Background and Objectives: Vasopressors are used for treating maternal hypotension. However, the appropriate administration method and effects on newborns have not been reported. We evaluated maternal blood pressure fluctuation and neonatal findings in patients who received continuous vasopressor administration during elective cesarean sections and those who received bolus vasopressor administration upon onset of hypotension. Materials and Methods: We retrospectively analyzed the data of 220 patients scheduled for elective cesarean delivery under spinal anesthesia at Mie University Hospital between April 2017 and March 2021. The patients were classified according to the method of vasopressor administration. Maternal information, intraoperative maternal blood pressure fluctuation, and neonatal findings were examined. A multiple regression analysis was performed for the administration of postpartum neonatal respiratory support using maternal background information and other variables related to blood pressure changes as independent variables. Results: The Continuous group and the Bolus group were composed of 98 and 122 patients, respectively. No difference was observed in maternal background information between the groups. Significant changes were noted in several blood pressure parameters between both groups. As for neonatal parameters, newborns of Bolus group patients had lower pO2, 1 min and 5 min Apgar scores, and required more respiratory support than those of Continuous group patients. In the multiple regression analysis, the groups and maternal post-anesthesia diastolic blood pressure variability were considered explanatory variables. Conclusions: Maternal hypotension and the need for neonatal respiratory support associated with anesthesia administration in elective cesarean section may be improved by continuous vasopressor administration upon induction of combined spinal–epidural anesthesia. Combined spinal–epidural anesthesia (CSE anesthesia) is often used for elective cesarean sections because it is characterized by reduced medication exposure for the fetus compared to general anesthesia. Moreover, it allows the mother to remain conscious during delivery. However, the main side effect of the administration of spinal anesthesia is maternal hypotension, which affects 90% of patients and has been suggested to cause nausea and vomiting. In severe cases, fetal bradycardia and cardiovascular collapse may ensue .Although there are various reports on this issue, studies on the continuous sequence of events involving the mother and newborn are scarce. For example, in a study that compared general anesthesia and CSE anesthesia for elective cesarean section, no difference was observed in the development of transient tachypnea between newborns that received general anesthesia and those that received CSE anesthesia, although maternal blood pressure was not evaluated .Spinal anesthesia has also been reported to be associated with neonatal acidosis, with sustained hypotension, and time to delivery is being implicated with this adverse event . ClinicaEphedrine, an alpha- and beta-receptor stimulant, or phenylephrine, an alpha-receptor stimulant, are commonly used vasopressors. Although there is an ongoing debate concerning the better option between these two vasopressors, only a few studies have reported the superiority of phenylephrine over ephedrine ,5,6.Moreover, reports describing maternal and neonatal effects of vasopressor administration are few. A study that compared bolus versus continuous administration of phenylephrine in elective cesarean sections performed with limited resources, such as in South Africa, concluded that phenylephrine use contributed to the prevention of maternal hypotension, although there was no detailed evaluation of its effects on newborns .We investigated continuous phenylephrine administration before CSE anesthesia to prevent maternal hypotension and continuous bolus administration of phenylephrine or ephedrine when there was an actual decrease in blood pressure. The primary outcome was a reduction in maternal blood pressure variability, and the secondary outcome was the effect on the newborn. Therefore, we focused on maternal blood pressure variability and maternal background, and we examined the neonatal impact from multiple perspectives. The phenylephrine model and the bolus model, in which no prophylactic hypotensive agents were administered and a bolus dose of phenylephrine or ephedrine was administered when hypotension was observed, were selected to analyze maternal circulatory changes and the effects on the newborn. The effects of these two types of administration on maternal and neonatal conditions were examined considering the maternal background so that a more appropriate anesthesia method could be considered for elective cesarean section, in which the condition of the fetus shortly before the cesarean section is presumed to be stable.The protocol was approved by the Mie University Clinical Research Ethics Committee in September 2021 (registration number: H2021-181).The study was not a randomized controlled trial. It is an observational study evaluating the maternal and fetal effects of different uses of vasopressors in elective cesarean sections performed during the study period. We retrospectively analyzed the medical records of 297 patients who were scheduled for elective cesarean delivery under spinal anesthesia during normal working hours at Mie University Hospital between April 2017 and March 2021. The reasons for a cesarean section are pregnancy after myomectomy, previous cesarean section, abnormal placental position, or maternal skeletal abnormalities. The exclusion criteria were patients with maternal complications that could affect the newborn, such as age <18 years, twin pregnancies, known fetal malformations, fetal growth abnormalities, and maternal heart disease and maternal hypertension requiring medical treatment. Patients with missing umbilical artery blood gas data and those with a maternal systolic blood pressure of 90 mmHg that could not be confirmed by anesthesia records before bolus administration of a vasopressor were also excluded.All patients were subjected to routine monitoring and, at the discretion of the anesthesiologist, received intravenous administration of prehydration, rehydration, or both via a large-bore venous access established in the upper extremity. All patients received CSE anesthesia, using 2 mL of 0.5% marcaine and 10 μg of fentanyl. The height of the block was assessed via cold stimulation with ice before surgery. In cases of continuous administration, 1 mg phenylephrine was adjusted in a 10 mL syringe and