groups in the supine position after a minimum 10-minute rest. In the patient group, measurements were carried out an hour before and an hour after the first dose of 100 mg levodopa/25 mg benserazide in the morning before the administration of any other drug.t-test or Mann–Whitney U test was used depending on whether or not the statistical hypotheses were fulfilled. For comparison of two related (paired) continuous variables, the paired sample t-test or Wilcoxon-signed rank test was used depending on whether or not the statistical hypotheses were fulfilled. Correlation analysis for the presence of NMS was performed between the PD subtypes. The statistical significance level for all tests was set at p < 0.05.All analyses were performed using IBM SPSS Statistics version 20.0 statistical software package. Categorical variables were expressed as numbers and percentages, whereas continuous variables were summarized as mean and standard deviation, or as median and minimum-maximum where appropriate. The chi-squared test was used to compare categorical variables between the groups. The normality of distribution for continuous variables was confirmed using the Shapiro–Wilk test. For comparison of continuous variables between the two groups, the Student's There were no significant differences between patients with PD and controls in terms of age, sex, and BMI. The mean duration of disease was 7.04 ± 4.22 years. The mean H&Y score was 2.56 ± 0.86. The demographic data are shown in p1) before LD intake. Diastolic blood pressure (DBP) and AI were also higher, but the differences were not statistically significant. However, after administration of LD, hemodynamic values changed and SBP, DBP, PP, AI, and CAP reduced significantly without any effect on HR (p1)  . Interesp1) and those with more severe disease  were similar. There was a significant reduction in SBP, DBP, PP, AI, and CAP in both groups (p3 and p4)  . The difSubgroup analysis was performed among patients with different PD subtypes and with and without NMS . When PDWhen the presence of other NMS was considered, most of the hemodynamic parameters, including AI and CAP, were higher in patients with incontinence and constipation than in patients without these NMS. In patients with OH, the only significant difference was in AI, which was higher than that in patients without OH . In all Patients with psychosis had lower baseline hemodynamic parameters than those without psychosis . In patiAll baseline parameters were higher in patients with dementia than in those without dementia; however, CAP and AI did not reach statistical significance . In patiIn our study, both CAP and peripheral arterial blood pressure values, as well as other cardiac hemodynamic variables (PP and AI), were higher in the PD group than in the control group. Age, sex, disease duration, and disease severity did not affect any of these parameters. There was a significant decrease in most hemodynamic parameters after LD intake, except for HR. In subgroup analysis, SBP and PP were significantly higher in the ARP group than in the TDP group. In patients with or without autonomic dysfunction, there was a significant reduction in most hemodynamic parameters, including CAP, SBP, DBP, PP, and AI after LD intake.High systolic and DBP may lead to increased microvascular damage, atherosclerosis, cardiac disease, and cerebral perfusion defects . SeveralThere was a significant decrease in most hemodynamic parameters after LD intake, except for HR. The more pronounced decline in CAP, AI, and peripheral arterial blood pressure indicated a decrease in peripheral arterial resistance. In our study, CAP, PABP, and AI reached even lower values than those of the control group after LD intake. Moreover, its effect was independent of disease severity, duration, and subtype. Several studies have shown that a CAP lower than peripheral arterial blood pressure is healthier for the heart –5. FurthIn subgroup analysis, SBP and PP were significantly higher in the ARP group than in the TDP group. The ARP subtype may be more prone to cardiovascular disease than the TDP subtype, and this finding is in accordance with several other studies –23. HoweIn patients with psychosis, the hemodynamic parameters of cardiac dysfunction were lower than those in patients without psychosis. This may be due to the use of antipsychotic medications to treat these patients. All hemodynamic variables were higher in patients with dementia than in those without but not all reached statistical significance. In fact, this may not be a reason but a result. According to Pierzchlinska et al, variability in hemodynamic parameters initiates the occurrence of dementia, causing white matter hyperintensity and microvascular damage . The resThe sympathetic noradrenergic denervation observed in patients with PD seems to occur independently of striatal dopaminergic denervation , 26–28. Our study had several limitations. We included a small number of participants, especially those with PD subtypes. Patients who were LD-naive were excluded from the study. The effects of other medications could not be excluded. Post hoc sample size calculations were not performed.Loss of postganglionic noradrenergic innervation is well-known in patients with PD. In our study, several cardiac hemodynamic parameters, such as CAP and AS, were affected, suggesting more severe cardiac autonomic dysfunction in these patients. After LD intake, there was a decrease in most of these parameters, which may have a positive effect on the vascular burden. Further research is required to clarify this suggestion. Further studies are needed to answer the questions and suggestions raised in this study.


Background: The subendocardial viability ratio (SEVR), also known as the Buckberg index, is a parameter of arterial stiffness with indirect prognostic value in assessing long-term cardiovascular risk. Materials and Methods: We conducted a prospective cohort study on 70 patients with uncomplicated hypertension admitted to a county medical reference hospital. We analyzed demographics, laboratory data, arterial stiffness parameters and cardiovascular risk scores (SCORE and Framingham risk scores) and aimed to identify paraclinical parameters associated with increased cardiovascular risk. Results: Of the arterial stiffness parameters, SEVR correlates statistically significantly with age, central and peripheral systolic blood pressure, as well as with heart rate. SEVR seems to have prognostic value among hypertensive patients by increasing the risk of major cardiovascular events assessed by SCORE and Framingham risk scores. SEVR correlates statistically significantly with serum fibrinogen (p = 0.02) and hemoglobin (p = 0.046). Between pulse wave velocity and lipid parameters (p = 0.021 for low-density lipoprotein cholesterol <LDL> and p = 0.030 for triglycerides) a statistically significant relationship was found for the study group. The augmentation index of the aorta also correlated with serum LDL-cholesterol (p = 0.032) and the hemoglobin levels (p = 0.040) of hypertensive patients. Conclusions: Age, abdominal circumference and Framingham score are independent predictors for SEVR in our study group, further highlighting the need for early therapeutic measures to control risk factors in this category of patients. Hypertension is one of the most common cardiovascular risk factors encountered, and its prevalence continues to rise in the face of primary prevention measures. Based on the fact that age and increased blood pressure values are the main determinants of arterial stiffness , the ideIn addition to hypertension, diabetes mellitus, dyslipidemia, smoking and chronic kidney disease are involved in pathophysiological processes at the level of the vascular wall that over time lead to decreased compliance and elasticity due to changes in the extracellular matrix components at that level . ArteriaThe subendocardial viability ratio (SEVR), also known as the Buckberg index , is an aIn the context of the continuous increase in the prevalence of cardiovascular risk factors and the continuous development of diagnostic and treatment methods, the identification of parameters with a prognostic role in this category of patients is useful in guiding therapeutic management .The aim of this study was to identify SEVR’s role in the assessment of long-term cardiovascular risk in hypertensive patients as well as its determinants in the study group, with the aim of preventing potentially fatal acute cardiovascular events. We aim to use different risk scores that were validated on different populations for a comprehensive overview.We conducted a prospective, single-center clinical study including 70 patients with uncomplicated hypertension, admitted to the Cardiology Department of “St. Spiridon” Hospital. Of the 70 patients, we excluded 13 patients in whom arterial stiffness parameters could not be recorded, as well as one patient with incomplete data regarding treatment or laboratory data. The final study group included 56 hypertensive patients who were followed-up for a period of 12 months.We included patients over the age of 18 years old with a diagnosis of essential arterial hypertension and who have given their written consent to participate in the study. The exclusion criteria were the refusal of patients to participate in the study, a personal history of arrythmias (including cardiac pacing), and diagnosis of cardiac ischemic disease with-/without interventional or surgical revascularization, stroke, cancer, as well as patients in whom arterial stiffness parameters could not be assessed.We analyzed a variety of parameters such as demographics , cardiovascular (CV) risk factors, anthropometric parameters, vital signs  as well as arterial stiffness parameters. The diagnosis of hypertension has been established according to current guidelines .The laboratory testing consisted of lipid profile , serum glucose, uric acid, renal function parameters , fibrinogen and hemoleucogram. The results were presented according to the International System of Units.Cardiovascular risk scores were calculated based on the CV risk factors obtained from the medical interview, physical examination and biochemical tests. Two major CV risk scores were computed: the Framingham risk score ,15 and SUsing an Arteriograph, several parameters of AS were determined noninvasively, and the focus was on pulse wave velocity (PWV), the augmentation index of the aorta (AixAo), systolic area under the pulse wave curve (SAI), and the diastolic area below the pulse wave curve (DAI). SEVR was determined using the ratio of the areas of the systolic and diastolic portions below the aortic pulse wave curve and denoted as systolic area index (SAI) and diastolic area index (DAI), respectively. Knowing that SAI is calculated as the product of mean systolic LV pressure and systole duration and DAI as the product of the difference between mean aortic diastolic pressure and mean diastolic LV pressure and diastole duration, we rewrote the calculation formula as follows  Figure :SEVR=(meThe parameter measurement protocol via the Arteriograph device involved the following steps: (1) recording general patient data ; (2) locating the area of maximum pulsatility of the brachial artery, with the positioning of the cuff of the device at this level; (3) the initiation of measurements, with the patient lying on his back and tracking the recording of pulse waves on the monitor to observe the morphology of the route; and (4) the interpretation of the results. In addition, before and during the recording the following measures were observed: the examination was performed in a quiet environment, and during patient mobilization, the avoidance of speech during the measurement was encouraged. When the “white coat” effect was suspected regarding hypertension, an attempt was made to reassure the patient and repeat the measurement. Smoking and coffee consumption were suppressed at least 3 h before the examination, copious meals were avoided during this period, as was the administration of nitrates. Alcohol consumption was prohibited for an period of 10 h before the administration.A statistical analysis was performed using SPSS statistics software . An initial descriptive analysis of the variables was performed for the continuous type variables calculating the mean, the median, minimum and maximum values, quartiles, and standard deviation. Skewness  and kurtosis (flattening coefficient) were determined to assess the normal distribution of continuous variables by using the Shapiro–Wilk test. All numerical variables had a normal distribution and were presented as means ± standard deviation.t-test (independent t test) and ANOVA  was used. Pearson (for continuous variables) and Spearman  correlation coefficients were used to assess the presence of correlations between the studied variables. For the subsequent analysis of the relationship between the variables that met the statistical threshold for the realized correlations, a simple linear regression was performed, and as well as by selecting several independent variables that influence a dependent