The aim of this study was to compare radial pulse characteristics between primary dysmenorrhea (PD) patients and healthy subjects throughout the menstrual cycle. A total of 48 females aged 20 to 29 years participated, and all subjects were assigned to two groups according to their visual analogue scale scores. The radial pulse of each subject was obtained using a pulse tonometric device during menstrual, follicular, and luteal phases. In addition, various pulse analysis indices were used to estimate the pulse characteristics. The pulse tension index (PTI) and pulse depth index (PDI) in the patient group were significantly lower than those in the healthy group during the menstrual phase . According to univariate logistic regression results, the PTI, PDI and optimal applied pressure (OAP) were significantly correlated with PD, and the model based on the PTI and OAP performed best (AUC = 0.828). This study is the first to analyze pulse tension inferred from the PTI and to apply this parameter to clinical practice. The results of this study confirmed the possibility of quantitatively measuring pulse tension and suggest that the PTI and OAP can serve as potential clinical indicators for pain disorders. Traditional Korean medicine (TKM) and traditional Chinese medicine (TCM) physicians perform pulse diagnosis by adjusting the pressure applied by their fingertips at three parts of the radial artery—cun, guan, and chi—of the patient’s wrist1. TKM physicians diagnose and provide prescriptions to patients on the basis of pulse characteristics; however, serious problems can arise due to reliance on the physician’s subjective point of view. The accuracy of pulse diagnosis depends on the individual’s experience, observational skills, and fingertip sensitivity2. Moreover, there is no clear diagnostic criterion, and it is difficult to define physical variables that reflect pulse characteristics. Recently, to overcome these problems, several scientific advancements have been achieved to quantify pulse diagnostic parameters, including the development of a pulse tonometric device (PTD)3. Various clinical studies using a PTD have been conducted with various variables for specific disorders, such as hypertension4, coronary heart disease5, diabetes mellitus6, cirrhosis7, and pancreatitis8. However, few studies have used a PTD for gynecological diseases.Pulse diagnosis can be used to diagnose physiological conditions and predict the prognosis of a pathological disorder9. Dysmenorrhea is also one of the clinical signs of endometriosis, which is a more intense disorder and corresponds to the severity of pain10. In addition, as pelvic and lower abdominal pain represents the key symptom of many gynecological diseases, it is important to have a correct diagnosis and appropriate treatment of primary dysmenorrhea due to the complex nature of the disease11. In young women, dysmenorrhea often occurs without an underlying problem, a condition known as primary dysmenorrhea (PD). In older women, dysmenorrhea is more often due to underlying issues such as uterine fibroids, adenomyosis, or endometriosis, a condition known as secondary dysmenorrhea12. PD is a common gynecological complication among women of reproductive age. Studies have shown that pain-related gynecological complications have a negative effect on psychological health, which may eventually lead to certain limitations in social activities and cause a significant impact on women’s mental health and quality of life13. Nonsteroidal anti-inflammatory drugs or oral contraceptive pills are widely used as first-line therapy for women with PD. However, these drugs may have side effects in some women and may not provide any long-term pain relief14. Therefore, many patients with PD are seeking alternative treatment through TKM and TCM, such as acupuncture, moxibustion, or herbal medicine15. Jeon et al.16 investigated whether radial pulse indices derived from a PTD were related to menstrual pain during menstrual and nonmenstrual periods. They reported that women with menstrual pain had decreased blood vessel elasticity, low pulsatile force and a reduced diastolic phase in the pulse wave during the nonmenstrual period16. Su et al.17 also reported that the amplitudes of the main wave and dicrotic wave and the systolic area of the radial pulse waveforms were greater in the luteal phase than those in the follicular phase. Chen et al.18 observed that pain could increase the width of the upper 1/3 of the main wave, the amplitude of the gorge of the main wave and the dicrotic notch but decrease the time of the gorge of the main wave and the amplitude of the dicrotic wave; therefore, they concluded that pulse waveform parameters change in opposite directions when PD patients experience pain and when they experience pain relief.Dysmenorrhea, also known as menstrual cramps, is pain during menstruation and is related to a wide range of psychiatric symptoms, especially depression, anxiety, psychosocial stress and a poor quality of lifeqi and blood, coagulation of cold-dampness, deficiency of blood and qi, or impairment of the liver and kidneys20. TKM physicians identify patterns of PD according to clinical information acquired through inspection, listening, inquiring and palpation21. Among this clinical information, pulse characteristics are one of the most important elements. As pulse characteristics vary according to the pattern of the disease, pattern identification should be considered in the pulse diagnostic research in TKM for a higher diagnosis accuracy and better clinical application. Second, all phases of the menstrual cycle were not considered for the PD patients in previous studies. Jeon SH measured the radial pulse during the follicular and menstrual phases, whereas Su SY measured the radial pulse during the late follicular and late luteal phases17. Additionally, Chen WH measured the radial pulse during the luteal and menstrual phases18. However, no studies considered all three phases  of the menstrual cycle. Such considerations are necessary because characteristics of the radial pulse change throughout the entire menstrual cycle22. Third, suitable analytical indices to investigate the pulse characteristics of PD patients have not been fully considered. In TKM and TCM, important pulse properties include the pulse depth, width, length, regularity, and tension23. Although many studies have been conducted to quantify these pulse properties, several indices have been unclearly calculated, which have yielded uncertain meanings, and the directly related variables were not used in prior fragmented studies24. In particular, an analytical index reflecting pulse tension characteristics has not been used, even though pulse tension is a major pulse characteristic of patients with pain. Therefore, a PD study using a PTD for this objective and suitable indicators is required. The aims of this study were to compare radial pulse characteristics between PD patients and healthy subjects throughout the menstrual cycle and to investigate the effects of menstrual pain on the radial pulse. To this end, a novel indicator reflecting the pulse characteristics of PD patients was considered.However, several limitations were identified in these prior works that used PTD in PD patients. First, pattern identification was not considered for the PD patients in these studies. In TKM, treatment methods for PD can be designed and tailored according to identified patterns, such as stagnation of qi and blood, whereas only one of the 23 patients was diagnosed with deficiency of blood and qi.Of the 48 subjects recruited, only the data sets of 47 subjects were analyzed. One participant was excluded from the data set because she violated the protocol of this study. The remaining subjects were grouped into the healthy group, which included 24 women, and the patient group, which included 23 women. The general characteristics of the participants in both groups are presented in Table blood and qi were excluded from the final analysis of radial pulse indices. In total, 46 participants were assigned to the PD patient (n = 22) and healthy subject (n = 24) groups. First, we compared the distributions of radial pulse indices between the patient and healthy subject groups at the cun, guan, and chi  and conception vessel (the ren meridian) can occur, which can induce many gynecology disorders. In addition, the chi pulse on the left hand is associated with Kidney yin, while chi pulses on the right hand correspond to Kidney yang and the uterus. The affiliation between Kidney and gynecology may explain why only the chi pulse showed differences in the distribution tendency of our result26.In this study, we focused our analysis only on the 27. Therefore, the pulse characteristics before menstruation begins, at the start of menstruation, and the day after menstruation begins may be different according to the excretion of prostaglandin. According to TKM and TCM textbooks, patients with typical stagnation of qi and blood generally have a string-like pulse, which is also known as a wiry pulse, whereas the deficiency of blood and qi pattern can be manifested as a deep and slow pulse19.A comparison of the pulse indices between the PD patients and healthy subjects throughout menstruation showed that significant differences were identified between the two groups during the menstrual phase but not during the follicular or luteal phases. Among the pulse indices, PDI and PTI showed significant differences for the two groups during the menstrual phase. Although OAP did not show significant differences between the two groups during the menstrual phase, OAP showed a similar tendency. These results may be due to the hormonal changes during the menstrual period when prostaglandin is excreted. The prostaglandins, in particular, cause intense vasoconstriction and affect the vessel wall tension, which eventually leads to changes in the pulse waveTogether with the above statements, the pulse signals measured by the PTD in this study could be considered to have characteristics of a string-like pulse. A string-like pulse can be described as a straight, long and taut pulse, which is similar to a musical string when touched. According to a modern expression with quantifiable physical properties, the major property of string-like pulses is tension, and depth and strength properties can also affect this type of pulse.28. This research was performed to study the descriptions of physical properties of specific pulses based on a consensus among experts and medical literature. The experts involved in this study agreed on a description of pulse tension as a section for which the degree of changes in increasing pulse amplitude according to the applied pressure is below a certain level. However, a pulse tension algorithm using a P-H curve has not yet been reported. A P-H curve showing the pulse pressure as a function of the applied pressure was originally used to determine whether the pulse was strong when the applied pressure was weak or strong1. In other words, this applied pressure-based method is considered more suitable for estimating pulse depth rather than pulse tension.The PTI developed in this study was inspired by the Delphi research conducted in Kyung Hee University Korean Medicine Hospital (KHUKMH)Instead, a sensor displacement-based method was used to calculate the PTI because the CETM was applied to the PTD in this study. The pulse pressure as a function of actual sensor displacement was obtained, and the PTI was calculated. The overall increasing tendency of the pulse pressure according to the applied pressure can be reflected by the PTI. Since this was the first study on a quantitative index for pulse tension, the various PTI values corresponding to the 20, 30, 50, 70, 80, and 90 percentages of the