administered at 0.3 μg/kg/min as a base dose. For bolus administration, when the maternal systolic blood pressure decreased to <90 mmHg after anesthesia, 0.1 mg of phenylephrine or ephedrine (5 mg) was administered, and, if there was no improvement, additional boluses were administered. Anesthesia for all cases is performed by specialists certified by the Japanese Society of Anesthesiologists, and all anesthesiologists are in agreement on how to manage anesthesia for cesarean section.Moreover, other medications  were available, as needed. Data collection continued from the induction of anesthesia until the delivery of the baby. In this study, blood pressure was measured at 1 min intervals, and due to the system, the blood pressure progress was recorded at 2.5 min intervals. The monitoring data were electronically recorded, and the anesthetist described the indications for surgery, the drugs administered, and the amount and method of vasopressors administered. Additionally, maternal background information , and BMI at delivery) and neonatal information ) were extracted from the electronic medical records in this study. Data on maternal blood pressure (maximum systolic blood pressure (maxSBP), minimum systolic blood pressure (miniSBP), pulse pressure (difference of SBP), maximum diastolic blood pressure (maxDBP), and minimum diastolic blood pressure (miniDBP), and difference in maximum–minimum diastolic blood pressure (difference of DBP)) were extracted from anesthesia records, which were automatically recorded every few min from the induction of spinal anesthesia until delivery. Information on whether the infant received neonatal respiratory support within 24 h of birth was also extracted from the electronic records. Regarding the type of respiratory support, the lower limit was set at the start of oxygen administration in an infant incubator in the NICU, and intubation management was evaluated. Transient use of oxygen for postnatal resuscitation in the operating room was not included as a form of respiratory support.Maternal background information and blood pressure-related parameters after anesthesia were compared between the two groups using the Mann–Whitney U test. The need for neonatal respiratory support and AS at 1 min after birth were assessed using the Chi-square test. A multiple regression analysis was performed, with respiratory support within 24 h after birth as the dependent variable and variables regarding the maternal background and blood pressure change as independent variables. Variables were selected using a stepwise method.p < 0.05.The correlation between individual blood pressure-related parameters and the relationship between blood pressure-related parameters and neonatal respiratory support were evaluated for all patients. Correlation analysis was performed using Spearman’s correlation coefficient, and a simple linear regression analysis was conducted to determine the association of individual parameters with neonatal respiratory support. The percentage of neonates with an AS of less than 7 was determined at 1 and 5 min after birth. Analyses were performed using SPSS 26.0 . Statistical significance was set at Of the 297 patients who underwent elective cesarean section during the study period, 220 were enrolled in the study, with 98 in the Continuous group and 122 in Bolus group. Altogether, 77 participants were excluded from the analysis. Of the 77 cases, 20 were cases with missing data , and the remaining 57 were inappropriate cases .p = 0.003) and miniSBP (p < 0.001) and differences in SBP (p < 0.001), miniDBP (p < 0.001), and DBP (p < 0.001) were noted. Meanwhile, no group differences in maximum DBP and operative times were noted. The results of the neonatal-related parameters, such as umbilical cord blood gas analysis and AS, are summarized in 2 value of umbilical cord blood gas analysis (p < 0.001) and in the 1 min and 5 min AS . There were no cases of AS values less than 7 at 5 min after birth (AS-5) in both groups. There was a significantly higher number of patients with an AS of less than 7 at 1 min (AS-1) in the Bolus group  than in the Continuous group  (p = 0.003) (p < 0.001). Regression analysis of the association between the need for respiratory support and maternal background factors and parameters related to blood pressure changes after spinal anesthesia are summarized in p < 0.001) was selected as an explanatory variable, and for blood pressure-related parameters, the difference in DBP (p < 0.001) was selected. As an additional analysis, regression analysis of individual blood pressure-related parameters and the need for neonatal respiratory support and the results of correlation analysis between blood pressure-related parameters are shown in Hence, we finally analyzed 98 patients in the Continuous group and 122 patients in the Bolus group. The indications for the patients and the analysis process are shown in = 0.003) . The perBlood pressure-related parameters were strongly correlated with one another, and the individual blood pressure-related parameters were associated with the need for respiratory support for newborns upon single regression analysis.2 and lower AS-1 min and AS-5 min values at birth than those of patients in the Continuous group. The rate of the requirement of respiratory support within 24 h of birth was higher in the Bolus group than in the Continuous group. Upon multiple regression analysis, respiratory support and maternal parameters were analyzed as the dependent variable and explanatory variables, respectively, and the method of administration of vasopressors and the difference of DBP were selected as significant explanatory variables.In this study, the Bolus group demonstrated greater maternal blood pressure changes from the administration of spinal anesthesia until delivery than the Continuous group. The newborns of patients in the Bolus group had lower pOBolus administration of vasopressors was shown to influence maternal blood pressure changes. It has been mentioned that maternal blood pressure change may impact the results of umbilical artery blood gas analysis. It has also been suggested that spinal anesthesia causes vasodilation, decreases blood pressure and maternal cardiac output, and increases the pulsatility index of the umbilical artery . Therefo2 decrease.Here, the vasopressor was administered only after hypotension was confirmed. Although hypotension did not persist, the Bolus group demonstrated more severe hypotension in both systole and diastole, suggesting that the improvement in the severity of hypotension by the prophylactic continuous administration of vasopressors reduced the severity of fetal hypocapnia and