variable, simple linear regression was extended to multiple regression. A p-value < 0.05 was considered statistically significant.To compare the mean values between two groups of continuous values in order to determine the statistically significant differences, the The study protocol was approved by the local Ethics Committee of the “Grigore T. Popa” University of Medicine and Pharmacy Iași and of “St. Spiridon” Clinical Emergency Hospital, and was conducted in accordance with the terms of the Helsinki Declaration. All participants signed an informed written consent before enrollment.We enrolled 56 patients diagnosed with uncomplicated essential hypertension who had been evaluated in an integrative and multidisciplinary approach. The study group included predominantly male patients (62.5%), with an average age of 67.62 ± 9.78 years.p = 0.538). DBP had an average value of 78.96 ± 16.44 mmHg, and the mean blood pressure (MBP) averaged 100.42 ± 19.7 mmHg. Pulse pressure (PP) had had an average value of 64.26 ± 17.71 mmHg, with a mean value slightly higher in women (67.23 ± 13.81 mmHg) compared to men (62.48 ± 19.65 mmHg)  .The mean heart rate was 67.16 ± 11.11 beats per minute (bpm) in the whole group , without identifying statistically significant differences between genders (67.33 ± 10.94 bpm vs. 67.05 ± 11.26 bpm). Regarding anthropometric parameters, special attention was paid to the value of abdominal circumference, which had an average value above the upper limit of the normal range of values for both females and males (109.88 ± 12.605 vs. 101.36 ± 11.95 cm).In addition to demographic and hemodynamic data, the duration of hypertension was also included in the statistical analysis. Thus, three patients (7.3%) had hypertension of up to 1 year old, 10 patients (24.4%) had hypertension from 1 to 5 years since diagnosis, 12 patients (29.3%) had hypertension from 5 to 10 years since diagnosis, and 16 cases (39%) had hypertension for more than 10 years since diagnosis. In 15 patients it was not possible to determine the duration of hypertension from the medical history or existing medical documents.We evaluated a variety of biological parameters, both hematological and biochemical, to outline the metabolic profile of the 56 patients enrolled in the study . Thus, mRegarding the parameters of arterial stiffness we used the oscillometric analysis of the pressure curves recorded at the level of the brachial artery by the Arteriograph device . We evalp = 0.005, r = −0.367) which highlights the decreasing trend of SEVR with age in our group. A simple linear regression was calculated to observe the influence of age on SEVR. A significant regression equation was highlighted (F (1.54) = 8.428, p = 0.005), with an R2 = 0.135. According to the analysis, SEVR associates a decrease of −1057 for an increase of age by one unit in the studied cases.In addition to a descriptive statistical analysis, various statistical correlations were made between SEVR and biological parameters, other arterial stiffness parameters, and risk scores as shown in p = 0.046, r = 0.27) and with fibrinogen levels (r = 0.455 at p = 0.02). The pathological values of fibrinogen were considered to be over 400 mg/dl, and after the application of the t-test there was a significant difference between patients with normal fibrinogen values (mean = 100.33 ± 23.98) and those with pathological values (mean = 119.93 ± 23.20), t (24) = −2.086, p = 0.048.SEVR was also analyzed in relation to the hematological and biochemical parameters evaluated on enrolment in the study. Two statistically significant positive correlations were highlighted, with hemoglobin levels (p = 0.02), with an R2 = 0.207. According to the analysis, the SEVR recorded an increase of 0.193 for an increase in fibrinogen by one unit in the cases studied.To further analyze the relationship of SEVR with fibrinogen, a simple linear regression was calculated. A significant regression equation was highlighted (F (1.24) = 6.257, p = 0.023, r = −0.304), peripheral SBP , PP , and heart rate . A multiple linear stepwise regression was calculated to observe the influence of the values of the different parameters of blood pressure and HR on SEVR. A significant regression equation was highlighted (F (2.53) = 9.78, p < 0.001), with an R2 = 0.270. According to the analysis, SEVR records a decrease of −0.672 for an increase in pulse pressure by one unit, and by −0.753 for an increase in HR by one unit. Both PP (p < 0.01) and heart rate (p = 0.01) are statistically significant independent predictors of SEVR.Furthermore, a series of negative correlations were observed between SEVR and central SBP  = 7.995, p = 0.07), with an R2 = 0.138. According to the analysis, SEVR registers a decrease of −2.41 for an increase of SCORE by one unit. To analyze the relationship of SEVR with Framingham risk score, a simple linear regression was calculated. A significant regression equation was highlighted with an R2 = 0.125.For the patients in the studied group, the SCORE and Framingham risk scores were also calculated. These correlated negatively with the SEVR values, for the Framingham score registering a 2 includes as independent predictors the abdominal circumference , age , and Framingham score , all three reaching the threshold of statistical significance (p < 0.05), with adjusted model R2 = 0.949, p <0.001. A significant regression equation was highlighted (F (3.8) = 69.541, p <0.001), with an R2 = 0.963. According to the analysis the SEVR decreased by −31,396 for patients with abdominal obesity, by −1513 to increase the Framingham score by one unit, and by 0.577 with the increase of age by one unit in the cases studied. Abdominal obesity, Framingham score and age are statistically significant independent predictors of SEVR.In an attempt to determine the variables that independently influence SEVR, a series of models were made by multiple linear regression. The equation with the highest value of adjusted Rp = 0.005), fibrinogen values , and Hb , all three reaching the threshold of statistical significance (p < 0.05), with R2 = 0.670 and adjusted R2 = 0.618.When only continuous variables that correlated with SEVR  were introduced into the analysis, a model was obtained with: SCORE , with an R2 = 0.670. According to the analysis, SEVR records a decrease of −2403 for each increase in SCORE by one unit, an increase of 0.182 for an increase in fibrinogen by one unit, and an increase of 6675 with an increase in Hb by one unit in the studied cases. SCORE, fibrinogen and Hb were thus determined as statistically significant independent predictors of SEVR.A significant regression equation was highlighted (F (3.19) = 12.845, Hypertension has a dual role as a cardiovascular risk factor and as a disease with an increasing prevalence in the context of accelerated global industrialization. It is also responsible for the occurrence of potentially fatal acute cardiovascular events in the absence of a personalized and integrative management of each individual patient. Identification of paraclinical parameters associated with increased cardiovascular risk is essential, having a dual role: prognostic and therapeutic.In our study, we demonstrated that SERV correlates with age, fibrinogen and hemoglobin serum levels, as well as with various arterial stiffness parameters such as pulse pressure, central, and peripheral SBP.p = 0.014). SEVR modulates the long-term prognosis of patients with hypertension via associated arterial stiffness, which is an indirect marker of aging or the onset/progression of atherosclerotic processes [p < 0.01) or without diabetes (p < 0.001) or even women without diabetes (p < 0.001), with statistically significant correlations after adjusting for various cofounders such as age, BP, HR or smoking. In a similar study published recently, Kaname et al. [p < 0.001). Saito et al. [SEVR is influenced by several factors, including demographics. In our study, we demonstrated that SEVR correlates negatively with age. In addition, based on the concept that age is an element of the Framingham score, we emphasized the impact of age on SEVR by obtaining a statistically significant correlation with this cardiovascular risk score . The same study also highlighted the independent predictive role of age, left ventricular mass index and diastolic BP alongside SEVR for coronary flow reserve.Tsiachris et al.  investigp = 0.031). Although no statistically significant correlations were found, changes in lipid, carbohydrate and uric acid profile parameters have a similar negative impact to classical cardiovascular risk factors, contributing to the development or evolution of atherosclerotic processes, justifying changes in paraclinical parameters of arterial stiffness. Jekell et al. [SEVR is an indirect marker of the pathophysiological burden of metabolic syndrome on arterial function. The pathophysiological rationale lies in the pathophysiological effect of the metabolic syndrome on subclinical vascular damage and increased arterial stiffness ,36,37. Ip value of 0.038) compared to normal-weight patients, similar to carotid-femoral pulse wave velocity and aortic systolic blood pressure (p = 0.043). Marčun-Varda et al. [In analyzing our group of patients we demonstrated that patients with abdominal obesity had a 31.39 lower SEVR compared to the other patients. Our results are consistent with data presented by similar clinical studies in the literature. In a recent study, a group of investigators, Tocci et al. , demonsta et al. .p = 0.012), even after adjusting multivariate regression for different cofactors such as age, gender or mean arterial blood pressure (p = 0.040). The number of metabolic syndrome components also influences the evolution of SEVR, its values decreasing with increasing number of metabolic syndrome elements (p = 0.005).The correlation between arterial stiffness, SEVR and the cardio-metabolic risk factors have been investigated by Fantin et al.  in a recp = 0.02), hemoglobin (p = 0.046) and SEVR there are statistically significant correlations for our study group. There is a complex pathophysiological relationship between anemia and cardiovascular risk, mediated in many cases by the presence of chronic kidney disease [p < 0.05). In patients with type 1 diabetes mellitus, reduced SEVR values correlate independently and negatively with the presence and degree of microalbuminuria and are a superior predictor of PWV in assessing the albumin excretion rate [Among the laboratory parameters included in the statistical analysis, between fibrinogen ( disease . Serum b disease  have shoion rate . The durion rate .p = 0.004) [Ekart et al.  demonstr= 0.004) . Not onl= 0.004) . Based o= 0.004) .p = 0.05) and PWVAo higher (p = 0.042) [The evolution of SEVR in relation to age, oxygen saturation and serum hemoglobin level was studied in a group of 41 hospitalized heart failure patients in order to identify predictors involved in the risk of rehospitalization at 30 days . Clinica= 0.042) .p = 0.044) and Aix (p = 0.029).In addition to demographic parameters and laboratory data, SEVR also correlates with arterial stiffness parameters. In our statistically analyzed group, we demonstrated that statistically significant correlations exist between SEVR and central SBP, peripheral SBP, and heart rate. Also, PP and frequency were found to be independent predictors of SEVR in multivariate regression, aspects correlating with the data presented in the literature. We also demonstrated that central SBP correlates statistically significantly with PWV (p = 0.017). In addition, central SBP, peripheral SBP and the total arterial compliance index were found to be predictors in univariate statistical analysis, with value retained after adjusting for heart rate. Pulse pressure also influences SEVR values in elderly hypertensive patients. Chemla et al. [Anyfanti et al.  also empa et al.  concludeOur study has several limitations due to the relatively small number of cases analyzed. We excluded patients from the study in whom arterial stiffness parameters could not be obtained or in whom the observation chart did not contain all the parameters necessary for statistical analysis.Our results support the notion that the assessment of SEVR in patients with hypertension has prognostic value, being a useful pillar in the assessment of long-term cardiovascular risk by modulating SCORE and Framingham risk scores. Age, serum fibrinogen level, haemoglobin, heart rate and central and peripheral SBP are parameters that correlate statistically significantly with SEVR, but independent predictive value in multivariate statistical analysis was demonstrated only for age, abdominal circumference and Framingham risk score.The value of SEVR as an index of long-term cardiovascular risk is even greater, as it is associated with a diversity of parameters, many of which are cardiovascular risk factors per se or have a defining role in increasing the cardiovascular risk of morbidity and mortality. These results raise the necessity of applying early specific therapeutic measures to control the CV risk factors in this group of patients.