maximum pulse amplitude were first calculated, and then the index that best reflected pulse tension was examined. In this study, the PTI70 had the largest effect size and AUC value; therefore, multiple logistic regression models with the PTI70 were constructed. For the PTI80 and PTI90, since the time interval between the maximum pulse amplitude point and the point greater than 80% or 90% of the maximum pulse amplitude was very short, the accuracy of the increasing trend for pulse pressure was limited. Furthermore, in addition to the PTI, the OAP was also considered to estimate pulse tension. Because a pulse with high tension exerts a strong resistive force against applied pressure, the pulse amplitude increases rapidly, even when only light pressure is applied. Therefore, a low OAP may reflect high pulse tension as well as low pulse depth. The OAP value of the PD patients was lower than that of the healthy subjects, as expected.qi and blood corresponds to a string-like pulse. Consequently, throughout the PDI, OAP and PTI, it can be concluded that the radial pulse of the patients with PD appeared string-like, whereas the radial pulse of the healthy subjects appeared normal.Pulse depth is another property of a string-like pulse. Although both string-like and tight pulses have identical characteristics, including a high degree of tension, a shallow depth is a typical characteristic of a string-like pulse, whereas a deep depth is a characteristic of a tight pulse, although this characterization is controversial. In this study, the PDI of the PD patients was significantly lower than that of the healthy subjects. The PD patients were considered to have a string-like pulse, which is consistent with TKM theory, in which stagnation of 18. Our results imply that pulse tension is an important major pulse characteristic of patients with PD and suggest that the PTI and OAP may be potential clinical indicators for pain disorders.In our study, we performed multiple logistic regression for the associations of radial pulse indices with the likelihood of a given menstrual severity score using four indices, including the PPI, PDI, OAP, and PTI70. Model 4 had the highest quality among the tested models. Moreover, the area under the ROC curve was 0.828, which also showed that this model was an excellent classifier. Only the PTI70 and OAP, which are related to pulse tension, were selected for Model 4 among the four indices since tension indices were considered to be potentially more relevant to pain than to other characteristics. This finding is consistent with reports from previous studies that pain is often associated with a string-like pulse, whose main property is pulse tensionqi and blood, with the exception of only one subject who was diagnosed with a deficiency in qi and blood. Third, this study could not explore the differences among pulse characteristics according to various types of pain, although tense pulse was expected as a major pulse characteristic. There was no previous study about a pulse difference among different types of pain. Because potential clinical indicators for menstrual pain were investigated in this study, further study for other types of pain based on radial pulse indices such as PTI and OAP will be of great value. We will conduct a large, multicenter trial that considers various pattern identification and types of pain after further reviewing the results of this study.This study has two limitations. First, this study was designed as a single-center, prospective case-control study without randomization, blinding or allocation concealment. Therefore, the results of this study should be interpreted with caution. Second, this study could not explore the differences in the radial pulse indices according to pattern identification because all subjects were diagnosed with stagnation of chi pulses of PD patients throughout the menstrual cycle using a PTD. In addition, pattern identification for the PD patients was observed, ensuring more accurate and reliable results. Furthermore, this is the first study to analyze pulse tension by developing the PTI and applying it to clinical practice. This information on pulse depth, width, length, regularity, and tension can be used as a reference for medical treatment guidelines in acupuncture, moxibustion, and herbal medicine. Hence, the objective and quantitative pulse diagnosis is one of the most important clinical processes. The results of this study confirmed the possibility of quantitatively measuring pulse tension, which could also provide a scientific perspective on the development of the PTD.Despite these limitations, we believe that this study provides a basis for further and more comprehensive studies. This study is the first among the current literature to investigate radial pulse indices focusing only on the This prospective, case-control clinical study was conducted at the KHUKMH in Seoul, Republic of Korea. The experimental protocol was approved by the Ethics Committee of the Institutional Review Board in KHUKMH, and the approval number was KOMCIRB-150622-HR-021. This trial was registered with the Korean Clinical Trials Registry (identifier number KCT0001604) and was conducted in accordance with the principles of the Declaration of Helsinki.30.The subjects were enlisted through recruitment posters displayed around Kyung Hee University and KHUKMH. All subjects were required to visit KHUKMH and were asked to sign the informed consent forms after receiving a full explanation of the study. This study enrolled 48 women aged from 20 to 29 years who were subsequently stratified according to inclusion and exclusion criteria. Furthermore, all subjects were obligated to provide their sociodemographic data and completed measurements of menstrual pain (MMP) and a Cox menstrual symptom scale (CMSS) questionnaireThe inclusion criteria for the participants were predefined as follows: (1) females between 20 and 30 years of age; (2) a normal menstrual cycle (lasting 28 ± 3 days) for the past 3 months; (3) the ability to communicate with the clinical researchers; (4) the ability to voluntarily agree to participate in this clinical study; and (5) the ability to provide written informed consent. The exclusion criteria were as follows: (1) secondary dysmenorrhea caused by uterine myoma, endometriosis or infection of the genitals confirmed by pelvic examination, an ultrasound, and laboratory tests; (2) a history of medical operations or procedures; (3) a history of major neuropsychiatric disorder or antidepressant, anti-serotonin agent, barbiturate, or psychotropic drug use within the past 3 months; (4) a history of major medical diseases, including hypertension, diabetes, hyperlipidemia, gastritis, enteritis, gastroesophageal reflux disease, and Crohn’s disease; (5) extreme dieting within one week prior to study initiation; (6) pregnancy determined by a urine pregnancy test, planned pregnancy or lactation; (7) congenital vascular anomalies or a history of wrist fracture; (8) participation in another clinical study in the previous month; and (9) exclusion at the investigator’s discretion.31. In this previous study, the systolic blood pressure showed a significant difference between the healthy subject group and PD patient group at the luteal phase. The systolic blood pressure is closely related to the pulse pressure32, and the pulse pressure was considered as the primary outcome at the time of this clinical study design. Therefore, the effect size of the pulse pressure was estimated as 0.83, which was obtained from the result of the systolic blood pressure described in Singh et al. With a statistical significance level of 0.05 (2-sided test) and a study power of 80%, the estimated sample size was calculated to be 19 participants per group . With consideration of a 20% of drop-out rate, 24 subjects were recruited for each group. Consequently, the total sample size was 48 subjects with a 1:1 ratio for group allocation.Calculation of the required sample size was guided by a previous studyqi and blood, coagulation of cold-dampness, deficiency of qi and blood, or impairment of the liver and kidneys)20. All three physicians were blinded to the diagnostic results. Participants with confusing patterns or an inconsistent diagnosis among the physicians were excluded from the analysis.Based on the TKM pattern identification protocol for women with PD, three TKM physicians with ten years of clinical experience independently diagnosed the PD patients’ patterns After completing the allocation process, the research investigator calculated the assessment period of each subject by considering her menstrual cycle length for the previous 3 months. Upon completion of the run-in period, the assessments were conducted at the beginning of menstruation, the follicular phase  and the luteal phase (the 22nd day from the start of menstruation). Another licensed physician who is an assessor evaluated the outcome variables and recorded vital signs as well as any adverse events during the assessment period. Any additional relevant information was provided by the subjects.nd edition, and the reliability and safety of the device were confirmed based on clinical good manufacturing practice in Korea33. The PTD consists of a main body with an arm holder and a sensing body attached to a mobile actuator. The six-channel piezoresistive sensor, arrayed in a row attached to the end of the actuator where the sensing element has dimensions of 1 × 1 square millimeters, was used to measure the pulse signal. The sensor array was positioned in a row at each palpation position. The guan is positioned at the center of the radial styloid at the wrist, where the tip of the physician’s middle finger is placed; the cun is positioned next to the guan on the distal side, where the tip of the physician’s index finger rests; and the chi is positioned on the proximal side, where the tip of the physician’s ring finger is placed. The responsive pulse signal was acquired at a sampling rate of 1000 Hz, and the continuously evolving tonometric mechanism (CETM) was applied to the PTD2. The CETM is described as follows: After positioning the sensor at three palpation positions, the sensor was gradually moved downward at 0.09 mm/sec until reaching the optimal applied pressure (OAP), where the pulse amplitude reached its maximum. Then, the sensor was stopped to maintain the applied pressure for 70 seconds. A trained operator measured the pulse signals according to standard operating procedures. After the removal of noise and the baseline wander of the acquired pulse signal, feature points were extracted.Pulse waves were obtained using a PTD . The electromechanical stability of the device was certified based on the IEC 60601-1 218. Therefore, a quantitative index reflecting pulse tension is critical to compare pulse signal characteristics between PD patients and healthy subjects. As the pressure applied to the pulse increases, the responsive pulse pressure generally increases until the blood vessel starts to deflate, which can be observed on the pulse signal measured by the CETM. A pulse with a high degree of tension exhibits strong resistive force against the applied pressure. Therefore, the pulse amplitude rapidly increases according to the applied pressure, and the maximum pulse amplitude is quickly reached. However, since a pulse with low tension exhibits strong compliance against the applied pressure, the pulse amplitude slowly increases as the applied pressure increases; therefore, the maximum pulse amplitude is slowly reached. To quantify the force of these resistive pulse sections against the applied pressure, the pulse tension index (PTI) was developed. Each time interval between the maximum pulse amplitude point and the starting points with greater than 20%, 30%, 50%, 70%, 