contributed to the suppression of the pO2 upon delivery, it has been shown that in the presence of underlying pathologies, such as fetal growth restriction, pO2 in umbilical cord blood is reduced, reflecting impaired oxygen diffusion due to long-term abnormal placental development [2 has also been reported to be inadequate in predicting high levels of risk in full-term neonates [2 alone is unclear and likely reflects transient abnormal fetal circulation in the prenatal period [2 in the cord blood gas analysis, AS was also affected by the method of administration of vasopressors. AS is a direct indicator of neonatal well-being [Regarding low umbilical artery blood pOelopment . Meanwhineonates . In summl period . Among tll-being , and altll-being , it is iHere, AS predominantly decreased in the Bolus group compared to the Continuous group. AS is a neonatal assessment score, and a low score reportedly indicates the requirement of respiratory support. In addition, neonatal mortality is inversely correlated with this score. In recent years, there have been many reports on this index, and there are discussions on the use of AS in clinical practice, considering the problem of prematurity in preterm and low-birth-weight infants and the impact of resuscitation interventions ,17.We focused on normal singleton pregnancies at term. There are no reports on differences in AS depending on the anesthesia method, with a focus on cesarean section cases. To the best of our knowledge, this study is the first to mention the possibility that the use of vasopressors associated with CSE anesthesia may have also affected AS. In general, it has been pointed out that 5 min values of the AS are more sensitive than 1 min values in assessing neonatal prognosis, and AS < 7 at 5 min is associated with neurological damage, gastrointestinal and infectious morbidities, and neonatal mortality ,18,19,202. This also affects the decreased AS at birth. The final scenario is that medical intervention in the form of respiratory support is necessary at birth.Regarding the need for respiratory support in neonates, which was the primary endpoint of this study, the frequency of need for respiratory support increased predominantly in the Bolus group. Although there are no clear criteria for initiating respiratory support in neonates, it is often used as first-line treatment following non-improvement of tachypnea and work of breathing. This study’s results indicate an association between the use of vasopressors during CSE anesthesia and the difference in DBP after CSE anesthesia in the background of increased requirement for respiratory support in newborns. Similarly, blood pressure-related parameters following CSE anesthesia were correlated with each other, suggesting that blood pressure changes after CSE anesthesia are related to each other. The decrease in blood pressure associated with CSE anesthesia first decreased the activity of fetal circulation. The greater the drop in blood pressure, the worse the fetal circulation. This transient deterioration affects umbilical cord blood gas analysis in the form of pO2. Another limitation is the lack of uniformity in the type of pressors administered by bolus upon onset of maternal hypotension. In this study, we only excluded cases with a history of medication that directly affects blood pressure, and we were not able to examine cases with complications that could potentially affect blood pressure. The timing bias of the cases included in the study must also be described. Although the anesthesia management methods, laboratory equipment, and perinatal management system in the study period were consistent, more cases were recruited to the Bolus group in the first half of the study period, and more cases were recruited to the Continuous group in the latter part.This study’s limitation is that the criteria for the initiation of respiratory support in neonates depended on the discretion of the neonatologist, and there are no definite criteria for the initiation of oxygen therapy. In most cases, respiratory support was initiated due to persistent neonatal tachypnea or an insufficient increase in SpOTherefore, maternal hypotension and respiratory support for newborns associated with CSE anesthesia in elective cesarean sections may be improved by administering vasopressors continuously with the induction of CSE anesthesia. In the future, we will conduct a prospective study involving the continuous administration of vasopressors to evaluate the appropriate dosage of vasopressor drugs and the risk of maternal hypotension.


Apart from blood pressure level itself, variation in blood pressure has been implicated in the development of stroke in subgroups at high cardiovascular risk. We determined the association between visit-to-visit blood pressure variability and stroke risk in the general population, taking into account the size and direction of variation and several time intervals prior to stroke diagnosis.p = 0.02) and unspecified stroke . The associations were stronger for all stroke subtypes with longer time intervals; the HR for any stroke was 1.29  at 3 years, 1.47  at 6 years, and 1.38  at 9 years. For DBP variability, we found an association with unspecified stroke risk. Both the rise and fall of SBP and the fall of DBP were associated with an increased risk for unspecified stroke. Limitations of the study include that, due to an average interval of 4 years between visits, our findings may not be generalizable to blood pressure variability over shorter periods.From 1990 to 2016, we included 9,958 stroke-free participants of the population-based Rotterdam Study in the Netherlands. This is a prospective cohort study including participants aged 45 years and older. Systolic blood pressure (SBP) variability was calculated as absolute SBP difference divided by mean SBP over 2 sequential visits (median 4.6 years apart). Directional SBP variability was defined as SBP difference over 2 visits divided by mean SBP. Using time-varying Cox proportional hazards models adjusted for age, sex, mean SBP, and cardiovascular risk factors, hazard ratios (HRs) for stroke up to January 2016 were estimated per SD increase and in tertiles of variability. We also conducted analyses with 3-, 6-, and 9-year intervals between variability measurement and stroke assessment. These analyses were repeated for diastolic blood pressure (DBP). The mean age of the study population was 67.4 ± 8.2 years and 5,776 (58.0%) were women. During a median follow-up of 10.1 years, 971 (9.8%) participants had a stroke, including 641 ischemic, 89 hemorrhagic, and 241 unspecified strokes. SBP variability was associated with an increased risk of