Acute oxalate nephropathy (AON) is an uncommon condition that causes acute kidney injury (AKI), characterized by the massive deposition of calcium oxalate crystals in the renal parenchyma. In previous studies, urinary oxalate excretion has been found to be increased in patients with diabetes mellitus (DM). Here, we report a case series of diabetic patients with AKI with biopsy-proven AON, aiming to alert physicians to the potential of AON as a trigger of AKI in diabetic patients in clinical practice.Cases with pathological diagnosis of AON who presented with AKI clinically and had DM between January 2016 and December 2020 were retrospectively enrolled. Their clinical and pathological manifestations, treatment, and prognosis were collected.2, while the other two patients remained with kidney dysfunction at the last follow-up. In two patients without corticosteroid treatment, one patient fully recovered with eGFR over 90 ml/min/1.73 m2 and the other patient remained with kidney dysfunction at the last follow-up.Six male patients with biopsy-proven AON out of a total of 5,883 native kidney biopsies were identified, aged 58.3 ± 9.1 years at the time of kidney biopsy. Only one patient who had received Roux-en-Y gastric bypass surgery took oxalate-rich food before the onset of the disease. None of them had clinical features of enteric malabsorption. Three patients were currently on renin-angiotensin system inhibitor treatment for hypertension, and 5 of them received non-steroidal anti-inflammatory drugs. Three patients presented with oliguria and 4 patients needed dialysis at the beginning with none requiring dialysis at discharge. Four patients received a course of corticosteroid treatment empirically. Among them, two patients had estimated glomerular filtration rate (eGFR) recovered to over 60 ml/min/1.73 mAON might be a rare but potentially trigger of AKI in patients with DM. A kidney biopsy could help physicians to make the correct diagnosis. The proper treatment to alleviate oxalate-induced injury needs to be further studied. Patients with diabetes mellitus (DM) may develop diabetic kidney disease (DKD), which develops progressively with a gradual decline in kidney function. Therefore, causes other than DKD should be differentiated when acute kidney injury (AKI) occurs in patients with DM. Acute oxalate nephropathy (AON) is diagnosed by the characteristic finding of widespread deposition of oxalate crystals in the kidney, which is a relatively uncommon cause of AKI in clinical practice , 2. The Elevation of plasma oxalate could lead to hyperoxaluria, which might induce oxalate crystal deposition in the kidney under certain circumstances. The causes of hyperoxaluria can be either primary or secondary . PrimaryThis retrospective analysis enrolled 6 patients with biopsy-proven AON who underwent native kidney biopsy at Peking University First Hospital from January 2016 to December 2020. The inclusion criteria were as follows: (1) AKI  or AKD (defined by > 50% increase in serum creatinine within 3 months) clinically; (2) extensive oxalate crystal deposition in the kidney associated with tubular injury, obstruction, interstitial inflammatory cell infiltration, and fibrosis; (3) exclusion of other causes of kidney disease apart from non-specific microvascular (nephrosclerosis) and diabetic nephropathy; and (4) DM. The study was approved by the ethics committee of Peking University First Hospital and performed in accordance with the Declaration of Helsinki. Informed consent was obtained from each patient at kidney biopsy.Demographic , medical history , biological data , and conditions known to predispose patients to hyperoxaluria were collected from electronic medical charts. Laboratory data of serum and urinalysis at the time of renal biopsy were also collected. Medication information, including renin-angiotensin system inhibitors (RASIs), diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), oxalate precursors, and antibiotics, was recorded.Frozen spot urine samples stored at –80°C were thawed overnight at 4°C. Then, the samples were centrifuged, and the supernatants were collected, acidified with hydrochloric acid, and further deproteinized by filtration through a Dionex OnGuard II RP 1 cc Cartridge  before measurement. Oxalate measurement was performed by Aquion Reagent-free Ion Chromatography (RFIC) .Diabetes mellitus was defined as fasting plasma glucose ≥7.0 mmol/l, a self-reported history of diabetes, or receiving either insulin or oral antidiabetic drugs. Hypertension was defined as blood pressure (BP) higher than 140/90 mm Hg and/or the current use of antihypertensive medications. eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Hematuria was defined as red blood cell (RBC) > 3/high-power field. Leukocyturia was defined as white blood cell (WBC) > 5/high-power field.We identified 10 cases with pathological findings of extensive oxalate deposition out of a total of 5,883 native kidney biopsies performed between January 2016 and December 2020. Three patients were excluded for concurrent findings of other kidney diseases . Another patient was further excluded for the absence of DM. Finally, six cases were included in the present study.Regarding pathological findings, acute tubular epithelial injury with extensive oxalate deposition was the most prominent finding. The tubular cells presented with vacuolar and granular degeneration and effacement of the brush margin, with occasional atrophy found. The interstitium was edematous with the focal distribution of fibrosis. Focal infiltration of lymphocytes and monocytes was observed in all the specimens, with scattered eosinophil infiltration found in 4 cases. None of the cases were found with oxalate crystal deposition in the glomeruli. Instead, ischemic glomerular sclerosis and ischemic wrinkling of the glomerular basement membrane (GBM) to different degrees were observed in these cases. Some also had mild segmental mesangial cell proliferation and matrix accumulation, accompanied by a thickness of GBM observed under electron microscopy. Arteriosclerosis and hyalinization of arterioles were also observed. The typical pathological changes are shown in 2 at the last follow-up, while 2 patients remained with kidney dysfunction. Regarding the remaining 2 patients who did not receive corticosteroids, one patient experienced full recovery with eGFR over 90 ml/min/1.73 m2, while the other patient remained with kidney dysfunction at the last follow-up.In the present study, we reported 6 cases of biopsy-proven AON that presented with AKI in patients with DM. No one was considered to have oxalate nephropathy before the biopsy. Here, we described their clinical manifestations, natural history, and prognosis, aiming to trigger physicians’ alert about AON as a potential cause of AKI in the setting of DM.Kidney excretion accounts for the majority of daily oxalate excretion from the body. Circulating oxalate is freely filtered at the glomerulus, reabsorbed, and secreted by the proximal tubule . Multipletc.  for the publication of any potentially identifiable images or data included in this article.DB and YW analyzed and interpreted the patient data and were major contributors to writing the manuscript. XY performed interpretation of pathological data. MZ interpreted the clinical data and substantively revised it. All authors have contributed to the article and approved the submitted version of the manuscript.