80%, and 90% of maximum pulse amplitude was calculated from the pulse signal measured by the CETM. Subsequently, the six indices were converted to motor displacement units of the PTD. Finally, the overall increasing tendency of the pulse pressure according to the applied pressure could be observed by calculating the PTI. Lower PTIs may reflect the entire increasing trend, including the initial sections, whereas higher PTIs may indicate a later increasing trend. Since no studies on a quantitative index for pulse tension are available, all six indices were first analyzed, and the index that best reflected the pulse tension was examined. In addition, the applied pressure value may be different even though the pulse has the same PTI value. Therefore, the OAP, one of the basic indices for pulse characteristics, was also calculated to estimate pulse tension characteristics. Pulse depth is one of the most important pulse characteristics. Pulse depth was measured based on the displacement of the sensor in the direction normal to the skin surface, and the pulse depth index (PDI) was calculated33. In addition, strength properties can also affect pulses. The voltage response of the sensor when the maximum pulse amplitude was reached was calculated as the pulse pressure index (PPI) to estimate the basic pulse strength. Table Pulse tension is a major pulse characteristic of patients with pain such as menstrual pain, headaches and chest pain2. The significance level for all statistical tests was set to α = 0.05. The demographic and baseline characteristics of the participants in this study were summarized as the mean and standard deviation (SD). Independent two-sample t-tests were applied to compare the mean differences in baseline values between the patient and healthy subject groups. Linear mixed effects (LME) models for each radial artery pulse parameter in the chi location were established to estimate the marginal means of both the patient and healthy subject groups for each stage of the menstrual cycle. Several confounders, such as age, BMI, systolic BP, pulse, and the amounts of caffeine and alcohol consumption (cups/day), were considered covariates in the LME models. The mean differences between the patient and healthy subject groups at each period of the menstrual cycle were tested based on the estimated marginal means from the LME models. The effect sizes in Tables et al.34. To investigate the associations between radial artery pulse markers and PD, the area under the receiver operating curve (ROC) for each radial artery pulse parameter was obtained. Multiple binary logistic regressions with different combinations of pulse parameters based on four distinct characteristics were applied to determine the best fitting model. The likelihood ratio test and Akaike information criterion (AIC) were employed to evaluate model performance35. For further analysis, ROC curves and their AUCs for each model were obtained based on leave-one-out cross validation.All statistical analyses were performed using R version 3.5.1Appendix 1


At each time point, APA group plasma aldosterone concentrations (PACs) were higher than those of the EH group. A circadian change in relation to PAC was observed in both groups. A correlation between PAC and BP was statistically nonsignificant in most study patients in either group. Our data indicated that the circadian BP pattern was not associated with a change in PAC levels in patients with APA.The absence of nocturnal blood pressure (BP) decline is associated with hypertensive complications. Data regarding circadian BP patterns in patients with aldosterone-producing adenoma (APA) are limited and equivocal. We evaluated the circadian BP profile in patients with APA and its relationship with the circadian aldosterone rhythm. BP in patients with APA and in those with essential hypertension (EH) were assessed through in-hospital 24-h ambulatory blood pressure monitoring. Over a 24-h in-hospital period, plasma aldosterone levels taken at midnight, 0400, 0800, 1200, 1600, and 2000 h were measured. To evaluate a correlation between BP and hormone rhythm, we included 27 patients with APA (APA group) and 27 patients with EH (EH group). Both groups had similar age, sex ratio, body mass index, duration of hypertension, family history of hypertension, and lipid profiles. The day-night BP differences in both patient groups were similar, whether expressed as absolute values or percentages. The proportions of patients with dipping BP profiles were also comparable (APA group, 5 of 27; EH group, 7 of 27;  Observational studies have shown a 10%–20% decline in blood pressure (BP) levels during sleep at night in most normotensive individuals and in patients with essential hypertension .Data regarding circadian BP patterns in patients with aldosterone-producing adenoma (APA) are limited and equivocal. Previous studies have reported that a circadian BP decline was blunted in APA patients , 5, whicIt is generally known that, in aldosteronism, overproduction of aldosterone leads to increased sodium and water retention and subsequent hypertension via its genomic effect, which is a relatively long-term action. Recent studies  have revFor patients with APA, it remains unclear whether an increase of plasma aldosterone concentration (PAC) or its change might affect the circadian BP pattern. This study aimed to evaluate the circadian BP profile in patients with APA and its relationship with PAC.The study participants comprised patients who had been consecutively referred to our center from June 2011 to March 2013 because of suspected primary aldosteronism (PA) or to exclude secondary hypertension . The protocol and informed consent documents were approved by the research ethics board of Sun Yat-sen University. All patients provided their written informed consent.Before and during the biochemical evaluation, phenoxybenzamine was administered to control BP, if necessary. Spironolactone or amiloride was discontinued at least 6 weeks prior to evaluation, as were angiotensin receptor blockers, angiotensin converting enzyme inhibitors, or thiazide diuretics at least 4 weeks prior to evaluation. Daily natrium and potassium supplements  were administered during the assessment period.We followed study methods previously described by Yanbing Li et al. in 2017  were perAn adrenal spiral computed tomography scan with sections at 0.3 mm intervals was conducted. Once an adrenal lesion was located, adrenalectomy was recommended. The final diagnosis of APA was later confirmed with pathology tests plus correction of hypokalemia postoperatively.All in-patients received continuous noninvasive 24-h ambulatory blood pressure monitoring (ABPM)  during hospitalization, following the same standard operating procedures as ambulatory blood pressure monitoring for out-patients. The monitor recorded systolic and diastolic BP every 30 min during the daytime (0700 to 2300 h) and every 60 min through the night (2300 to 0700 h). The ambulatory data were included in the analysis if the monitoring period was >20 h and there were no periods of >2 h without measurements. Dippers or a dipping BP pattern were defined as >10% decline in both systolic and diastolic BP , 10.Within 24 hours of in-patient ABPM, blood samples were drawn at midnight, 0400, 0800, 1200, 1600, and 2000 h, for measurements of plasma aldosterone.Urine tests, measurements of serum creatinine, 24-h urine free cortisol, 24-h urine vanillylmandelic acid, and ultrasonography of renal arteries and veins were performed to screen common secondary causes of hypertension. Patients with renal hypertension, pheochromocytoma, or Cushing's syndrome were excluded. If the above tests including 24-h urinary aldosterone, plasma aldosterone, renin activity and aldosterone-renin ratios, 24-h urine free cortisol, 24-h urine vanillylmandelic acid, 24-h urine free cortisol, and 24-hour urine vanillylmandelic acid were normal, a diagnosis of nonfunctional adrenal tumor would be made.All statistical analyses were performed using SPSS 13.0. Values are expressed as mean ± SD, unless otherwise noted. Values between groups were compared using a two-tailed t-test. Variables that were not normally distributed were log transformed before analyses. Categorical values were compared using a chi-squared test. The correlation between PAC and BP was evaluated using a Pearson's test for each patient. Logistic analysis was performed to evaluate the independent predictors of dipping BP patterns in both groups. Statistical significance was considered at a value of P < 0.05.Forty patients were recruited, of whom 13 were excluded for other causes of secondary hypertension. Twenty-seven patients with APA (APA group) were included and received biochemical and in-patient ABPM assessments, as did 27 patients with EH (EH group). No participants received any antihypertensive medication during the evaluation.Demographic, biochemical, and hormone values of the two groups are shown in χ2 = 0.429; P = 0.513).BP profiles of the two groups are presented in The circadian profiles of PAC in the two groups of patients are shown in The circadian change of BP and concomitant PAC in each group are shown in To ensure a more precise and detailed evaluation, a Pearson's correlation of BP and PAC was conducted for each patient, and the results are presented in In the present study, we did not find any significant differences in BP level, nocturnal BP decline, or the proportion of patients with a dipping BP pattern, between patients with APA and those with EH, which is consistent with some previous reports , 11–15. Previous studies have shown that, in APA patients, the circadian aldosterone change was similar to that of normotensive individuals and those with EH –21. SimiThe main finding in our study was the absence of statistically significant correlations between PAC and concomitant SBP and DBP  in eitheA rapid direct vascular effect of aldosterone has recently been reported . In an iSome possible mechanisms through which secondary hypertension may modify the circadian BP include sympathetic nervous system activation, fluid retention, and increases in peripheral vascular resistance. Inappropriate activation of the sympathetic nervous system during sleep has been considered to be a major factor contributing to elevation of sleep BP in pheochromocytoma , hyperthOur study had some limitations. The sample size was relatively small. Within the 24-h in-hospital ABPM, blood samples for measurements of plasma aldosterone were drawn at midnight, 0400, 0800, 1200, 1600, and 2000 h; and blood sampling and hospitalization may have impaired sleeping patterns and the nocturnal dip of BP. This could have had a significant effect on the results. Moreover, we only measured seven time points for plasma aldosterone, and it is possible that more frequent blood sampling for aldosterone measurement would have offered a more precise estimation of the aldosterone rhythm. We used 24-h urine vanillylmandelic acid to exclude pheochromocytoma; however, this is not the gold standard method for the diagnosis of pheochromocytoma. These major limitations are likely to have weakened the strength of our research and should be taken into consideration when analyzing or applying the findings of our study.Studies with larger samples and with more frequent blood sampling for aldosterone measurement or studies that use another technique that is not affected due to hospitalization are warranted to further evaluate the circadian BP profile in patients with APA and its relationship with circadian aldosterone rhythm.In conclusion, the circadian BP pattern was not associated with a change in PAC in patients with APA. Further studies are needed to address the mechanisms involved in the reduction of nocturnal BP decline in patients with APA.