hemorrhagic stroke (HR per SD 1.27, 95% CI 1.05–1.54, In this population-based study, we found that visit-to-visit blood pressure variation was associated with an increased risk of unspecified and hemorrhagic stroke, independent of direction of variation or mean blood pressure. In a population-based cohort study, Alis Heshmatollah and colleagues investigate the associations between blood pressure variability and risk of stroke among adults in the Netherlands. Increased blood pressure is a known and major risk factor of stroke. Growing evidence suggests that, despite hypertension control and medication adherence, visit-to-visit variation in blood pressure is also a risk factor for stroke in high-risk populations.It is not known whether variation in blood pressure is also associated with an increased risk of stroke in the general population.In this analysis of a prospective cohort study, we followed 9,958 stroke-free participants between 1990 and 2016 and measured blood pressure variation over 2 sequential visits that were an average of 4 years apart.We found that variation of systolic blood pressure, independent of its direction, was associated with an increased risk of stroke, in particular for hemorrhagic and unspecified stroke.Regarding diastolic blood pressure, we found that variation, and in particular a fall but not a rise, in diastolic blood pressure was associated with unspecified stroke.Blood pressure variability may be a modifiable risk factor for stroke, and future studies should focus on whether lowering blood pressure variability results in lower stroke incidence. Hypertension is a major modifiable risk factor for stroke and cardiovascular events . From moHowever, previous studies on the association between blood pressure variation and stroke have primarily been conducted within trials of high-risk individuals with hypertension, high cardiovascular risk, or previous stroke or transient ischemic attack, or within post-menopausal women –10. PopuThus, studies within the general population are needed to determine the clinical relevance of blood pressure variability in the risk of stroke and its subtypes. Moreover, such studies can provide further evidence for future interventional trials that focus on reducing blood pressure variability in addition to blood pressure level.In this analysis of a prospective population-based study, we determined the association between visit-to-visit blood pressure variability and the risk of stroke and its subtypes, taking into account the magnitude and direction of variability and several time intervals prior to stroke diagnosis.n = 1,732), no informed consent for follow-up data collection (n = 74), previous stroke at first examination (n = 239), or incident stroke between the first and second examination (n = 103). In total, 9,958 participants were left for the systolic blood pressure analysis. For the analysis of diastolic blood pressure variability, an additional 3 participants with missing diastolic blood pressure measurements were excluded, resulting in 9,955 individuals for analysis.This study is based on the Rotterdam Study, a large prospective population-based cohort in the Netherlands designed to study the occurrence and determinants of diseases in the general population . The cohThe Rotterdam Study was approved by the Medical Ethics Committee of Erasmus MC (registration number MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport . All participants provided written informed consent to participate in the study. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline .n = 145), blood pressure variability assessed at the previous examination was used.During each examination at the research center, blood pressure was measured twice at the right upper arm after at least 5 minutes of rest in a seated position. The mean of the 2 readings was used. Blood pressure was measured in the same way in all examination rounds. Before 7 November 2006, a Hawksley random-zero sphygmomanometer was used. Omron M6 Comfort and Omron M7 devices were used thereafter. Systolic blood pressure variability within individuals between 2 sequential visits was defined as the absolute difference in systolic blood pressure divided by the mean systolic blood pressure over the 2 visits (|difference|/mean) and then transformed into a normal standardized distribution. This formula is easily translated into clinical practice and also allows calculation of the percentage difference: (|difference|/mean) × 100%. Furthermore, the formula can be adapted to calculate directional systolic blood pressure variability, which differentiates rises and falls in systolic blood pressure. This was defined as the difference in systolic blood pressure between the 2 visits divided by the mean ([latter − former]/mean). We recently used this same approach in other studies assessing variation in blood pressure ,16. To aStroke was defined according to the World Health Organization (WHO) criteria as a syndrome of rapidly developing clinical signs of focal or global disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin . History2). Blood samples were drawn to assess levels of cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), and glucose. Type 2 diabetes mellitus was defined as a fasting glucose of ≥7.0 mmol/L, a non-fasting or post-load serum glucose of ≥11.1 mmol/L, or use of blood-glucose-lowering medication. Additionally, diagnosis of type 2 diabetes mellitus, atrial fibrillation, and coronary heart disease was based on repeated screening and review of medical records.Participants were interviewed at home every 4 to 5 years with standardized questionnaires on health status, medical history, and medication use including use of blood-pressure-lowering medication, lipid-lowering medication, and anti-thrombotic agents. They additionally underwent physical examinations on average every 4 years at the dedicated research center. Participant educational level was categorized as primary education, lower education, intermediate vocational or higher general education, and higher vocational education or university. Smoking status was classified as current, former, or never. Alcohol consumption was recorded as grams of alcohol intake per week. Body mass index (BMI) was calculated as weight divided by the square of height  for the association between systolic and diastolic blood pressure variability measurements and the risk of incident any stroke, ischemic stroke, hemorrhagic stroke, and unspecified stroke. Blood pressure variability was assessed both continuously and after categorizing it into tertiles, with the reference group defined as the lowest tertile for absolute variability. Directional blood