We measured kidney function (CKD-EPI eGFR), protein-to-creatinine ratio, vascular function , augmentation index, waist circumference, sitting, and 24-h-ambulatory blood pressure (BP), intact parathyroid hormone (iPTH) and serum calcium at baseline and study end, and compared Vit D levels with laboratory variables. We quantified plasma FGF-23, PAI-1, and flOPN by enzyme-linked immunosorbent assay. Multiple regression analyzed the relationship between log flOPN, FGF-23, and PAI-1 with vascular and renal risk factors. Results: Compared to placebo, Vit D3 repletion increased Vit D3 2-fold (p < 0.0001), decreased iPTH by 12% (p < 0.01) and was significantly correlated with PWV (p < 0.009). Log flOPN decreased (p = 0.03), log FGF-23 increased (p = 0.04), but log PAI-1 did not change. Multiple regression indicated association between log flOPN and PWV (p = 0.04) and diastolic BP (p = 0.02), while log FGF-23 was associated with diastolic BP (p = 0.05), and a trend with eGFR (p = 0.06). Conclusion: Vit D3 repletion may reduce flOPN and improve vascular function in high risk AAs with Vit D deficiency.Background: 25-hydroxy vitamin D (Vit D)-deficiency is common among patients with chronic kidney disease (CKD) and contributes to cardiovascular disease (CVD). African Americans (AAs) suffer disproportionately from CKD and CVD, and 80% of AAs are Vit D-deficient. The impact of Vit D repletion on cardio-renal biomarkers in AAs is unknown. We examined Vit D repletion on full-length osteopontin (flOPN), c-terminal fibroblast growth factor-23 (FGF-23), and plasminogen activator inhibitor-1 (PAI-1), which are implicated in vascular and kidney pathology. Methods: We performed a randomized, placebo-controlled study of high-risk AAs with Vit D deficiency, treated with 100,000 IU Vit D3 (cholecalciferol;  Twenty-five hydroxy vitamin D (Vit D) is a fat-soluble vitamin which is hydroxylated in the liver and converted to 1,25-dihydroxy vitamin D , in the renal proximal tubule ,4,5. AppAlthough, the prevalence of Vit D deficiency (<30 ng/mL) has been reported to be 30–50% in the general population , AfricanIn the current study, we tested the hypothesis that Vit D supplementation in a Vit D deficient AA cohort with controlled hypertension and preserved kidney function may improve clinical and biochemical indicators of cardiovascular and kidney pathology. To demonstrate this, we quantified a number of biomarkers that have been implicated in the pathology of CVD and CKD: full length osteopontin (flOPN), c-terminal fibroblast growth factor-23 (FGF-23), and plasminogen activator inhibitor-1 (PAI-1), to assess the effects of Vit D repletion after 12 weeks on these established indicators of vascular and kidney function. In particular, flOPN is a multifunctional, ubiquitously expressed adhesion protein that plays a pivotal role in coexistent cardiometabolic disorders including obesity, CKD, and CVD ,21. Furt2), stroke or congestive heart failure, history of kidney stones, allergy to cholecalciferol or microcrystalline cellulose, abnormal liver function tests, recent (<6 months) hospitalization for myocardial infarction, used immunosuppressive, chronic steroid therapy, or non-steroidal anti-inflammatory drugs [ClinicalTrials.gov .For this study 737 participants were screened between September 2009 to August 2011 at affiliated medical clinics at Charles R. Drew University and Morehouse School of Medicine ,27. A toIn addition to a brief medical history, a limited physical examination measured height (cm), weight (kg), and waist circumference (WC), as well as calculated body mass index (BMI). Participants were randomized to receive a monthly dose of 100,000 IU of cholecalciferol  or a plaAt baseline and week 12 visits, blood pressure , vascular function, endothelial function, and pulse wave velocity (PWV) were assessed. The function of the vasculature was evaluated using radial artery tonometry and computer-aided measurement of the augmentation index  using the SphygmoCor product family, which is designed to measure the pressure wave in the ascending aorta from an external measurement. In order to assess endothelial function, the Endopat noninvasive vascular finger device was used to measure percent flow-mediated dilation .Plasma levels of flOPN, C-terminal FGF-23, and PAI-1 were measured using the commercially available ELISA kits. The flOPN kits were purchased from Immuno-Biological Lab America ; sensitivity 3.33 ng/mL, measurement range 0.07~4.75 ng/mL) and the manufacturer’s instructions were followed to perform the ELISA. Briefly, 100 μL each of test samples, diluted standard, reagent blank, and test sample blank was put into the pre-coated wells. The plate was incubated for 1 h at 37 °C and washed four times. After washing, we used 100 μL of labeled antibody into the wells of test samples, diluted standard, and test sample blank. The plate was incubated for 30 min at 4 °C and washed five times with prepared wash buffer. Then, 100 μL chromogen was used in the wells and the plate was incubated for 30 min at room temperature in the dark and 100 μL of stop solution was used to stop the reaction. The absorbance was measured at 450 nm.The kits for FGF-23 were purchased from QUIDEL ; sensitivity 1.5 RU/mL, measurement range 19.4–1455 RU/mL). The assay was performed following the manufacturer’s protocol. In summary, 100 μL of standard, control, or sample were added to the designated wells and working antibody solution (50 μL) was added to each well. The plate was incubated at room temperature for three hours on a horizontal rotator set at 180–220 RPM and was washed five times. Then, 150 μL of ELISA HRP Substrate was added into each well and the plate was incubated at room temperature for 30 min on a horizontal rotator. The absorbance was taken at 620 nm within 5 min against the 0 RU/mL standard wells as a blank. Immediately 50 μL of stop solution was added into each of the wells and was mixed on a horizontal rotator for 1 min. The absorbance at 450 nm within 10 min was read against a reagent blank.The PAI-1 ELISA kits were purchased from Fischer Scientific ; sensitivity < 30 pg/mL, measurement range 31.3–2000 pg/mL) and assay was performed according to the manufacturer’s instructions. Briefly, 100 µL of standards, pre-diluted samples or controls were added to the appropriate wells and the plate was incubated for two hours at room temperature. The plate was washed 4 times with wash buffer. Then, 100 µL Hu PAI-1 biotin conjugate solution was added into each well, except the chromogen blanks. The plate was incubated for 2 h at room temperature and was washed 4 times. 100 µL of 1X streptavidin-HRP solution was added to each well except the chromogen blanks. The plate was incubated for 30 min at room temperature then washed and 100 µL of stabilized chromogen was added to each well. After 30 min of incubation at room temperature in the dark, 100 µL stop solution was added to each well. The absorbance was measured at 450 nm.t-tests for continuous variables Serum flOPN, FGF-23, and PAI-1 levels were not normally distributed and therefore were log-transformed  or JMP pro 16 . We compared baseline characteristics between the two groups using Chi-Square tests for categorical variables and nsformed . Multiva2, mean WC was 104.7 ± 12.4 cm, mean BP was 127 ± 16/83 ± 11 mm Hg, PWV was 9.1 ± 2.2 m/s, mean augmentation pressure was 11.7 ± 6.6 mm Hg, mean serum calcium (9.32 ± 0.3 mg/dL) and AI was 29.8 ± 11.4% , Vit D levels did not differ between placebo and Vit D3-treated groups.Baseline demographic, physiologic and clinical data were reported as part of a prior analysis of this cohort to assess the association of Vit D3 supplementation and both inflammatory and oxidative mediators of arterial stiffness . Briefly ± 11.4%  with no p < 0.0001) after 12 weeks. The increase in the serum Vit D levels was associated with an ~12% decrease in serum iPTH  and log FGF-23 was increased in the treated group (p = 0.04) but no change was observed in log PAI-1, The monthly cholecalciferol dose of 100,000 IU was associated with a 2-fold increase in serum 25(OH)D from 17 ± 5 ng/mL to 35 ± 7 ng/mL (p = 0.04), and positively associated with diastolic BP (p = 0.02). The increase in log FGF-23 between baseline and week 12 was positively associated with a trend in eGFR (p = 0.06), and diastolic BP (p = 0.05)  b.To our knowledge, this is the first evidence of a direct effect of Vit D3 repletion on circulating levels of cardiorenal biomarkers that have been implicated in cardiac and kidney pathology. We showed that Vit D3 repletion correlated with lower PWV. In addition, lower flOPN correlated with lower PWV and higher diastolic BP, and higher FGF-23 levels correlated with higher diastolic BP, while Vit D3 repletion had no impact on PAI-1 levels. PWV is a measure of arterial stiffness, and is a strong and independent predictor of future CV events and all-cause mortality . NotablyInterestingly, the ability for flOPN to modify vascular injury has also been explored . In partFGF-23 is an emerging novel and powerful risk factor of mortality and CV events in patients with CKD and end stage renal disease . Studies2. Phosphate retention, low plasma calcium, and high FGF-23 with subsequently decreased plasma Vit D concentration, all contribute to the involvement of secondary hyperparathyroidism [We also observed that Vit D3 supplementation for 12 weeks was sufficient to change the Vit D level by 100% with a significant reduction in iPTH. This finding is consistent with a previous study where lower levels of Vit D were reported to be associated with higher levels of serum iPTH in the absence of kidney disease . Throughyroidism ,58.The strengths of this study are that it was a randomized controlled trial and demonstrated the well-proven therapeutic effect of Vit D3 repletion on 25 (OH) D and iPTH ,59. MostIn conclusion, our findings indicate that Vit D3 repletion may improve vascular function in high risk AA study participants with Vit D deficiency, obesity and controlled hypertension, and that flOPN could be a more sensitive marker of vascular function, compared to FGF-23 in this population, with no significance related to PAI-1. Further study is warranted in other larger, geographically diverse, racial and ethnic populations to validate our findings and to increase generalizability.