Does postpartum blood pressure trajectory after a hypertensive disorder of pregnancy differ by race?In this prospective cohort study that included 1077 women after a hypertensive disorder of pregnancy, blood pressure trajectories evaluated using mixed-effects linear regression models differed significantly by self-reported race. At the conclusion of the study, 68% of Black women and 51% of White women met the criteria for stage 1 or stage 2 hypertension.This study suggests that postpartum blood pressure trajectories indicate persistence of higher blood pressures among Black women in this cohort, which may have important implications for postpartum morbidity and mortality associated with hypertensive and cardiovascular conditions in this population. Maternal morbidity and mortality are increasing in the United States, most of which occur post partum, with significant racial disparities, particularly associated with hypertensive disorders of pregnancy. Blood pressure trajectory after a hypertensive disorder of pregnancy has not been previously described.To describe the blood pressure trajectory in the first 6 weeks post partum after a hypertensive disorder of pregnancy and to evaluate whether blood pressure trajectories differ by self-reported race.This prospective cohort study included deliveries between January 1, 2018, and December 31, 2019. Women with a clinical diagnosis of a hypertensive disorder of pregnancy were enrolled in a postpartum remote blood pressure monitoring program at the time of delivery and were followed up for 6 weeks. Statistical analysis was performed from April 6 to 17, 2020.Mixed-effects regression models were used to display blood pressure trajectories in the first 6 weeks post partum.P = .01; mean [SD] peak diastolic blood pressure at 1 week post partum: White women, 92 [9] mm Hg vs Black women, 94 [9] mm Hg; P = .02; and mean [SD] peak systolic blood pressure at 3 weeks post partum: White women, 129 [11] mm Hg vs Black women, 136 [15] mm Hg; P < .001; mean [SD] peak diastolic blood pressure at 3 weeks post partum: White women, 84 [8] mm Hg vs Black women, 91 [13] mm Hg; P < .001). At the conclusion of the program, 126 of 185 Black women (68.1%) compared with 393 of 764 White women (51.4%) met the criteria for stage 1 or stage 2 hypertension (P < .001).A total of 1077 women were included . Systolic and diastolic blood pressures were found to decrease rapidly in the first 3 weeks post partum, with subsequent stabilization . A significant difference was seen in blood pressure trajectory by race, with both systolic and diastolic blood pressure decreasing more slowly among Black women compared with White women (mean [SD] peak systolic blood pressure at 1 week post partum: White women, 143 [14] mm Hg vs Black women, 146 [13] mm Hg; This study found that, in the postpartum period, blood pressure decreased rapidly in the first 3 weeks and subsequently stabilized. The study also found that, compared with White women, Black women had a less rapid decrease in blood pressure, resulting in higher blood pressure by the end of a 6-week program. Given the number of women with persistent hypertension at the conclusion of the program, these findings also appear to support the importance of ongoing postpartum care beyond the first 6 weeks after delivery. This cohort study describes the blood pressure trajectory in the first 6 weeks post partum after a hypertensive disorder of pregnancy and evaluates whether blood pressure trajectories differ by self-reported race. Recent data from the Centers for Disease Control and Prevention2 demonstrate that Black women are 3 to 4 times more likely to die in childbirth compared with women of other races/ethnicities, a finding that persists across socioeconomic strata and is thought to be associated with social determinants of health as well as implicit and explicit biases within the health care system, resulting in inequitable treatment.4Recent evidence suggests that maternal morbidity and mortality are increasing in the United States, most of which occur in the 6 weeks after delivery, referred to as the “fourth trimester.”5 Black women are at increased risk of hypertensive disorders of pregnancy, and hypertension and cardiovascular diseases are more frequently associated with morbidity and mortality among Black women compared with White women.3 These differences are particularly notable in the postpartum period. Despite this finding, prior studies and clinical management guidelines focus overwhelmingly on antepartum and intrapartum management, with relatively little emphasis placed on postpartum management.6 One reason for the lack of management guidelines is our limited understanding of the postpartum blood pressure trajectory after delivery and hospital discharge. At present in the United States, women are typically discharged from the hospital on postpartum days 2 to 4 and the American College of Obstetricians and Gynecologists (ACOG) recommends a single blood pressure check between 3 and 10 days post partum for women with a hypertensive disorder of pregnancy.7 Women with persistent hypertension or the need for titration of antihypertensive medications are typically seen more frequently in the postpartum period for medication management; however, as there are no clear guidelines on optimal blood pressure management in this period, this varies by clinician and institution.8 Subsequently, women are typically seen at 4 to 6 weeks post partum for a comprehensive postpartum visit and referred to their primary care physician if there are additional needs for antihypertensive medication management.6 This strategy is limited by poor adherence to follow-up, with prior studies showing visit attendance rates of 45% to 60% in this period.9Hypertension complicates 10% to 20% of pregnancies in the United States and is significantly associated with maternal morbidity and mortality in the postpartum period.7 A previous study has demonstrated feasibility, high engagement, retention, and patient satisfaction with a postpartum hypertension remote monitoring program as well as improved adherence with postpartum visits.10 Given poor adherence to recommended follow-up in the postpartum period and resultant lack of longitudinally collected serial blood pressure measurements, the trajectory of a decrease in blood pressure in the postpartum period has not been previously well studied, to our knowledge. Prior work has focused on small historic cohorts or a predominantly White population.13 Therefore, the aims of this prospective cohort study were 2-fold. The first aim was to describe the trajectory of postpartum blood pressure after a hypertensive disorder of pregnancy using remote blood pressure monitoring in a large, contemporaneous cohort. The second aim, given the disparities in maternal morbidity and mortality associated with hypertensive disorders in the postpartum period, was to investigate differences in postpartum blood pressure trajectory by race.The ACOG and others have suggested the use of telemedicine or remote health care interventions to facilitate care in the fourth trimester.6 Regardless of diagnosis, hypertension in pregnancy was defined as blood pressure of 140 mm Hg or more systolic or 90 mm Hg or more diastolic. Maternal, obstetric, and sociodemographic data were obtained from the electronic medical record and subsequently the Clinical Data Warehouse at UPMC. The program was approved by the UPMC Quality Improvement Review Committee and the University of Pittsburgh institutional review board, which waived a requirement for informed consent because the data were deidentified. The reporting followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.This is an ongoing quality improvement project that included women admitted to the postpartum unit of a single tertiary care hospital  between January 1, 2018, and December 31, 2019. Eligible women had 1 of the following hypertension-related diagnoses: gestational hypertension, preeclampsia, eclampsia, or new-onset postpartum hypertension. Women with prepregnancy chronic hypertension were excluded. To be included in the program, women must have been English-speaking and have access to a text messaging–enabled mobile device. Diagnoses were made by the clinical care team according to ACOG criteria.10 In brief, we created a remote patient monitoring platform that used Vivify Health as its core vendor. The monitoring platform was integrated with electronic health records and the Clinical Data Warehouse for both ordering and results. Patients were enrolled in the program by their primary obstetric clinician while admitted as inpatients on the postpartum unit or after a postpartum readmission. After identification and verification of eligibility, the clinician placed an order in the electronic medical record with the patient’s telephone number, which automatically generated a text message to enroll the patient. We used the A&D UA-651  automatic upper arm blood pressure monitor. The patient was trained on the use of the blood pressure device by a program-specific nurse educator prior to discharge from the hospital. During program enrollment, bedside nursing staff recorded blood pressure on both the home blood pressure monitoring device and the hospital device to confirm accuracy. The program was managed through a nursing-staffed UPMC call center with documentation of telephone calls and blood pressures directly into the electronic medical record.A description of the remote monitoring program has been previously described.14 After discharge from the hospital, women were prompted to check their blood pressure 5 days per week for the first week of the program and between 3 and 5 times per week for the remainder of the program through 6 weeks post partum. Blood pressures were reported using text messaging. The initial choice of antihypertensive agent was dictated by the clinical care team while the patient was an inpatient. After hospital discharge, titration of medication or, in the case of medication initiation, selection of the antihypertensive agent was based on clinical judgment from the call center physician. There are currently no standardized management guidelines for specific antihypertensive agents or parameters for medication titration in the postpartum period.8 Women with symptoms including chest pain, severe headache, blurry vision or vision disturbances, shortness of breath, or blood pressures of 180 mm Hg or more systolic or 110 mm Hg or more diastolic were referred to the emergency department for further evaluation. Discontinuation or downward titration of antihypertensive therapy is based on patients having 3 consecutive blood pressures less than 120/70 mm Hg.We designed nursing call center–driven blood pressure management and treatment algorithms that were developed by local expert stakeholders, consistent with national guidelines on goals for postpartum hypertension management.For the first objective, mixed-effects regression models were used to display blood pressure trajectories in the first 6 weeks post partum, with weeks post partum as the timescale for all analyses. We used repeated blood pressure measurements to fit mixed-effects linear regression models with each blood pressure measurement as the outcome, participant identifier as random intercepts, and weeks post partum as a fixed effect expressed using restricted cubic splines with 4 knots positioned at 0.6, 1.9, 3.6, and 5.9 weeks. The optimal number of knots was chosen comparing both Akaike information criterion and bayesian information criterion between models. Mixed-effects regression models were further adjusted for predefined covariates known to be associated with blood pressure, including prepregnancy body mass index , tobacco use, type of hypertensive disorder, and use of antihypertensive medication.15 In sensitivity analyses, we repeated all regressions stratified by type of hypertensive disorder, use of antihypertensive medication, and obesity, as each could modify the association.For the second objective, we repeated all models stratified by race . Stratified mixed-effects regression models were again adjusted for the same covariates. The number and position of splines were not different by race. In addition, in sensitivity analyses we repeated all analyses including gestational weight gain and BMI at the time of delivery. Differences between races in the associations between blood pressure and weeks post partum were tested via likelihood ratio test between models with and without parameters representing the interaction between race and prepregnancy BMI, BMI at delivery, and gestational weight gain based on results of prior studies.P values were from 2-sided tests, and results were deemed statistically significant at P < .05.Statistical analysis was performed from April 6 to 17, 2020. All analyses were performed using Stata IC, version 16 software package (StataCorp LP). All A total of 1114 women  were enrolled in the program between January 1, 2018, and December 31, 2019; 37 women reported less than 2 blood pressure measurements and were excluded, leaving 1077 in the analytic sample. For the first objective, we included all 1077 women, who contributed 17 146 blood