pressure variability was also divided into tertiles, but using the middle tertile as the reference group. We used time-independent (sex and education) and time-dependent covariates , which were updated simultaneously with blood pressure variability after each visit to the research center. The proportional hazards assumption was met. This assumption was tested by assessing the relationship between the scaled Schoenfeld residuals of each covariate and time, and by additional graphical inspection of these residuals against time for any non-random pattern. Model I was adjusted for age, sex, and mean systolic or diastolic blood pressure (whichever was applicable), and model II additionally included all other abovementioned covariates. We then repeated the analyses with varied latency periods to account for possible reverse causation. We estimated the associations considering a lag period of 3, 6, and 9 years . The yeaFurthermore, to assess potential effect modification, we stratified the analysis of systolic blood pressure variability and the risk of any stroke by age (median as cut point), sex, systolic blood pressure (mean as cut point), and use of blood-pressure-lowering medication. We adjusted these analyses for age, sex, mean systolic blood pressure, and the previously mentioned propensity score. For the stratification by blood-pressure-lowering medication use, we calculated a new generalized propensity score that did not include blood pressure medication use.There was no documented prospective analysis plan for the study. However, analyses were planned before examination of the data, and we made no data-driven changes to the analyses. In response to peer review, we added alcohol consumption, anti-thrombotic medication use, and type of blood pressure measuring device as adjustments in model II. We additionally tested whether there was an interaction between systolic blood pressure variability and stroke and its subtypes by adding an interaction term in the model (systolic blood pressure variability × baseline systolic blood pressure). Finally, we repeated the systolic blood pressure variation analysis using only complete cases.Alpha level (type I error) was set at 0.05. All statistical analyses were performed using R 4.1.1 software.Of the 9,958 participants included, 5,776 (58.0%) were women, and mean age was 67.4 ± 8.2 years . At basep < 0.001), hemorrhagic stroke , and unspecified stroke  in model II, adjusted for all covariates (p = 0.35). Diastolic blood pressure variability was associated with any stroke  and unspecified stroke  only. When exploring tertiles of blood pressure variability, we found that especially the highest tertile of variability was associated with an increased risk of unspecified stroke for both systolic  and diastolic blood pressure . Furthermore, the lag-period-specific analyses revealed that the association between systolic blood pressure variability and incident stroke and all stroke subtypes was stronger over longer intervals up to a lag period of 6 years  , except for the association with hemorrhagic stroke, which remained stable over longer time intervals. Using model I in the blood pressure variability analysis  ; Fig 2. analysis , includianalysis , yieldedanalysis  Tables ap < 0.001; HR highest tertile [rise] 1.50, 95% CI 1.04–2.17, p = 0.03). An association with incident hemorrhagic stroke was also present but was not significant . The analyses of rise and fall of diastolic blood pressure showed much weaker associations, with a significant association only between fall of diastolic blood pressure and unspecified stroke . The lag-specific analyses showed stronger associations between rise and fall of systolic blood pressure and incident stroke, with the strongest associations being with incident any stroke for the 9-year lag period   . Regardi = 0.03) , includi = 0.03) , yielded = 0.03)  Tables ap-value for interaction for any, ischemic, hemorrhagic, and unspecified stroke, respectively: 0.67, 0.45, 0.78, and 0.50). The association between systolic blood pressure variability and risk of any stroke was especially pronounced in participants aged >70 years  . We found no differences between men and women or between individuals with different baseline systolic blood pressure levels. When repeating the analysis using complete cases only , 59% of the strokes remained in the analysis. In this analysis, we did not find an association between systolic blood pressure variation and stroke  . Furtherd stroke .We found that a larger visit-to-visit variation in blood pressure was associated with an increased risk of stroke, in particular for unspecified and hemorrhagic strokes. These associations were more pronounced for variation in systolic than diastolic blood pressure and were stronger as the interval between blood pressure variability measurement and diagnosis of stroke increased. Additional sensitivity analyses with lag time periods supported these associations. Finally, a higher risk of stroke was associated with both rises and falls in systolic blood pressure, suggesting that larger variation, rather than the direction, was associated with stroke risk.n = 1,095) or no  use of antihypertensive medication [Previous population-based studies on visit-to-visit blood pressure variability and stroke risk within selected participants have yielded contradictory results. A study of 470 chronic kidney disease patients in the CMERC-HI cohort found that systolic blood pressure variability was strongly associated with a composite outcome of cardiovascular events including stroke and all-cause mortality . Diastoldication . Possiblno n = 1,42 use ofdication .We found that systolic blood pressure variability was associated with increased risk of hemorrhagic and unspecified stroke, whereas diastolic blood pressure variability was not associated with hemorrhagic stroke. Of the abovementioned studies that found an association between blood pressure variability and stroke, 3 studies stratified by stroke subtype ,9,10. OnSeveral pathophysiological mechanisms have been proposed to underlie the association between blood pressure variability and stroke. Repeated fluctuations in blood flow, amplified by blood pressure variability, increase mechanical stress on the arterial walls, prompting structural vascular remodeling such as arterial stiffening ,23,24, eAnother explanation that has been proposed for the association of blood pressure variability and stroke is that accumulating cerebrovascular pathology and ischemia could be a common cause of both stroke and blood pressure variability, via impaired autonomic control . We addrn = 145) missed an examination round. Blood pressure variability