Targeted maintenance of blood pressure for hypertensive patients requires accurate monitoring of blood pressure at home. Use of multiparametric vital signs ECG, heart sounds, and thoracic impedance for blood pressure estimation at home has not been reported previously. In an observational multi-site study, 120 subjects ) between 18 and 83 years of age were recruited with the following stratification , prehypertensive (37%), stage 1(26%), and stage 2 (18%). From these subjects, 1686 measurements of blood pressure from a sphygmomanometer were associated with simultaneously acquired signals from the SimpleSense device. An ensemble of tree-based models was trained with inputs as metrics derived from the multiparametric and patient demographics data. A test Mean Absolute Difference (MAD) of ± 6.38 mm of Hg and ± 5.10 mm of Hg were obtained for systolic and diastolic blood pressures , respectively. Comparatively, the MAD for wrist-worn blood pressure cuff OMRON BP6350 (GUDID—10073796266353) was ± 8.92 mm of Hg and ± 6.86 mm of Hg, respectively. Machine learning models trained to use multiparametric data can monitor SBP and DBP without the need for calibration, and with accuracy levels comparable to at-home cuff-based blood pressure monitors. Recently, Zhang et al. demonstrated the significance of intensive blood-pressure control in older Chinese patients resulting in a lower incidence of cardiovascular events2.Hypertension is a critical public-health challenge worldwide. Between 1990 and 2019, the number of men and women with hypertension doubled to 652 million and 626 million. A pooled analysis of 1201 population-representative studies suggested that a dual approach of reducing hypertension prevalence through primary prevention, treatment, and control is achievable in the full spectrum of income settings3. Apart from the inaccuracies of measurements leading to incorrect hypertensive classifications, psychophysiological changes in patients with conditions such as white coat hypertension can lead to a false positive diagnosis of hypertension. The recommended measurement of BP for the diagnosis of hypertension across several international guidelines is out-of-office or at-home BP measurement using ambulatory BP monitoring (ABPM) and Home BP monitoring (HBMP). The available evidence suggests that HBPM and ABPM present similar values and correlate with target-organ damage4. However, there are challenges with both HBPM and ABPM.The potential sources of errors in blood pressure measurement remain a significant challenge even in controlled clinical settings. Discrepancies in measurements as obtained by different operators raise the concern of methodologic errors by one operator, such as under-cuffing, excessive pressure on the head of the stethoscope, rapid deflation of the cuff, or use of different arms. Kallioinen et al. investigated 29 potential sources of inaccuracy and categorized them as relating to the patient, device, procedure, or observer. They found significant directional effects with 27 sources with some inconsistency in terms of the direction of whether increase or decrease in measured BP. Some of the significant sources of directional effects caused changes in the range of  − 23.6 to + 33 mmHg SBP and − 14 to + 23 mmHg DBP5. Reports on sleep quality while using a cuffless blood pressure monitoring device (CLBPM) that is based on pulse wave analysis from a finger photoplethysmography sensor are scarce. The sleep quality was found to be comparable to ABPM6.Regarding HBPM, although patients are trained on how to perform an at-home BP self-measurement, the circumstances that must be created for repeatability of measurements are impractical for some patients, and compliance to these instructions is also not guaranteed. In the case of ABPM, the operation of the cuff during a measurement is perceptible to the patient and makes the measurements susceptible to a condition like white coat hypertension. Some patients must perform physical work such as construction that precludes the use of an ambulatory monitor, which requires the cessation of all movements during the oscillometric measurement time window. Furthermore, cuff-based ABMP is known to interfere with sleep7. Clinically, such devices are not yet prevalent due to significant variability in the estimation of aortic-SBP, and the superior invasive measurement methods are only indicated for patients suspected of having coronary artery disease8. The clinical evidence only supports a marginal difference. It is plausible that the incremental value of using central instead of brachial BP is masked by the errors in measurement of ABPM and HBPM, which are not encountered with invasive central BP measurements. Therefore, marginal superiority central BP offers as a risk predictor of cardiovascular events may be accessible with brachial BP by improving the calibration method of the brachial or peripheral BP monitoring device8.All commercially available ABPM and HBPM devices are calibrated to measure brachial BP, not central BP. A systematic review of invasive validation studies on the accuracy of estimation of aortic SBP using non-invasive devices could not draw specific conclusions9, Pulse Wave Transit Time10, Pulse Arrival Time11, and estimation of the pre-ejection period because these methods require calibration against the readings from a cuff based sphygmomanometer for each patient. There are known confounders that decorrelate the relationship between photoplethysmography (PPG)-based parameters and SBP and DBP, such as changes in arterial stiffness , arterial wall viscosity, and assumptions on the radius of the arterial lumen (gender and BMI-related difference). None of the methods reported in the literature thus far have considered these demographic data to develop a generalized cuffless BP estimation method. Studies that have reported the use of only centrally measured cardiovascular parameters for the prediction of BP are scarce. Innovative use of ECG and deep learning to predict BP was reported12 but did not meet the minimum criteria for accuracy as per the IEEE and ANSI standards. In this paper, a novel approach is presented to estimate SBP and DBP that uses only centrally measured physiological parameters. The method takes as input the multiparametric data inclusive of two channels of ECG and thoracic impedance, heart sounds near the apex of the heart, activity, and posture captured by the FDA cleared SimpleSense device (510 (k) number K212160)  combined with demographics data  which is added as a predictor so that the confounding effects encountered by pulse wave-based techniques could be potentially mitigated. SimpleSense is a non-invasive, wearable, and portable medical device that uses cloth-based nanosensor technology13  was approved by the independent Institutional Review Board (IRB) Advarra Inc. . The study was conducted according to the stipulations of the 1964 Declaration of Helsinki and in accordance with relevant FDA regulations. Written informed consent was sought and obtained from all subjects and all subjects completed the study. The accuracy of the estimated blood pressure was evaluated following a validation plan based on the IEEE standard 1708a-201915. The BP used for classification was the entry BP measured at the beginning of the test. Three measurements were taken from the subject sitting with the elbow, back of the elbow, and back resting on a chair. The averaged value was used as the entry BP to determine the subject's BP classification.From February 8 to July 16, 2021, subjects were screened for eligibility and recruited. The targeted subject selection and stratification are presented in Table Two trained observers performed all measurements using the SimpleSense device and gold standard sphygmomanometer for each subject. The training of the observers was as described in Section 5.2.2 of ISO 81060-2019.First, the subjects wore the SimpleSense system. The device recorded data while the two observers took the blood pressure measurements using a standard sphygmomanometer and Omron blood pressure wrist cuff GUDID 10073796266353. The simultaneously and synchronously acquired data from SimpleSense was used to calibrate the algorithm against the blood pressure measurements from the sphygmomanometer.Reference measurements were provided by the two trained observers and measured simultaneously with one reference sphygmomanometer (using a "Y" connector), as shown in Fig. Simultaneous measurement was used for the sphygmomanometer and SimpleSense device. The left arm was used for reference measurement. By design, the SimpleSense system is a cuffless device and does not rely on an arm or wrist cuff for blood pressure measurement. It can record all the physiological parameters during the inflation and deflation of the reference sphygmomanometer without any mutual interference. At least a 60-s delay was observed between consecutive readings from the sphygmomanometer to avoid venous congestion.Sequential measurement was used for the Omron Wrist Cuff. When the wrist cuff device is used with the sphygmomanometer reference measurement, either arm will interfere with the reference device measurement. The Omron wrist cuff measurement was done at least 60 s after the reference measurement but not more than 90 s to avoid increased variability due to expected physiological trends.Subjects were asked to perform activities that modulated blood pressure to increase the dynamic range of observed SBP and DBP. The lowering of BP was induced by asking the subject to sit with feet raised on a stool or chair and hold a warm water bottle (warm stimulus) in their hand wrapped with an insulating cloth. The increases in BP were induced by asking the subject to walk briskly (mild exercise), as physically able, for about 10 min and holding an ice pack (cold presser) in their hands for 5–10 min as tolerated. Three consecutive recordings of simultaneous and sequential measurements of BP were performed after each of these BP modulating activities.The SimpleSense data for each patient was first subjected to a data quality assessment. Segments of data that were of insufficient quality due to the presence of noise due to any movements were removed from further consideration. From the recorded data that was deemed to be of acceptable quality, within a 300-s window preceding a time-stamped observation of SBP and DBP by the observers using the gold standard sphygmomanometer, a 60-s window of data with acceptable quality was extracted and associated with that observation. These steps were performed for each recorded BP value from the gold standard device. Thus, a dataset was prepared with the 60-s-long segments of SimpleSense device data and the associated target SBP and DBP values for training the SimpleSense-BP algorithm. The systolic and diastolic reference measurements acquired from the gold standard device were then randomly split into two sequestered sets of 