pressure measurements across the first 6 weeks post partum. Overall, women contributed a mean (SD) of 20.3 (7.1) blood pressure values during the program. The demographic and delivery characteristics of the overall cohort are shown in eTable 1 and eTable 2 in the P < .001; and mean [SD] maximum diastolic blood pressure, 98 [12] vs 94 [9] mm Hg; P < .001). In addition, Black women reached peak blood pressures at slightly later time points post partum compared with White women . As shown in P = .01; mean [SD] peak diastolic blood pressure at 1 week post partum: White women, 92 [9] mm Hg vs Black women, 94 [9] mm Hg; P = .02; and mean [SD] peak systolic blood pressure at 3 weeks post partum: White women, 129 [11] mm Hg vs Black women, 136 [15] mm Hg; P < .001; mean [SD] peak diastolic blood pressure at 3 weeks post partum: White women, 84 [8] mm Hg vs Black women, 91 [13] mm Hg; P < .001). In analyses adjusting for clinical covariates , our findings were unchanged. We tested for interaction between race and prepregnancy BMI and found that the interaction term was not statistically significant. In addition, we tested for interaction between race and type of hypertensive disorder, preterm hypertensive disorder, and parity and found no evidence of an interaction. Multivariable-adjusted blood pressure trajectories remained higher in Black women compared with White women during the first 6 weeks post partum . At the conclusion of the program, mean blood pressure was higher among Black women compared with White women . Similarly, Black women were significantly more likely than White women to meet criteria for stage 1 or stage 2 hypertension at the conclusion of the program  , Black women (n = 213) were younger  and were more likely to have public health insurance (139 [65.3%] vs 209 [26.0%]), be multiparous (107 [50.2%] vs 303 [37.7%]), and to have lower mean (SD) diastolic blood pressure at the initiation of prenatal care (70 [9] vs 74 [8] mm Hg) . Infants < .001) .Sensitivity analyses were stratified by antihypertensive medication use, type of hypertensive disorder, and obesity. We observed similar findings in both the unadjusted and adjusted models . There were no maternal deaths in the cohort during this period.Finally, to understand race-specific blood pressure trajectories in context, we examined the incidence of hospital readmission for hypertension in the postpartum period and observed the incidence to be higher among Black women compared with White women during the first 6 weeks post partum . Our findings have potential implications for addressing postpartum maternal morbidity and mortality, as well as longer-term cardiovascular health, in this population. In this study, there were no differences by race in early pregnancy blood pressure or in the highest blood pressure prior to hospital discharge. However, the more adverse postpartum blood pressure trajectories seen in Black women are consistent across various sensitivity analyses and translate to a higher incidence of hypertension-related hospital readmission.In this study, we found that, in the postpartum period, blood pressure decreased rapidly in the first 3 weeks and subsequently stabilized, although a substantial proportion of women continued to have hypertension at 6 weeks post partum. We also found that, compared with White women, Black women had a less rapid decrease in blood pressure post partum, resulting in higher blood pressure by the end of the 6-week program. By 6 weeks post partum, 68.1% of Black women met criteria for stage 1 or stage 2 hypertension, compared with 51.4% of White women (17 Recent studies have demonstrated the causal overlap between peripartum cardiomyopathy and hypertensive disorders of pregnancy.19 It is well documented both within our data as well as in prior studies that hypertension is exacerbated at 3 to 7 days post partum.20 The cause of this exacerbation is unclear; however, others have speculated that it may be due to mobilization of fluid during this period.20 If these fluid shifts result in volume overload or subclinical heart failure, perhaps our findings may mirror the differences seen by race in peripartum cardiomyopathy. This finding would suggest that additional postpartum diuresis might be particularly important in this population, as has been demonstrated by recent work in a predominantly African American population.21 Our findings are consistent with recent work from Lopes Perdigao et al,13 who demonstrated in a cohort of 84 women that women with higher BMI and of Black race had higher mean blood pressure values and were less likely to have resolution of their hypertension by 16 days post partum.There are several possible explanations for our findings. In previous studies evaluating the association of race with cardiovascular recovery after peripartum cardiomyopathy, cardiac recovery takes twice as long in Black women compared with White women.22 A previous study has demonstrated the feasibility of, high engagement with, retention in, and patient satisfaction with our remote monitoring program as well as improved adherence with postpartum visits.10 Given poor adherence to recommended follow-up in the postpartum period, the trajectory of a decrease in blood pressure post partum has not been well studied previously. This trajectory may be particularly important in consideration of rising maternal morbidity and mortality in the postpartum period.1 Furthermore, prior studies have shown lower adherence to recommended follow-up among Black women and women of lower socioeconomic status.23Within the context of small randomized clinical trials or research studies, text message–based postpartum hypertension monitoring programs have been shown to increase patient engagement and improve adherence with blood pressure follow-up.27 Prior studies have shown that postpartum care after a hypertensive disorder of pregnancy is often fragmented, without a systematic transition from the obstetrician to an internist or cardiologist.25 Given the fragmented care and poor attendance rates, our findings raise the question of whether universal home blood pressure monitoring and management with antihypertensive therapy for women with persistent hypertension beyond the first 6 weeks post partum may be warranted. This is particularly important given the proportion of women in our cohort with ongoing hypertension at 6 weeks post partum and our finding that Black women with a hypertensive disorder ended the program with systolic blood pressures 9 mm Hg higher systolic and diastolic blood pressures 5 mm Hg higher than White women. More important, there were no differences by race in prenatal blood pressure and our findings suggest that a hypertensive disorder of pregnancy may have an adverse association with blood pressure. We cannot assess from our findings whether this persistent postpartum hypertension represents new-onset chronic hypertension or the ongoing resolution of the hypertensive disorder of pregnancy. For women with public health insurance, in many states within the United States, Medicaid coverage lasts only through 60 days post partum. Most maternal deaths occur in the postpartum period, with approximately one-third occurring after 6 weeks post partum.2The American Heart Association and ACOG have identified hypertensive disorders of pregnancy as risk factors for later-life cardiovascular disease; however, effective evidence-based interventions have not yet been adequately studied or implemented, to our knowledge.Our study has several strengths. This was a large, prospective cohort from a single tertiary care center. Participants provided real-time blood pressure measurements using validated, calibrated blood pressure monitors. We used standardized management protocols to reduce the impact of clinician variability in management approaches. Our inclusion of prenatal and in-hospital postpartum blood pressure values also strengthens our findings.28 However, it is possible that a larger proportion of high-risk women may not have access to a text- messaging–enabled phone; thus, the applicability of our findings to a broader population within the United States may be limited. The single-site nature of the study limits the generalizability of our findings. In addition, all blood pressure values are self-reported through the program; thus, we cannot exclude the possibility that participants may not report accurate measurements, as no external validation was performed. As with all analytic approaches, mixed-effects regression modeling has several limitations. However, owing to the structure of our data and the ability to account for some heterogeneity over time, this was the most appropriate approach. Black women reported statistically fewer blood pressure values through the program and reported their final blood pressure value at an earlier postpartum time than White women. Although these differences are statistically significant, the clinical significance is likely less important given the overall number of blood pressure values reported and the median follow-up time across both groups with more than 85% follow-up beyond 3 weeks. However, we cannot exclude the possibility that our findings may be associated with bias in attendance vs nonattendance at the postpartum visit and adherence to the remote monitoring program.Our study also has several limitations. Participants were enrolled in the program by a clinical care professional. We cannot exclude the possibility that women enrolled in the program differ from those who were not enrolled in the program or that implicit bias or structural racism were associated with participant enrollment in the program. The program requires that women have access to a text messaging–enabled telephone. Prior studies have shown that approximately 92% to 96% of reproductive-aged women have access to a smartphone.30 These recommendations have not been assessed in a pregnant or postpartum population. Within our cohort, β-blockers and calcium channel blockers were used equally among Black and White patients. Although our findings persisted among women not taking any antihypertensive agent, we cannot exclude the possibility that the interaction of race and type of antihypertensive agent used could have been associated with our results. Further study is needed to assess whether findings regarding race and effectiveness of specific antihypertensive agents are upheld in a pregnant and postpartum population. Finally, race is a heterogenous and multifaceted exposure that in our health care system encompasses an economic, social, and physiological construct that includes both biological and nonbiological aspects. It is possible that our findings are secondary to other unmeasurable factors such as implicit and explicit bias within the structure of our medical institutions or the remote monitoring program itself. Unfortunately, because we used data from a program built into clinical care, we are unable to assess whether there are management differences in response to elevated blood pressures by race. The structure of the program does not allow for accurate ascertainment of antihypertensive medication changes, as they are frequently changed through a verbal recommendation rather than through issuing a new prescription or documentation in the medical record. Blood pressure management through the program follows a standard protocol as described previously and information regarding patient race was not available to the on-call physicians managing blood pressure through the program.10 Thus, we are unable to assess whether variable treatment based on race could have been associated with our findings, but this remains of particular concern given prior work suggesting differential treatment based on race33 and remains an area of active investigation for our team. We also continue to investigate whether the differences we see in blood pressure trajectory are associated with the racial disparities in morbidity and mortality associated with hypertensive and cardiovascular conditions.Our remote monitoring program concludes at 6 weeks post partum; thus, a further decrease in blood pressure beyond this period cannot be assessed. Furthermore, our cohort includes only women with a hypertensive disorder of pregnancy. We cannot assess how these blood pressure trajectories may differ from those of women without a diagnosed hypertensive disorder. Outside of pregnancy, multiple randomized clinical trials have shown differing effects of antihypertensive agents by race, such that the American College of Cardiology and American Heart Association guidelines recommend calcium channel blockers as first-line antihypertensive agents in African Americans.The findings of this cohort study suggest that, compared with White women, Black women have a postpartum blood pressure trajectory with persistence of higher blood pressure values that may be associated with the increased risk of morbidity and mortality seen in this period. Given the difficulty with adherence to care in this period, our findings support the use of remote monitoring among women at highest risk for hypertensive-related morbidity and suggest the importance of ongoing access to care beyond 6 weeks post partum.