could therefore not be updated for a longer period for these participants, introducing heterogeneity in our measurements. However, this group was a small percentage (1.5%) of our study population, and excluding this group may introduce selection bias of healthier participants. Furthermore, although we adjusted for mean systolic blood pressure and blood-pressure-lowering medication use, we cannot rule out the possibility of some individuals with severe hypertension being successfully treated and as a result being misclassified as having a fall of blood pressure. Finally, we used a multiple imputation approach to account for missing data on the covariates since we could not satisfy the strict condition of missing completely at random (MCAR) for an adjusted complete case analysis [Several limitations of this study need to be taken into consideration. We assumed a constant rate of blood pressure variability between visits over a period of several years, possibly introducing random measurement error, which could attenuate our findings. Due to an average interval of 4 years between visits, we may have not captured blood pressure variability as timely as in other studies with more frequent visits. Due to this interval between visits, we based blood pressure variability on 2 measures to prevent immortal time bias and healthy volunteer effects. Moreover, although use of blood-pressure-lowering medication was updated during each visit to the research center, we could not account for initiation of antihypertensive medication in between visits. Despite these limitations, we found consistent and strong dose–response associations over several time intervals. Similarly, a small number of our participants Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


Glaucomatous eyes often show strong intraocular pressure (IOP) fluctuations and individual measurements at different time points are necessary for personalized therapy. To survey IOP variations 48-hours diurnal and nocturnal IOP measurements were performed on two consecutive days. Aims of this study were to investigate the short-term repeatability of 48-hours measurements within one patient’s IOP profile and long-term repeatability between two separate IOP profiles of the same patient.A retrospective cohort study was performed evaluating data of 90 glaucoma patients in a German university medical center between 2006 and 2013. All patients underwent two separate diurnal IOP profiles of 48 h. IOP was measured at 8 am, 2 pm, 6 pm, 9 pm using Goldmann applanation tonometry and at 12 midnight using Perkins tonometry in supine position on two consecutive days. Intraclass correlation coefficients (ICC) were calculated to evaluate agreement for the same time points (each time point agreement) and for consecutive measurements within the IOP profiles (between time point agreement). ICC ≤ 0.4 was defined as poor agreement, 0.4–0.75 as moderate and ≥ 0.75 as excellent. Differences between time points were investigated by Bland Altman plots.Each time point measurements of profile 1 showed moderate to excellent agreement (ICCs 0.62–0.93). There was a moderate to excellent agreement for measurements between time points of profile 1 . Profile 2 was performed at a median interval of 12.0 months (quartiles 11.0 to 21.0). Each time point agreements within profile 2 showed ICCs from 0.23 to 0.81. It showed moderate to excellent agreement for changes between time points (ICCs 0.53–0.94). Day two demonstrated ICCs from 0.74 to 0.88. Long term IOP repeatability (over both pressure profiles) showed moderate to good agreement (ICCs 0.39–0.67).Short and long-term agreement of IOP measurements evaluated by diurnal IOP profiles is moderate to good. Due to mostly moderate agreements, which we believe represent IOP fluctuations, we conclude that it is necessary to perform 48-hours IOP profiles to gain a better overview of the individual IOP fluctuations. A major risk factor for the development of glaucoma as well as disease progression is an elevated intraocular pressure (IOP) . IOP is There are different and contradictory opinions concerning reproducibility of diurnal pressure profiles. In two separate prospective studies including 40 healthy subjects and 47 primary open angle glaucoma (POAG) patients Realini et al. criticized the short and long-term repeatability of diurnal pressure profiles measured by GAT under the aspect of reproducibility between time points of measurements. IOP measurements were performed between 8 am and 8 pm every two hours for one day and at a second day after one week , 7. TheyBarkana et al. described the importance of 24-hours measurements outside normal office hours. In a study with 32 POAG patients, they measured IOP using GAT every two hours from 7 am until 12 midnight. Additionally, Perkins tonometry in a supine position was performed at 6 am. They did not find a sufficient comparability of IOP measured at daytime and in the evening or at night time and concluded that 24-hours monitoring of IOP has a great role for the review of glaucoma progression .Wilensky et al. also demonstrated poor repeatability for IOP measurements. They found that only 34 % of 176 POAG patients as well as 28 % of 55 ocular hypertension (OHT) patients showed a long time reproducibility of pressure values. The pressure measurements were performed with self-tonometry at home five times a day over four to eight consecutive days. Time points of measurements were in the morning after waking up, 12 noon, 4 pm, 7 pm and bevor sleeping, but they had no measurements at night time. Seventy-five of these patients repeated the diurnal self-tonometry after 1 to 45 months .In contrast, Katavisto et al. and De Venecia et al. reported reproducible values for 24-hours pressure measurements in glaucomatous eyes as well as for healthy individuals. In their studies measurements were performed by using Schiotz tonometry , 11.In a prospective study Hatanaka et al. were able to demonstrate short-term reproducibility of IOP measurements in 88 patients with non-treated OHT and POAG. They performed IOP measurements at 8 am, 11 am, 2 pm and 4 pm on two consecutive days. With ICC from 0.80 to 0.86 they concluded that there is an excellent agreement between day one and day two .Concerning the long-term repeatability of IOP measurements Aptel et al. published a prospective cohort study. Analyzing 92 patients with POAG, they performed four diurnal pressure profiles with intervals of six months between every pressure profile. Time points of measurement were 9 am, 10 am, 11 am, 12 am, 2 pm, 3 pm, 4 pm and 5 pm performed with GAT. There was only poor to moderate agreement with ICCs between 0.26 and 