80%/20% (training/test).Mean Absolute Difference (MAD) Eq. , Mean Ab16. The description of the method to compare models described by Natarajan et al.17 presents a convenient method to measure overall accuracy through bootstrap RMSE. First, we trained a reference model that uses only the demographics data  on the same training data as SimpleSense-BP, to estimate SBP and DBP. The reference model training procedure used the same training hyperparameters for the automl framework as the SimpleSense-BP model. We took 10,000 random samples of the test set measurements with replacement. The number of samples per iteration was equal to the size of the test set. For each sample, we computed the Root Mean Square Error (RMSE) for each model and the difference between the RMSEs of the two models for comparison as (SimpleSense-BP estimated BP—Demographics only estimated BP for SBP and DBP). The criteria to support the superiority of one model over the other was that the difference in RMSE errors should have an upper 95% Confidence Interval (CI) less than 0 mmHg.Further, we evaluated the contribution of the SimpleSense device measured inputs and demographics for BP estimation in comparison to models that use only demographics data. The comparison method follows the recommendation by Mukkamala et al.The ECG features were RR intervals and timing of the R peaks occurrence. The R peaks of the ECG waveform were detected algorithmically. The detected R peaks were used to determine the bounds of the RR intervals for each heartbeat. An ensemble average was computed for one minute of data centered on the measurement of the blood pressure from the reference device.Heart sound ensembles were defined based on the RR intervals extracted from the ECG waveform. The ensemble average was computed across one minute of data centered at the blood pressure measurement from the reference device like the ECG waveform. The S1 and S2 times of occurrence and root mean square amplitudes were algorithmically extracted from the ensemble average.Based on the extracted timing of the R peak of the ECG and the S1 and S2 peaks of the heart sound, a timing feature was extracted. The time elapsed between the R peak and the S1 and S2 sounds is illustrated in Fig. Table A total of 120 patients were recruited for the study. The recruited subject population was representative of the adult US census. The age distribution was 48.7 ± 16.8 years, with 48% male. Figure After the preparation of data collected in the study, the training set had 1348 observations of adequate quality, and the test set had 338 observations of adequate quality for use. Figure A random forest regression model was trained on the complete list of features in the training dataset for SBP and DBP. Impurity-based feature importance was used to compute feature importance. Features that had more than 2% overall relative importance were selected. Figure Similarly, for DBP—Respiration rate 2, Relative Tidal Volume 1, Relative Tidal Volume 2, impedance, R to S2 time, Mean interbeat interval, the ratio of S1 RMS to S2 RMS, S1 RMS, S low, S mid, S high, S1 low, age, height, and weight. Based on these feature selections, it is evident that demographic data is a strong predictor of SBP and DBP values. However, there is potential benefit in terms of accuracy improvements resulting from using the SimpleSense measured signals in addition to demographics and machine learning methods to find the association with a hemodynamic parameter that can be used to estimate BP. Here, we seek empirical evidence for this potential improvement.18. With an overall time for a task set to 4 min and individual evaluations set to 30 s, the final diastolic model included eight tree-based regression models, and the systolic model included five regression models.The Systolic and Diastolic models are ensembles of regression trees. The ensemble model was trained using the auto-sklearn framework14. Additionally, age-related increases in variability of BP are known19.Figure Figure The results of bootstrap RMSE with the 95% CI are presented in Table The upper 95% CI for the difference between the SimpleSense-BP and the baseline model for both SBP and DBP are below zero with the differences in RMSE calculated as (SimpleSense-BP—baseline model). With this result, we conclude that the SimpleSense-BP model has a statistically significant improvement in performance over a model that uses demographic data only. We calculated the p-value as the percentile value at which ≥ 0 mmHg difference in RMSE was observed . Table The test protocol includes induced variation of blood pressure within an individual participant using a cold pressor test, heating of extremities, relaxed posture, and brisk exercise in the form of walking. Further, bootstrap resampling was done for the systolic BP model and Diastolic BP model to obtain a 95% confidence interval for MAD values. We performed 1000 iterations of resampling with replacement with each sample size equal to the test set size and the confidence intervals for the systolic and diastolic MAD were found to be  and , respectively.First, the use of heart sounds, ECG, and thoracic impedance as inputs to estimate SBP and DBP, and second, the size of the subject population for the evaluation of such a cuffless approach is the largest to date in the literature. The device and model are cuffless and do not require a cuff calibration procedure. This removes the burden on the user to calibrate the device and eliminates errors due to the wrong calibration. The performance observed in this study supports a determination that this approach is indeed feasible for monitoring BP of adults without a diagnosed arrhythmia or actively taking vasoactive anti-hypertensive medications. It is further observed that performance may improve at the low and high BP ranges of measurement by increasing the number of subjects in those stratifications. However, as a generalized approach that should be reliable for the US population, the presented model meets the criteria for required performance as per the current IEEE 1708 standard. Recent work by Mukkamala et al. has revealed limitations to the approaches described herein. The measurement of errors in BP must be done in a longitudinal study with tracking of BP over time for the same individual. This should be a part of the evaluation of new BP estimation methods. There are practical challenges in the recruitment of patients to meet the criteria for the subject population outlined in the latest amendment to IEEE 1708a 2019; the standard requires a separate study for age groups over 50 yrs., but requires recruitment of at least 21 subjects overall in each stratification of BP. Finding subjects under 50 years of age with stage 2 hypertension is challenging regardless of the resources available because we face the ethical conflict of not immediately recommending their treatment with vasoactive drugs, and subjects under vasoactive drug treatment must be excluded. This study explored the possibility of including a broader population in terms of age, and we present the results with age-stratified accuracy presented in Tables Two ensemble models were trained on the data collected from 120 subjects. The two models predict systolic and diastolic pressures based on features extracted from the SimpleSense data and demographics data, inclusive of Age, Gender, Height, and Weight. This approach would be consistent with the class of BP measurement called cuffless BP monitors. There are two novel aspects reported herein—The BP estimation method presented herein was not developed to monitor BP in ambulatory patients while performing activities involving movements. SimpleSense is wearable, and estimates of BP can be calculated during movements. However, since the gold standard sphygmomanometer and existing ABPM devices do not claim BP during movements, the training and testing data were collected with the subjects in a stationary state. A claim justifying truly ambulatory BP monitoring using SimpleSense would need further clinical study. Similarly, the current research that is presented emphasizes the algorithm that is developed to predict blood pressure. The algorithm was trained and validated based on the data presented in this article. It should be noted that an independent evaluation and validation would be required before the device can be fully incorporated into commercial applications.Supplementary Information.


The DAO activity in patients with mild rhinitis was 52.93 ± 8.72 HDU/mL, in those with moderate rhinitis it was 120.33 ± 71.63 HDU/mL, and in those with severe rhinitis it was 92.58 ± 27.75 HDU/mL (p = 0.006). The NPIF in patients with a DAO activity deficit was 107.92 ± 34.05 L/min, compared to 72.35 ± 27.16 L/min in patients with normal enzymatic activity (p < 0.001), demonstrating a linear correlation between activity levels and nasal obstruction . Therefore, patients with a DAO deficiency and idiopathic rhinitis could present a milder disease course, because the repeated and continuous activation of TRPV1 led to a partial or total decrease in their response (desensitization). This new theory represents a different perspective for the study of idiopathic rhinitis and its relationship with TRPV1, with the regulation or modulation of the desensitization of TRPV1 being an important therapeutic target for patients with idiopathic rhinitis in the future.Idiopathic rhinitis represents more than 50% of non-allergic rhinitis, a heterogeneous group that involves the symptomatic inflammation of the nasal mucosa. The TRPV1 receptor of unmyelinated C-type neurons appears to be involved in its pathophysiology. Histamine, whose main catabolic enzyme is DAO, is one of the mediators that can activate this receptor. The failure of DAO causes an increase in the level of histamine in the body and, consequently, the activation of TRPV1. The objective was to investigate the existence of a DAO enzyme activity deficit in idiopathic rhinitis and its correlation with symptoms. A cross-sectional study was conducted in 116 idiopathic rhinitis patients, and DAO activity, nasal peak inspiratory flow, and rhinitis severity were recorded. The prevalence of a DAO activity deficit was 41.38% (95%CI 0.33–0.50;  Rhinitis is defined as a symptomatic inflammation of the inner lining of the nose, classically divided into allergic rhinitis (AR) and non-allergic rhinitis (NAR). NAR comprises a large heterogeneous group of patients without systemic signs of allergic inflammation  or clinical signs of infection. Of these cases, up to 50% do not have a clear etiology underlying the symptoms and are defined as idiopathic rhinitis (IR) ,2,3.Several mechanisms have been postulated to explain IR pathophysiology. One of the most widely accepted suggestions is the nociceptive transient receptor potential vanilloid 1 (TRPV1) signaling pathway, which is found upregulated in IR patients ,5. WithiThis receptor can be