We confirmed the presence of SNPs associated with hydrochlorothiazide, some of which were significantly associated with uncontrolled hypertension in the study sample. Findings open doors for further studies on personalized therapy for hypertension in the country.This study described single nucleotide polymorphisms (SNPs) in hydrochlorothiazide-associated genes and further assessed their correlation with blood pressure control among South African adults living with hypertension. A total of 291 participants belonging to the Nguni tribes of South Africa on treatment for hypertension were recruited. Nineteen SNPs in hydrochlorothiazide pharmacogenes were selected and genotyped using MassArray. Uncontrolled hypertension was defined as blood pressure ≥140/90 mmHg. The association between genotypes, alleles and blood pressure response to treatment was determined by conducting multivariate logistic regression model analysis. The majority of the study participants were female (73.19%), Xhosa (54.98%) and had blood pressure ≥140/90 mmHg (68.73%). Seventeen SNPs were observed among the Xhosa tribe, and two (rs2070744 and rs7297610) were detected among Swati and Zulu participants. Furthermore, alleles T of rs2107614 (AOR = 6.69; 95%CI 1.42–31.55;  Hypertension is the leading cause of death globally, accounting for 10.4 million deaths per year . In addi+) reabsorption in the distal convoluted tubule [PRKCA), lysine deficient protein kinase 1 (WNK1) beta-2 adrenergic receptor (ADRB2) and nitric oxide synthase 3 (NOS3) have been of particular interest due to the role they play in blood pressure control [Hydrochlorothiazide (HCTZ) is a thiazide diuretic that is indicated for the treatment of hypertension . The drud tubule ,5. Althod tubule ,7. As su control ,9,10.PRKCA gene encodes an enzyme that plays an important role in the modulation of ion channels [2+) handling in myocytes [WNK1 gene encodes for a ubiquitously expressed protein that regulates vasoconstriction and blood pressure response [PRKCA is an important predictor of HCTZ blood pressure response. The study further demonstrated that rs16960228 A allele carriers had a greater blood pressure response compared to GG carriers [WNK1) showed increased ambulatory blood pressure as compared to carriers of CT and TT genotypes [WNK1 gene were associated with a greater reduction in whole-day ambulatory blood pressure among patients with essential hypertension who were treated with HCTZ [The channels . In vivomyocytes . On the response ,13. A stcarriers . In addicarriers . InverseADRB2 and NOS3 genes are central components of the renin–angiotensin system (RAS) that controls blood pressure by regulating the volume of fluids in the body [ADRB2) were associated with an increased reduction in whole-day ambulatory blood pressure following hydrochlorothiazide treatment [NOS3) who were treated with anti-hypertensive drugs including diuretics may have an increased risk for resistance to medication as compared to patients with the CT or TT genotype [NOS3) with blood pressure response to HCTZ is yet to be established.The the body ,15. As sreatment . On the genotype . HoweverYEATS4 gene encodes the protein GAS41, which has been shown to mediate RNA transcription and cell viability [ADRB2, PRKCA and WNK1 genes, there was no reference found in the literature that connects the YEATS4 gene with pathways associated with hypertension or drug response. However, carriers of rs7297610 (CC genotype) were associated with greater blood pressure responses to HCTZ in comparison to T allele carriers. It was further demonstrated that such an association was absent among atenolol-treated participants [YEATS4 could affect blood pressure response to thiazide diuretic medication. However, further research is needed to verify this association.The iability . Unlike icipants . TherefoPharmacogenomics has progressed and matured into an efficient and effective tool for mapping genes underlying human phenotypes associated with drug response. This tool holds the promise of using genome-based technologies to improve health by effectively treating diseases including hypertension ,20,21,22The Senate Research Committee of the University of the Western Cape approved the study protocol . Permission to implement the study was granted by the clinical governance of the respective hospitals in the Eastern Cape and Mpumalanga Provinces. Participants were issued with a research information sheet detailing the study, and it was made available in three indigenous languages . Each participant indicated their voluntary participation by signing a consent form. The rights to privacy and confidentiality of the medical information of each participant were honored during and after the study.A total of 291 Nguni  patients attending chronic care for hypertension were recruited consecutively between January 2019 and June 2019 from Cecilia Makiwane Hospital , Piet Retief Hospital, Thandukukhanya Community Health Center and Mkhondo Town Clinic . Participants were eligible for participation if they were 18 years or older and were on continuous treatment for hypertension for at least a year prior to the study. Individuals who were bedridden, pregnant and unable to give consent were excluded from the study.A trained research nurse measured the blood pressure (BP) of each participant by using a validated automated digital BP monitor (Macrolife BP A 100 Plus model) according to standard protocols. Thereafter, BP was recorded in triplicate, and the average was used to categorize participants into two groups: controlled (blood pressure < 140/90 mmHg) and uncontrolled (blood pressure ≥ 140/90 mmHg). DNA samples were collected in the form of buccal swabs and stored at −20 °C until they were processed.The age, ethnicity, smoking status and salt intake were self-reported by each participant and documented in a proforma designed for this study. The number and type of anti-hypertensive drugs prescribed for each participant were retrieved from their clinical records.Genomic DNA was extracted from buccal swab samples using a standard salt-lysis procedure. Briefly, DNA samples were incubated in lysis buffer at 62 °C overnight. Thereafter, DNA was precipitated with NaCl followed by the addition of 75% ice-cold ethanol and incubated at −20 °C overnight. Precipitated DNA was purified using 70% ethanol and re-suspended in nuclease-free water. Samples were stored in 2 mL Eppendorf tubes at −20 °C until further use. DNA was quantified using a NanoDrop™ 2000/2000c spectrophotometer  and Gel Doc™ EZ Gel Documentation System .TM) were designed and optimized by Inqaba Biotechnical Industries  in January 2017. Each multiplex was used to genotype selected SNPs, using an assay that is based on a locus-specific PCR reaction. This reaction is followed by a single base extension using the mass-modified dideoxynucleotide terminators of an oligonucleotide primer, which anneals upstream of the site of mutation. Matrix-Assisted Laser Desorption/Ionization–time-of-flight (MALDI-TOF) mass spectrometry was used to identify the SNP of interest.Two multiplex MassARRAY systems  and Hardy–Weinberg equilibrium (HWE) tests were calculated using Genetic Analysis in Excel (GenAIEx) Version 6.5.Statistical analyses were performed using International Business Machines (IBM) Statistical Package for Social Science (SPSS) Version 25 for Windows . The general characteristics of the participants were expressed as frequency (percentages). The associations between alleles, genotypes and blood pressure response to hydrochlorothiazide were assessed by multivariate logistic regression model analysis (unadjusted and adjusted odds ratios) and their 95% confidence intervals (95%CI). The final model of the adjusted logistic regression analysis for the Xhosa population included rs11189015, rs1458038, rs16960228, rs17010902, rs2106809, rs2107614, rs2269879, rs2277869, rs2400707, rs2776546, rs292449, rs4149601, rs4551053, rs4791040 and rs5051. For the Swati and Zulu population, the final adjusted regression model analysis included rs6083538, rs2070744 and rs7297610. Results for the unadjusted logistic regression model analysis were expressed as unadjusted odds ratios (ORs) and adjusted odds ratios (AORs) for the adjusted logistic regression model analysis. A Nineteen SNPs previously associated with hypertension or hydrochlorothiazide efficacy were selected using Pharmacogenomics Knowledge Base Ensembl  as well n = 213) were female and 26.04% (n = 78) were male. The mean age (SD) of the participants was 60.45 ± 11.90 years. The cohort was composed of individuals belonging to the Xhosa (n = 160), Zulu (n = 112) and Swati (n = 19) tribes of South Africa. The majority of the participants were non-smokers (67.35%), consumed low-moderate salt (81.44%) and had blood pressure ≥140/90 mmHg (68.73%)  .n = 160), the remaining two (rs2070744 and rs7297610) were detected among Swati and Zulu participants. The majority of the seventeen SNPs detected among the Xhosa tribe demonstrated an expression frequency above 90%, with variants rs4791040 and rs5051 showing an expression frequency of 73.10% (n = 117) and 68.75% (n = 110), respectively. Variant rs2070744 and rs5051 showed a 100% expression efficiency among Swati (n = 19) and Zulu (n = 112) participants, of whom 51.17% (n = 109) were female, and 44.44% (n = 40) were aged 60 years and above . Seventeen out of nineteen SNPs were exclusively detected among the Xhosa tribe (nd above . The minnd above . None ofp ≤ 0.0001) was independently associated with uncontrolled hypertension, although carriers of the genotype of rs2400707 AA  were less likely to have uncontrolled hypertension. No association was established in the remaining sixteen SNPs detected among the Xhosa tribe. In the adjusted logistic regression model, the direction of association for the A allele of rs2400707 shifted, and carriers of the A allele  were less likely to have uncontrolled hypertension. Furthermore, carriers of allele T of rs2107614  and C of rs2776546  were almost seven times and four times more likely to have uncontrolled hypertension, respectively. On the other hand, carriers of rs4791040 allele C  were less likely to have uncontrolled hypertension. After Bonferroni correction, all the alleles of rs2400707 (A), rs2107614 (T), rs2776546 (C) and rs4791040 remained significant with p-values < 0.0029 (In the multivariate logistic regression (unadjusted) model analysis, the allele A of rs2400707  were four times more likely to be associated with uncontrolled hypertension, whilst rs2070744 TC , rs7297610 CT  and allele T  carriers were less likely to have uncontrolled hypertension. After adjusting with each SNP, genotypes rs2070744 TC  and CC  were significantly associated with uncontrolled hypertension. In addition, allele T of rs7297610  was independently associated with uncontrolled hypertension. After Bonferroni correction, the genotypes of rs2070744 and T allele of rs7297610 remained significantly associated with uncontrolled hypertension (p < 0.0025)  .Thiazide diuretics are among the most prescribed anti-hypertensive drugs worldwide . FurtherCurrent research suggests that the genomes of indigenous African individuals carry the greatest depth of genetic variation compared to other population groups from around the world . Thus, sWNK1 gene encodes a protein that plays an important role in renal ion transport [ADRB2 gene mediates a rise in intracellular cAMP concentration, which, through smooth muscle relaxation, leads to vasodilation [WNK1) was significantly associated with uncontrolled blood pressure among Xhosa participants, however, no