0.77 and in conclusion they found no long-term reproducibility of pressure profiles .The aim of this study was to survey the agreement of 48-hours inpatient pressure profiles to detect IOP fluctuations and survey nighttime pressure spikes and the importance of performing nighttime IOP measurements. In order to find the optimal therapeutic procedure and detect IOP fluctuations on time that might cause disease progression we routinely perform these pressure profiles. In this manuscript the evaluation of diurnal pressure profiles concerning short and long-term agreement is described.To the best of our knowledge, this is the first study that evaluates 48-hours pressure profiles including nighttime measurements in supine position.To evaluate short- term and long-term agreement of diurnal IOP profile measurements a retrospective cohort study was performed. Data of 90 glaucoma patients that underwent at least two different diurnal intraocular pressure profiles during two subsequent days in the period of 2006 to 2013 at the Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, were analyzed. Ethics Committee approval was not required for this scientific project, as only routine health data of patients treated in the Department of Ophthalmology, University Medical Center Mainz, have been investigated by retrospective chart review. No so-called third persons have been allowed to have a direct inspection of original health data of individual patients and the analysis and publication has been performed with anonymised data only. A more detailed formal approval is not required, because this type of investigation is regulated by the „Landeskrankenhausgesetz, §§ 36–37“ .Patients with the different glaucoma subtypes POAG, OHT, normal tension glaucoma (NTG), pseudoexfoliative (PEX) glaucoma and pigment dispersion glaucoma (PDG) as well as patients with optic discs suspicious for glaucoma were included. Anti-glaucomatous therapy was the same or none in both eyes during one diurnal pressure profile. A change of therapy between the two pressure profiles was possible. Patients that had any IOP lowering surgeries before or during the pressure profile were excluded. The duration of the disease was not taken into account. Furthermore, we did not differentiate whether the patients had received several diurnal IOP measurements in the past or whether the patients were naive to diurnal IOP measurements.IOP measurements were performed at five time points within 24 h  on two consecutive days. IOP was measured with GAT sitting at the slit lamp during the day and Perkins tonometry at 12 midnight when lying in bed. One value was measured for each eye. The wards physician performed daytime measurements at 8 am and 2 pm, at 6 pm the physician on duty measured and another physician measured at 9 pm and 12 midnight. It was not documented which eye was measured first, but routinely the right eye is measured before the left eye, and there was no evaluation if patients received pupil dilation before measurement. IOP measurements were not masked between the different physicians who measured IOP during the IOP profile in this retrospective study. Missing measurements due to absence of patients for this time point of measurement were not imputed.Primary endpoints for the evaluation of short-term repeatability were each time point agreement, defined as agreement of measurements between the same time points within the pressure profile  and between time point agreement, defined as agreement of measurements between consecutive time points within the pressure profile . These measurements were performed for IOP profile 1 and 2.As secondary endpoint, long-term agreement of profile one and profile two, each time point agreements were performed between the same time points between day 1 at profile 1 and day 1 at profile 2. The same was done for days two between profile one and two.Patient characteristics were summarized using descriptive statistics. Categorical variables were described using absolute and relative frequencies. Normally distributed continuous variables were described by means and standard deviation otherwise by median and quartiles. To quantify the agreement of measurements, intraclass correlation coefficients (ICC) were calculated stratified for side (left/right eye) using two-way random models. ICC ≤ 0.4 was defined as poor agreement, 0.4–0.75 fair to good (moderate) agreement and ≥ 0.75 as excellent agreement after Landis and Koch scheme . Sample IRB/Ethics Committee ruled that approval was not required for this study.Data of 90 patients with glaucoma were included in this study Table . Thirty-During one diurnal IOP profile patients had equal anti-glaucomatous therapy on both days and there was no change in medication within this profile. Thirty-five patients had a change in therapy from profile 1 to profile 2.Seventy-five patients (83 %) were phakic at the first diurnal IOP profile of which two received cataract surgery before measurement of the second diurnal IOP measurement (73 phakic patients at profile 2). All other patients were pseudophakic in both eyes.The average IOP measurements in both pressure profiles ranged between 13.1 mmHg to 19 mmHg. The IOP during profile 1 was highest at 12 midnight. IOP values for both pressure profiles are demonstrated in Table The IOP measurements of each time point between day 1 and day 2 for both pressure profiles are illustrated in Table The IOP agreement between time points of measurements for each day at the two pressure profiles are displayed in Table For all measurements the ICC values showed mostly moderate agreements with values from 0.23 to 0.93 for each time point comparison and 0.53 to 0.94 for change between time points comparison.Figure Table Subjects‘ profiles between the high-agreement group and low-agreement group were evaluated regarding glaucoma subtype, lens status, anti-glaucomatous therapy and change of therapy between the two pressure profiles. No significant differences between the groups were found. Aim of this study was to evaluate the short-term and long-term agreement and reproducibility between two 48-hours IOP profiles in 90 patients with different types of glaucoma . Overall, there was moderate to good agreement in the comparison of IOP values within and between the pressure profiles. The discrepancy between the different IOP values demonstrated in the Bland Altman plots showed a large variance. Particularly, when comparing the nighttime measurement at 12 midnight and 8 am the next morning, the variation was larger in comparison to other time points of measurements. These results show that there is not always a predictable pattern of IOP values for every