activated, directly or indirectly, by a large number of mediators: ethanol, tissue damage, mechanical stimuli, acid pH, temperature above 43 °C, osmotic pressure alterations, cations, leukotrienes, nitric oxide, lipoxygenases, capsaicin, substance P, nerve growth factors, and prostaglandins  6,7,12,,15,16,17Histamine intolerance (HIT), an imbalance between the supply of histamine and the body’s ability to degrade it, belongs to the group of pharmacological non-IgE-mediated food intolerances. Its prevalence in the general population is approximately 1%, but this figure is probably underestimated due to the condition’s wide spectrum of symptoms ,19,20,21The physiology of the TRPV1 receptor and its response to histamine could allow for a subgroup of patients with IR and a DAO activity deficit in which the symptomatology and clinical course vary; therefore, these patients could benefit from personalized treatment. The objective of this preliminary study was to investigate the existence of a DAO enzyme activity deficit in patients diagnosed with IR and its correlation with symptoms.A cross-sectional study involving patients diagnosed with IR according to the European Academy of Allergy and Clinical Immunology criteria  was perfCandidate patients were required to present at least two of the following symptoms for at least 1 h daily for 12 weeks per year: nasal obstruction, rhinorrhea (anterior or posterior), sneezing, and nasal/ocular itch. Patients with rhinosinusitis and occasional or nasal symptoms were excluded. Selection was based on a structured interview and physical examination (anterior rhinoscopy and flexible fibronasoendoscopy) revealing no evidence of important nasoseptal deformities or polyps, performed independently by at least one otorhinolaryngologist and one allergist. For each participant, a detailed history of allergies was collected, including a skin-prick test for common aeroallergens. The relevant subgroups of NAR in clinical practice  were excluded based on this clinical history, with support from the necessary complementary tests as appropriate. The key feature of IR is the presence of nasal hyperresponsiveness , the diaSeveral diagnostic strategies involving various tests have been proposed, because direct HIT-specific diagnostic criteria are lacking. Following the recommendations of the clinical guidelines, only cases matching the analytical criteria and presenting a compatible clinical history  were classified as DAO deficiency ,32,33,34Only adults over 18 years old were included. The exclusion criteria were: pregnancy; treatment with the DAO enzyme for the past 2 weeks; treatment with any medication that may have caused a secondary decrease  or increase (heparin) in DAO activity and could not be suspended ,21; a hiSociodemographic variables; DAO enzyme activity; nasal peak inspiratory flow; and IR severity score  based on a visual analogue scale  were recorded ,35.Nasal peak inspiratory flow (NPIF) is a rapid and simple technique performed using a plastic cylinder calibrated between 30 and 370 L/min with a facial mask attached. In this study, we used the In-Check portable inspiratory flow meter . From an expiratory maneuver to residual volume, a forced inspiration was made while the lips were sealed. The best of three measurements that varied by no more than a 10% was chosen. Normal reference values for Caucasian adults are 143 ± 48.6 L/min for males and 121.9 ± 36 L/min for females ,36.DAO enzyme activity was determined by ELISA in accordance with the manufacturer’s instructions  and previous literature reports, with a venipuncture after an 8 h fasting period in an EDTA tube . The thrIn order to exclude patients with allergies, a skin-prick test with a calibrated lancet (1 mm) held vertically while introducing a drop of diluted purified allergen was used. According to the protocol of the Hospital’s Allergology Service, and based on the allergens typical of the area in which the study was carried out, the extracts included were Dermatophagoides pteronyssinus, Lepidoglyphus destructor, Tyrophagus putrescentiae, Gliciphagus, Blomia tropicalis, Chortogliphus, Alternaria alternata, Phleum pratense, Cynodon dactilon, Plantago lanceolata, Parietaria judaica, Betula verrucosa, Populus nigra, Cupressus arizonica, Platanus acerifolia, latex, profilina, and dog and cat epithelium. A drop of histamine (10 mg/mL) and saline solution were used as a positive and negative control, respectively. The maximum or mean diameters of the wheals for various allergens were read at 15 min. A wheal ≥2 mm in diameter was considered positive, indicating sensitization to the allergen.®, Vienna, Austria). Normality was evaluated by the Kolmogorov–Smirnov test and variances using the Levene test. All tests were two-tailed with a 95% confidence interval (CI). Quantitative variables were expressed as mean ± standard deviation (SD) and/or median, as appropriate. For the qualitative variables, frequency and percentage were used. The comparison of means was performed using Student’s t test, while qualitative or categorical differences between groups were evaluated by the χ2 test or Fisher’s exact test, as appropriate. In cases where non-normality was significant, non-parametric methods were applied. Correlation between variables was assessed using Pearson’s test or Spearman’s test, as appropriate.Statistical analysis was performed with R program 3.6.1 . The mean DAO activity in the normal-function group  was 143.05 ± 63.96 HDU/mL, compared to 60.72 ± 10.16 HDU/mL in the group with an activity deficit (p < 0.000).A total of 116 Caucasian patients with IR were recruited: 20 men (17.24%) and 96 (82.76%) women. The mean age was 45.36 ± 11.41 years . The prevalence of DAO activity deficits in patients with IR was 41.38% . The mean DAO enzyme activity of the 116 patients was 108.98 ± 63.9 HDU/mL: 85.60 ± 43.15 HDU/mL in men and 113.85 ± 66.57 HDU/mL in women ((p = 0.393). After stratification according to severity groups, the mean score was 2 in the mild IR group, 6.05 ± 0.89 in the moderate IR group, and 8.50 ± 0.73 in the severe IR group (p < 0.001). The DAO activity in patients with mild rhinitis was 52.93 ± 8.72 HDU/mL, in moderate rhinitis it was 120.33 ± 71.63 HDU/mL, and in severe IR it was 92.58 ± 27.75 HDU/mL (p = 0.006).According to the severity of the symptoms measured using the VAS, 8 (6.90%) patients had “mild” rhinitis, 80 (68.97%) “moderate” rhinitis, and 28 (24.14%) “severe” rhinitis. The global mean was 6.35 ± 1.78 points, being 5.6 ± 2.3 for men and 6.51 ± 1.63 for women p = 0.514). In the mild group, the NPIF was 85 ± 10.69 L/min, in the moderate group it was 88.25 ± 37.29 L/min, and in the severe group it was 84.28 ± 32.48 L/min (p = 0.904). The NPIF in patients with a DAO activity deficit was 107.92 ± 34.05 L/min, compared to 72.35 ± 27.16 L/min in patients with normal enzymatic activity (p < 0.001) (p < 0.001).The mean NPIF of all patients was 87.06 ± 34.82 L/min, being 89 ± 26.23 L/min for men and 86.67 ± 36.46 L/min for women (< 0.001) , demonstHIT, also known as sensitivity to dietary histamine or enteral histaminosis, can be defined as a dysfunction caused by a reduction in DAO activity that affects the degradation of histamine in the intestine. Under physiological conditions, DAO creates an intestinal enzymatic barrier that protects the body from the absorption of histamine ingested with food ,20. HIT IR represents a diagnostic and therapeutic challenge . The mecThe activity and efficiency of TRPV1 under physiological conditions are low. An inflammatory process activates peripheral sensory nociceptors that are capable of locally releasing numerous pro-algesic chemical mediators, such as histamines, serotonins, bradykinins, prostaglandins, cytokines, and growth factors. All of these contribute to enhancing the local inflammation process, and consequently, the function of TRPV1 is synergistically enhanced by the simultaneous action of these released pro-inflammatory substances. These substances cause an increase in the sensitivity and response of peripheral nociceptors, which leads to a decrease in the activation threshold of these terminals and an increase in the magnitude of their response. This phenomenon is known as peripheral sensitization ,42.One particularity of TRPV1 is that the repeated and continuous activation of nociceptors leads to a partial or total decrease in their response. The TRPV1 becomes refractory, being unable to respond to new stimuli  10,43].,43.10,43Histamine could act as a competitive agonist against other molecules, displacing a possible stronger response to the activation of TRPV1. In fact, previous studies suggest that the increase in calcium concentrations stimulated by histamine is slower, with a lower amplitude and shorter duration compared to capsaicin activation, even in the continuing presence of the agonist . FurtherIn this study, DAO activity was investigated in patients diagnosed with IR. Other authors have studied serum or intracellular DAO concentrations . NeverthSeveral authors have detected a correlation between DAO concentrations and female sex hormone changes , but thiAn important limitation of this study is the impossibility of extrapolating the prevalence of DAO activity deficiencies in the general population, as the patients were recruited only from the outpatient department, and there was no control group. For this reason, it is not possible to conclude whether the IR subgroups established on the basis of DAO activity represent the variability of the general population or non-IR patients. Patients’ motivation to seek care can be influenced by symptom severity, introducing an inclusion bias. In other words, patients with very mild or very severe symptoms may not recognize them as pathological ,51. ThisAlthough our results were not sufficient to definitively clarify the link between IR severity and DAO activity, this study opens up a new range of possibilities. No study has addressed the role of DAO SNPs in patients with IR. It can be hypothesized that, as in the case of AR, the presence of these polymorphisms may modify the pathogenesis of IR due to the involvement of DAO in the metabolism of circulating histamine.The hypothesis of this manuscript was that the repeated stimulation of TRPV1 could be caused by supra-physiological histamine levels generated due to a deficit in their degradation, producing a less severe symptomatology in a subgroup of patients with IR. The results of the pilot study supported this claim: patients with mild rhinitis had lower DAO activity than patients with moderate and severe rhinitis, and the decrease in DAO activity was inversely proportional to nasal obstruction assessed according to NPIF. This represents a new perspective for the study of IR and its relationship with TRPV1, with the regulation or modulation of the desensitization of TRPV1 being an important therapeutic target for patients with IR in the future.


Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are the antihypertensive drug class of choice in patients with chronic kidney disease (CKD). Head-to-head comparisons of the renal or non-renal outcomes between ACEI/ARB users and nonusers have not been conducted in all population groups. We examined the renal and cardiovascular outcomes in users and nonusers enrolled in the Indian Chronic Kidney Disease (ICKD) Study.A total of 4,056 patients with mild-moderate CKD were studied. Patients were categorized as ACEI/ARB users or nonusers. Major adverse kidney events , all-cause mortality, and cardiovascular mortality were analyzed over a median follow-up period of 2.64  years between the two groups.Out of a total of 4,056 patients, 3,487 (87%) were hypertensive. The adjusted sub-hazard ratio (SHR) and 95 % CI for ACEI /ARB users was 0.85  for MAKE, 0.80  for a 50% decline in eGFR, and 0.72  for ESKD. For cardiovascular mortality, ACEI/ARB users were at lower risk . Diuretic users were at increased risk of all-cause mortality  and cardiovascular mortality . There was non-significant association between the use of other antihypertensives and any of the end points.ACEI/ARB use is associated with slower rate of decline in eGFR in those with CKD stage 1-3. ACEI/ARB users had a significantly lower risk of renal outcomes, and cardiovascular mortality. Hypertension is both a consequence and risk factor for the development and progression of chronic kidney disease (CKD). Optimal blood pressure control in patients with CKD usually requires the use of multiple anti-hypertensive agents , 2. DrugIn this manuscript, we describe the antihypertensive drug usage in a wellcharacterized cohort of patients with mild-moderate CKD enrolled in the Indian Chronic Kidney Disease (ICKD) Study, and examine the impact of angiotensin pathway blockers on the progression of CKD as well as all-cause mortality and cardiovascular mortality.2 or proteinuria >500 mg/d, from 11 large hospitals in India. Those with eGFR <15 ml/min/1.73 m2, kidney transplant recipients, and those on immunosuppressive drugs, with malignancy or poor functional status are excluded. The study has approval from the institutional review board at each center, and all participants provide written informed consent.The details of the ICKD cohort study design have already been published . BrieflyDemographic details, diagnosis, comorbidities, clinical, laboratory, and treatment details are recorded and stored anonymously in a secure central database. All the enrolled patients are followed regularly, and outcome events are recorded.Participants were categorized into different CKD stages as per Kidney Disease Improving Global Outcomes (KDIGO) criteria . GFR is 2), normal (18–24 kg/m2), and overweight (≥25 kg/m2).Diabetes is defined as fasting plasma glucose of >126 mg/dl, glycated hemoglobin of ≥6.5%, or the use of glucose-lowering drugs. Hypertension is defined as blood pressure >140/90 mm Hg or the use of antihypertensive therapy. CVD is identified by a history of heart failure, coronary artery disease, prior revascularization, stroke, or peripheral vascular disease. All comorbidities are either self-reported or on the basis of chart review. Body mass index (BMI) is categorized as underweight (<18 kg/m2), uncontrolled systolic (≥140 mm Hg) and diastolic (≥90 mm Hg) blood pressures, albuminuria, concurrent use of other antihypertensive medications namely (CCBs and BBs), diuretic and statins.All prescriptions were captured from records. We were primarily interested in the use of ACEI or ARBs, CCBs, BBs, and diuretics at the point of entry to the study. Use of these agents was confirmed by reviewing the prescription of the patient, which is entered into the ICKD database. Patients were categorized as ACEI/ARB user at baseline if they had been on either of these agents for >3 months. We also analyzed the ACEI or ARB use in albuminuric and non-albuminuric subjects. In analysis of factors associated with the use of ACEI/ARB (coded as a binary variable), we included CKD stage, age at enrolment (≥60 vs. <60 years), sex, annual household income, residence, education level, diabetes mellitus, obesity  , ≥50% GFR decline, ESKD, all-cause mortality and CVD mortality, among users of each antihypertensive drug class adjusting for the baseline covariates including age, residence, sex, income, presence or absence of heart failure, eGFR, albuminuria, diabetes mellitus, obesity, blood pressure, aspirin use, statin use, and a family history of stroke. Deaths were identified through retrieval of death certificates, review of hospital records or reports from next of kin.P value <0.05 is considered to be significant.Descriptive statistics were used to describe the demographic and clinical characteristics and prescription use patterns of study subjects. Continuous data were presented as mean ± standard deviation (SD) or median , and categorical data were presented as frequency (percentage). For the purpose of analysis, complete case data were considered. Unadjusted and adjusted logistic regression models were used to assess the association between ACEI/ARB users and nonusers and baseline demographic and clinical characteristics with prescription use as an outcome of interest. Cox proportional hazard models were used to study the association of time to occurrence of events with reference to different anti-hypertensive drugs and after adjusting for other covariates including baseline age, residence, sex, income, heart failure, eGFR, baseline albuminuria, diabetes, obesity, blood pressure, aspirin use, statin use, and family history of stroke. We used the Cox proportional hazard model to estimate the hazard ratio (HR), to capture the effect of an intervention on an outcome of interest over the time as compared to the control group. We used competing risk model to estimate the sub-hazard ratio (SHR) accommodating the risk of an event whose occurrence could preclude the occurrence of the primary outcome of interest. For CVD mortality as an outcome of interest, death due to any other cause was considered as competing event. For 50% GFR decline, ESRD and MAKE as outcomes of interest, non-renal death was considered as competing event. 2, i.e., were overweight or obese. A total of 1,849 (46.6%) participants were using ACEIs/ARBs, followed by CCBs , diuretics  and BBs . A total of 1,602 (40.4%) participants were receiving statins. Use of ACEIs/ARBs at baseline in albuminuric patients was significantly more as compared to non-albuminuric patients .The baseline sociodemographic and clinical characteristics of the overall study cohort as well as users and nonusers of ACEIs/ARBs are shown in The majority of the patients were in CKD stage G3 (78.65%) . Males o2. Out of 3,339 participants with available follow up data, MAKE event was observed in 622 (18.63%) and ESKD was observed in 428 (12.83%) participants. Among 3,104 participants for whom eGFR was available at last follow up, 468 (15.08%) experienced ≥50% eGFR decline. Overall mortality and cardiovascular mortality were reported in 317 (9.49%) and 103 (3.08%) participants out of 3,339 for whom follow-up data were available (Flow chart of the data analyzed in this study have been mentioned in vailable .In a separate multivariable analysis , we exam2 as compared to 2.40 ml/min/1.73 m2 in the nonusers. The annual rate of decline in eGFR in stage 1 CKD was 10.58 ml/min/1.73 m2 in ACEI/ARB nonusers and 8.71 ml/min/1.73 m2 in users. The rate of eGFR decline in those with stage 2 CKD was 6.89 and 5.59 ml/min/1.73 m2 in ARB nonusers and users respectively. In those with stage 3 disease the nonuser and users showed a rate of decline of 2.38 and 2.08 ml/min/1.73 m2 respectively. Finally, the eGFR decline was 0.17 in users and−0.13 ml/min/1.73 m2 in nonusers of ARB in stage 4 CKD.According to unadjusted regression, compared to nonusers, ACEI/ARB users had a significantly lower risk of developing a MAKE (unadjusted SHR= 0.82, 95% CI: 0.70, 0.97, In this large prospective cohort study, we observed that ACEI/ARB use decreased and the use of CCBs, BBs, and diuretics increased with advancing CKD stages. Many patients, despite being hypertensive, were not receiving ACEI/ARB in the early stages of CKD despite clear recommendations by all major clinical practice guidelines –16. The Similar to our study, a sub-study of CRIC cohort showed that the use of BBs, CCBs, and diuretics steadily increased, whereas the use of ACEI/ARB decreased with advancing stages of CKD . In that2 from Sweden (2 did not find any difference in the long-term rate of decrease in the eGFR following the discontinuation of RAS inhibitors (The cardiovascular protection conferred by ACEI/ARBs across all stages of CKD has been confirmed in several systematic reviews and observational studies (summarized in m Sweden  showed tm Sweden . Howeverm Sweden , 27. A rm Sweden . Finallyhibitors . The highibitors , 31. Thehibitors .The effect of other antihypertensives was neutral with regard to the end points studied. Similar to our study, CCBs did not increase all-cause mortality incidence in patients with CKD and showed a weak reno-protective effect, compared to ACEI/ARBs . A systeThe major strength of our study is prospectively collected data of ICKD cohort, and the comparison of all anti-hypertensive used in the management of hypertension in CKD patients. Besides kidney outcomes, we also analyzed all cause- mortality and cardiovascular mortality and adjusted for all variable affecting the outcome. This is the only data available from this part of the developing world. Our study has some limitations, however. These include relatively short duration of follow-up and a small number of patients with stage 4 CKD. About 17% of patients were lost to follow-up, which could have caused bias. We were also unable to determine the overall exposure to ACEI/ARBs in relation to the treatment duration or dose effect. We also cannot comment on the reasons for the low ACEI/ARB use. Low-cost generic preparations of these agents are widely available in India. Although we have adjusted the analysis for a range of factors, the effect of unmeasured confounders cannot be totally ruled out. However, the impact on the outcome with the use of ACEI/ARB users was huge, even on short follow-up, and emphasizes the need to encourage the use of ACEI/ARB in early CKD. During the COVID pandemic, there has been a debate on the ability of ARBs to protect against development of severe disease. Our data, however, was collected mostly before the pandemic .In conclusion, the use of ACEI/ARBs decreased with advancing CKD stages from stage 1 to 4. ACEI/ARB users exhibited a slower rate of decline in eGFR, especially in CKD stages 1–3, with a neutral effect in stage 4. However, they had a significantly lower risk of cardiovascular mortality across all stages. Diuretic use was associated with higher mortality in our cohort. Use of agents that block angiotensin pathway is reno-protective and cardioprotective in patients with CKD.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Institute Ethics Committee, Postgraduate Institute of Medical Education and Research, Chandigarh, India. The patients/participants provided their written informed consent to participate in this study.NP, AY, and VJ conceptualized the study. AY and VK performed data curation. MK and AG analyzed the data. AJ, DS, GM, MS, NG, SVi, SVa, SS, SG, SP, and VK verified clinical data and investigations. NP and AY drafted the original manuscript. VJ and SB-A supervised the study. VJ reviewed and edited the manuscript. All authors reviewed and approved the final version.