association was established with any of the genotypes. In contrast, Turner et al. (2005) showed that the genotypes CC and CT of rs2107614 (WNK1) were associated with an increased reduction in whole-day ambulatory blood pressure among individuals with non-complicated hypertension treated with HCTZ [ADRB2) were less likely to have uncontrolled blood pressure. These observations are in line with previous findings, where the AA and AG genotypes of rs2400707 (ADRB2) were associated with an increased reduction in whole-day ambulatory blood pressure in individuals with essential hypertension undergoing HCTZ treatment [The ransport . On the dilation . Bluntedith HCTZ . On the reatment . These fCSMD1) that encodes a product that functions as a complement control protein [CSMD1 gene was associated with an increased risk of hypertension among Korean patients [CSMD1 in the pathophysiology of hypertension is not completely understood, the findings of this study bring attention to clinically relevant loci of blood pressure response to thiazide diuretics among individuals of African ancestry and further highlight the need for more studies with larger sample sizes that could validate the direction of association of each allele and genotype.The variant rs2776545 occurs in the regulatory region of the CUB and Sushi multiple domains 1  gene expression and cell growth and proliferation [PRKCA polymorphisms may influence blood pressure response to hydrochlorothiazide owing to their role in the modulation of ion channels.The feration  that harferation . AlthougNOS3 gene. In addition, rs2070744 has been implicated in the variable response of thiazide diuretics. Carriers of the CC genotype treated with anti-hypertensive drugs including HCTZ demonstrated an increased risk of resistant hypertension as compared to TC and TT carriers [Single nucleotide polymorphism rs2070744 is an intronic variant that sits on the carriers . It was YEATS4 polymorphism (rs7297610) on blood pressure response to hydrochlorothiazide. The T allele of rs7297610 was independently associated with uncontrolled hypertension among Swati and Zulu patients. This study further demonstrated that carriers of CT genotype were less likely to have uncontrolled blood pressure. The observations made in this study are in line with previous findings, where allele C was associated with an increased reduction in blood pressure among individuals of mixed ancestry (African American and Afro-Caribbean) treated with hydrochlorothiazide as compared to allele T [This study also investigated the effect of allele T . Althougallele T . Additioallele T . Of noteYEATS4 polymorphisms in blood pressure response to hydrochlorothiazide. However, replication of these findings in a larger South African cohort is needed to confirm the associations observed in this study. Further elucidation of the exact mechanism in which these SNPs affect blood pressure in response to hydrochlorothiazide can ultimately aid in improving individualized anti-hypertensive therapy and the identification of new drug targets.Using a candidate gene approach, we identified seventeen SNPs among the Xhosa tribe and two SNPs among the Zulu and Swati tribes previously associated with hydrochlorothiazide efficacy and hypertension. The minor alleles of rs2107614 and rs2776546 were independently associated with uncontrolled hypertension among Xhosa participants. Furthermore, the T allele of rs7297610 was independently and significantly associated with uncontrolled hypertension among Swati and Zulu participants. This study also provided preliminary information for the association of


Essential hypertension is a multifactorial disease, which is affected by genetic and environmental factors, and can cause diseases such as cerebrovascular disease, heart failure, coronary heart disease, and chronic renal failure. High salt intake is a risk factor for hypertension, stroke, and cardiovascular disease. Blood pressure variability (BPV) is a reliable independent predictor of cardiovascular events and death. At present, there are few studies about the correlation among high salt intake, BPV, and target organ damage (TOD) in patients with hypertension.The purpose of this study is to compare 24-hour urine sodium excretion, BPV, carotid intima–media thickness, left ventricular mass index, and serum creatinine or endogenous creatinine clearance rate. To clarify the relationship between high salt load and BPV and TOD in patients with hypertension.This study is a cross-sectional study. It will recruit 600 patients with essential hypertension in the outpatient and inpatient department of cardiovascular medicine of Chengdu Fifth People's Hospital. Researchers will obtain blood and urine samples with the patient's informed consent. In addition, we will measure patient's blood pressure and target organ-related information.The study protocol was approved by the Chengdu Fifth People's Hospital. Written informed consent will be obtained from all the participants. The trial was registered in the Chinese Clinical trial registry, ChiCTR2000029243. This trial will provide for the correlation among high salt intake, BPV, and TOD in patients with essential hypertension. High salt intake can not only increase blood pressure, but also reduce the efficacy of antihypertensive drugs. And 24-hour urine sodium test is the best way to measure an individual's daily sodium intake. Blood pressure variability (BPV) is a basic characteristic of blood pressure and can reflect the magnitude of blood pressure fluctuations over a period of time. Recent research shows that BPV can better reflect cardiovascular activity than blood pressure levels and is more closely related to target organ damage (TOD) in hypertension.–6 Failure to detect and treat essential hypertension early can damage important organs such as the heart, brain, and kidneys, causing diseases such as left ventricular hypertrophy, atherosclerosis, and renal failure.,8 Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor in patients with essential hypertension.,10 Intima–media thickness (IMT) is a marker that can be used to assess the severity of atherosclerosis. Serum creatinine, endogenous creatinine clearance rate (Ccr) and 24-hour urine microalbumin (MA) were commonly used indicators of renal function. However, the relationship among high salt load, BPV, and TOD in patients with hypertension is unclear. This study recruited patients with essential hypertension in the Department of Cardiovascular Medicine of Chengdu Fifth People's Hospital. Collect basic patient information, blood pressure measurements, blood specimens, 24-hour urine specimens, and other clinical examination results. Carotid IMT, left ventricular mass index (LVMI), serum creatinine or Ccr, 24-hour urine MA, and other indicators were used to evaluate TOD. To clarify the relationship among high salt intake, BPV, and TOD. To lay a good foundation for early detection of TOD in essential hypertension and related measures.Essential hypertension is a common circulatory system disease, which is affected by both genetic and environmental factors,22.1The objective of this study is to investigate the relationship among high salt intake, BPV, and TOD in patients with hypertension. Through laboratory inspection, echocardiography, and ambulatory blood pressure monitoring, we could identify risk factors and take steps to reduce the risk of damage to the patient's target organs.2.2This trial was registered in the Chinese Clinical trial registry, ChiCTR2000029243. The flow chart of this study is shown in Figure 2.32.3.12.3.1.1Outpatients and inpatients with primary hypertension are over 18 and are not limited in gender. The diagnostic criteria for hypertension are based on 2010 Chinese guidelines for the management of hypertension.2.3.1.2Participants who will meet any of the following will be excluded:(1)Acute or chronic renal insufficiency: eGFR ≤45 mL/minute(2)Severe cardiovascular disease(3)Exclude patients with malignant tumors, hematological diseases, rheumatic immune system diseases(4)Heart failure (systolic)(5)Take routine dose or overdose of diuretics continuously for 2 weeks (but the fixed compound of RASI + 12.5 mg thiazide diuretics can be included).2.4All patients consisted of outpatients and inpatients with essential hypertension in the Department of Cardiovascular Medicine of Chengdu Fifth People's Hospital from July 2017 to July 2018. Consent will be obtained by the investigators with the principle of informed consent, which confirms the participants’ voluntarism. The participants will sign the consent form that would include the information on the use of their blood sample, urine sample, ambulatory blood pressure data, and echocardiography results.2.5According to the schedule depicted on Table 2.5.1The participants will complete a questionnaire that would include general sociodemographic information , personal habits , anthropometric measurements , pregnancy, menstrual pattern and history, history of present illness, medication history, history of hypertension in relatives, and relevant comorbidities .2.5.2The patient begins to measure blood pressure after resting for 5 minutes in a quiet room. No matter what position the patient is in, the upper arm should be placed at the heart level. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were determined using the Corson sounds 1st and 5th, respectively, and each person's blood pressure was measured at least 2 times at intervals of 1 to 2 minutes. If there is a big difference between the 2 measurements, we will measure again.2.5.3All subjects used a fully automatic noninvasive cuff blood pressure monitor (fixed model) for blood pressure monitoring. The cuff is fixed to the subject's left upper arm and can be used for daily work and activities, but strenuous exercise should be avoided. Monitoring time: measured every 30 minutes during the day (8:00–22:00), every night at 22:01 to 7:59 the following day, every hour. The daily effective blood pressure reading is greater than 85% of the set number, and the effective value needs to be greater than 48 times. Effective blood pressure readings: SBP 70–260 mm Hg (1 mm Hg = 0.133 kPa), DBP 40 ∼ 150 mm Hg, pulse pressure 20 ∼ 120 mm Hg. Monitoring indicators: 24-hour mean SBP (24-h SBP), 24-hour mean DBP (24-h DBP), day-time mean SBP, night-time mean SBP, day-time average DBP, and night-time mean DBP. The blood pressure standard deviation (SD) and its coefficient of variation (CV) at each time period were used as indicators of BPV at that time period.  CV is the ratio of the SD to the mean. Expressed by the formula: CV = σ/μ. Monitoring normal reference value: 24 hour mean blood pressure <130/80 mm Hg, daytime blood pressure <135/85 mm Hg, nocturnal blood pressure <120/70 mm Hg. Blood pressure circadian rhythm = (average blood pressure during the day − average blood pressure during the night) / average blood pressure during the day; >10% is normal blood pressure circadian rhythm (dipper type hypertension), otherwise it is nondipper type hypertension, <0 is the anti-dipper type hypertension; CV-SBP is grouped with a cutoff of 12%.2.5.4Keep a normal diet and avoid strenuous exercise before urine retention. Record the start and end time of urine retention and use a wide-caliber container to collect urine for 24 hours. After mixing, measure and record the total urine volume. The urine sodium, urine potassium, and urine protein were measured in the laboratory of Chengdu Fifth People's Hospital and the 24-hour urine sodium excretion and 24-hour urine MA volume were calculated.2.5.51.Blood vessels: Detection of carotid IMT: The patient lies on his back and turn the head to the opposite side. The distance between the intimal surface of the common carotid artery bifurcation 1 cm non-plaque and the outside of the median was measured, and the maximum value was taken on both sides. According to the relevant diagnostic criteria in the 2010 Chinese guidelines for the management of hypertension, the carotid intima media thickness >0.9 mm is defined as thickening and the local protrusions protrude from the arterial lumen >0.5 mm or IMT > 1.5 mm is defined as carotid atheromatous plaque.2.3 − LVDd3) + 0.6; LVMI = LVM / body surface area.Heart: LVMI: Measure the left ventricular end diastolic diameter (LVDd), interventricular septum, and left ventricular posterior wall, measure 3 consecutive cardiac cycles and take the average. According to the Devereux formula, calculate left ventricular mass (LVM) and LVMI: LVM (g) = 0.8 × 10.4 × . After the natural logarithm is converted to the normal distribution data for analysis, the nonparametric statistical method is used for comparison between groups. Nonparametric test was used to compare data between groups. Correlation analysis used Pearson correlation analysis. Covariance analysis was used to compare the differences in BPV between groups, and multiple stepwise regression analysis was performed on target organ factors related to BPV. 2.8The study protocol was approved by the Fifth People's Hospital of Chengdu City. The approved protocol was registered. Each participant will be provided with information regarding the study protocol. Written informed consent will be obtained from each patient. The privacy of all participants will be protected. Personal medical records will be reviewed by investigators, who will promise to keep the content confidential. It will be performed in accordance with the standards of the International Committee on Harmonization on Good Clinical Practice and the revised version of the Declaration of Helsinki principles.2.9Any modifications to the protocol which have substantial effects on the conduct of the study, potential benefits to the patient, or impact on patient safety, including changes to eligibility criteria, patient population, sample size, study objectives, study design, and study procedures will require a formal amendment to the protocol. Such amendment will be sent to the Ethics Committee for further approval before implementation. Administrative changes of the protocol defined as minor corrections having no effect on the way the study is to be conducted will be documented and the Ethics Committee may also be notified of them.3,13Hypertension is a major cause of many chronic and life-threatening diseases, such as cardiovascular disease and kidney failure. However, due to mild nonspecific symptoms, awareness is relatively low and patient compliance and control is poor. Hypertension is a complex syndrome affected by many genetic and environmental factors. Many epidemiological studies have shown a significant relationship between salt intake and blood pressure.BPV is associated with an increased risk of clinical TOD, such as cardiovascular and renal damage, and an increase in cardiovascular mortality. There are 3 different types of BPV, depending on the time period in which it occurs: very short-term BPV, short-term BPV, and long-term BPV. Average consolidation rate (ARV) was introduced as a new BPV index. The ARV is the sum of the differences between every 2 consecutive readings. A systematic review of ARV assessment studies at 24 hour BPV was conducted in 19 studies, of which 17 reported a significant correlation between high ARV and TOD. In all these studies, BPV remained a significant independent predictor of all cardiovascular events. The increase of BPV in hypertensive patients is significantly correlated with the increase of TOD severity. Subsequent studies have shown that an increase in BPV is associated with an increased risk of cardiovascular events.,19 It is speculated that TOD is not only associated with uncontrolled hypertension, but also with increased BPV. Whether the mechanism of TOD mediated by hypertension is caused by changes in blood pressure remains unclear. Our present protocol will provide a new sight in the association between among high salt intake, BPV, and target organ damage in patients with essential hypertension.Blood pressure exhibits highly observed oscillations.Jianbo Lei orcid: 0000-0002-2073-1076.


The introduction of sodium/glucose cotransporter 2 inhibitors (SGLT2i) has opened new perspectives for the management of diabetic population at risk of or with chronic kidney disease (CKD). More important, recent, large real-world studies have repositioned the nephroprotective efficacy of SGLT2i emerged from randomized trials within the frame of effectiveness. Furthermore, the salutary effects of these agents may extend to the nondiabetic population according to the positive results of current studies. Nevertheless, the clear benefits of these agents on the prevention of organ damage contrast with their unexpected, limited use in clinical practice. One potential barrier is the acute decline in glomerular filtration rate (GFR) commonly observed at the beginning of treatment. This phenomenon is reminiscent of the early response to the traditional nephroprotective interventions, namely blood pressure lowering, dietary protein and salt restriction and the inhibition of the renin–angiotensin system. Under this perspective, the “check-mark” sign observed in the GFR trajectory over the first weeks of SGT2i therapy should renew interest on the very basic goal of CKD treatment, i.e., alleviate hyperfiltration in viable nephrons in order to prolong their function. In the last decade, the epidemiology of chronic kidney disease (CKD) and focus on the nephrology community have changed in parallel. Two major changes have occurred. First, the CKD population has grown, due not only to the expression of the demographic expansion in developing countries, but also to the ageing of the general population in developed countries, with CKD associated with increased incidence of geriatric diseases  . Second,The purpose of this review is twofold: (1) analyze the information supporting the hypothesis that the clinical effectiveness of SGLT2i is mainly related to the attenuation of hyperfiltration; and (2) carefully review data on SGLT2i nephroprotection to highlight similarities between SGLT2i and old strategies to reduce renal hyperfiltration , control, low-protein–low-salt diet).A recent review by Chan and Tang has clearly described two main unmet needs in nephrology practice : (1) theOverall, the results of the four large RCTs demonstrated, along with cardiovascular benefits ,13, a maOf note, SGLT2i-nephroprotection was not encumbered by significant adverse effects. In particular, the incidence of acute kidney injury (AKI) and hyperkalemia was not higher in the four CVOTs on SGLT2i ,9,10,11,On the other hand, when compared to other antihyperglycemic agents, SGLT2i are associated with a 3-fold increase in risk of genital infections , and a sn = 29,887) with patients receiving dipeptidyl peptidase 4 inhibitors (DPP4i) . As in CVD-REAL3, only a minority (3%) had CKD at baseline. Analysis showed that SGLT2i were associated with 58% (95% CI 47% to 66%) lower risk of the composite renal endpoint  compared to DPP4i.It is noteworthy that evaluating effectiveness above and beyond efficacy is needed when examining a new drug. In this regard, the experience with spironolactone in heart failure (HF) provides a great example. The Randomized Aldactone Evaluation Study (RALES) study demonstrated that spironolactone significantly reduced the risks of death and hospitalization in HF patients . In the The information emerging from real-life practice is as important as that generated from randomized trials, since individuals selected for SGLT2i trials can be poor representatives of the “generic” patients seen in daily practice . TherefoUnderstanding the mechanism(s) underlying the beneficial effects of SGLT2i on renal survival is crucial to enhance the confidence of physicians toward these new drugs. Indeed, despite the solid evidence of cardio- and nephro-protection, the current prescription is still modest in daily practice (<10% of eligible patients) even six years after their initial marketing ,22,23,24The nature of diabetic kidney injury is complex with the involvement of hemodynamic and nonhemodynamic factors primarily activated by hyperglycemic milieu . Based oNoteworthy, the reduction in glucose reabsorption with SGLT2i is associated with significant changes in renal hemodynamics. Micropuncture studies performed in hyperglycemic diabetic rats demonstrated that poor glucose control is associated with increased GFR (hyperfiltration) at the whole kidney and single nephron level. The presence of hyperfiltration is now recognized as a major mechanism of diabetes-induced renal injury in both humans and experimental animals . Based oSGLT2i restore proximal tubule flow rate by counteracting “hyper-reabsorption”. The reduction in proximal sodium reabsorption increases delivery to macula densa, thus reactivating TGF and restoring a normal (lower) nephron filtration and, likely, intra-glomerular capillary pressure. In addition, SGLT2i also inhibits sodium/hydrogen exchanger 3 in the proximal tubule, another potential contributor to higher distal delivery of sodium chloride . FinallyThe TGF-dependent modulation of afferent arteriolar tone, with and without SGLT2i, has been confirmed in vivo by the direct visualization of arterioles in diabetic mice . Some suTherefore, SGLT2i alleviates glomerular hypertension and hyperfiltration, thus reducing glomerular barotrauma and albuminuria. Of note, a potential additional consequence of attenuation of hyperfiltration is the decrease in oxygen (O2) demand for the active tubular transport of solutes, sodium in primis, with improved renal tissue oxygenation and prevention of fibrosis ,40.SGLT2i-related cardionephroprotection is, for the most part, independent from the glucose lowering effect. This was consistently reported in the first three CVOTs enrolling patients with mild or no kidney disease ,9,10 andp = 0.97). As additional proof of concept, the reduction in primary outcome with dapagliflozin among nondiabetic individuals did not differ between those with prediabetes and those with normal HbA1c. Whether a similar beneficial response among diabetic and nondiabetic patients also applies to kidney survival could not be adequately tested in this trial aimed at evaluating HF outcome. Nevertheless, the expectations regarding SGLT2i-nephroprotection in nondiabetic CKD are now becoming more realistic based on the recent report of early stop for “overwhelming efficacy” of the DAPA-CKD study [NCT03036150], that is, the phase III trial specifically designed to test the benefit of dapagliflozin on kidney survival in CKD patients independent of diabetic status  and the still recruiting EMPA-KIDNEY trial [NCT03594110] will hopefully provide conclusive information on the appropriate role of SGLT2i in the therapeutic algorithm aimed at optimizing nephroprotection in the whole CKD population, irrespective of diabetic status. Given the well-recognized pathophysiological role on CKD progression of hyperfiltration and albuminuria, it is plausible that in the future SGLT2i will be considered as the “ideal companion” of RASi, or, alternatively, replace these traditional nephroprotective agents in patients that do not tolerate them because of AKI and/or hyperkalemia.