day but the IOP can vary individually. It is important to perform several measurements at different time points and particularly also at nighttime.There are several studies evaluating IOP fluctuation over time in glaucomatous eyes and healthy individuals, but comparability of the results is often limited. Nevertheless, it is important comparing these studies to find appropriate diagnostic standards for glaucoma patients.Realini et al. made similar points to the current examination in their study with 40 healthy subjects. Measuring IOP every two hours from 8 am to 8 pm on two visits one week apart they found no repeatable IOP pattern and with these results they concluded that diurnal measurements are important to get knowledge of individual IOP variations and are not replaceable by single-day measurements , 7. It iIn contrast to these studies, we analyzed IOP measurements performed over two consecutive days. Furthermore, the time points of measurement varied in comparison with previously mentioned studies by examining the patients at 8 am, 2 pm, 6 pm, 9 pm and 12 midnight. Realini et al. performed two additional measurements at daytime but, in contrast, no nighttime measurements were performed. In their studies IOP measurements were performed by a certified ophthalmic technician.Various studies demonstrate that IOP at night and in a supine position shows higher values than at daytime , 15. ThaIn the current study, IOP also showed highest values at 12 midnight in pressure profile 1 at both days of measurements. The ICCs in the comparison between time points around midnight (9 pm to 12 midnight and 12 midnight to 8 am) were only moderate. In the second night, IOP values were lower in comparison to the first night of measurements. An explanation for these values can be given in an increased patient`s compliance with consistent application of anti-glaucomatous medication during hospitalization.A limiting factor concerning elevated IOP values after waking patients at nighttime while sleeping is partly due to stress-related artifacts by waking up patients for the examination . AdditioAnother limiting factor in the presented study could be the interobserver variability due to different physicians performing the day and nighttime measurements. Considering the literature this confounder can cause differences in IOP around 2mmHg . In the In the presented case, we included six different subtypes of glaucoma. Realini et al. only included healthy individuals in the first study and patients with POAG in the second study. That is another limitation in comparability of the studies. It is known that glaucoma subtypes show differences in IOP manifestation. For example, OHT patients mostly have higher IOP levels but are infrequently treated with anti-glaucomatous therapy. NTG are characterized by lower IOP levels . PEX glaHatanaka et al. examined 88 patients with OHT and POAG on two consecutive days in a prospective study. They performed IOP measurements at 8 am, 11 am, 2 pm and 4 pm. With ICCs from 0.80 to 0.86 they concluded that there is an excellent agreement between day one and day two , 24.In the current study as well as in the survey of Realini et al. most patients received anti-glaucomatous therapy and there was no differentiation if patients had monotherapy or combined therapy in the data evaluation. In our study, we surveyed patients with different topical therapies. There was every kind of eye drop combination and some patients did not use any anti-glaucomatous therapy. This treatment variety must also be considered in the critical evaluation of the study and may be able to reduce the validity of this evaluation. Moreover, in the study of Hatanaka et al. the nighttime measurement is missing which is also true for the other studies discussed so far . RegardiAnother limitation of this retrospective study was the potential bias, that IOP measurements were not masked to the different physicians performing Goldmann and Perkins tonometry during the IOP profiles. This should be improved in consecutive studies.A further limitation of our data is given by the fact that the evaluation of the retrospectively collected data showed that at the first day for the measurement at 8 am there were less documented values of IOP measurement (24/25 patients in profile one and 5/5 patients in profile 2). A reason for these missing values was partly the late arrival of the patients in the hospital and the time consuming diagnostic assessments on the first day  that might have led to missed or delayed IOP measurement. The missing IOP values lead to lower power in the respective evaluation of the 8 am measurements at the first days of IOP profiles and should be noted when reading the results. In following studies, this circumstance should be considered by starting the examination at later time points. Another limitation of this retrospective analysis is that various glaucoma subtypes were included. Thirty-seven (41 %) patients included in the study were suffering from POAG, 16 (18 %) patients had a history of OHT, 21 (23 %) patients presented with NTG, 5 (5 %) patients with PEX glaucoma, 4 (4 %) patients with PDG and 7 (8 %) patients belonged to the glaucoma suspect group . Due to the inhomogeneous group sizes and the small numbers in some groups, no subtype evaluations were performed. This should be improved in consecutive studies.At the first day of measurement during one pressure profile over two days IOP values were averagely higher than in the second day. An explanation for this can be given in the patient’s excitement for the hospitalization. They might have had long stressful arrivals and had to start their days early. Another aspect is the compliance in eye drop application. Without the control of nursing staff the daily routine eye drop application may happen inaccurately. During hospitalization anti-glaucomatous medication is applied by nursing staff at fixed time points and there is no distraction for the patients.Another interesting analysis would be how many subjects showed high fluctuations and if there were any differences in the clinical and ocular data between the high fluctuation-group and the stable group. This analysis will be part of a second manuscript, which is currently under preparation.When examining the long-term agreement we compared IOP values of IOP profile 1 with values of profile 2 on the two days of measurements. The second pressure profile was performed an average 19 months after profile 1. The comparison of the same time points from day one in profile one to profile two and day two in both profiles showed only poor to moderate agreements (ICCs from 0.39 to 0.86). These values indicate that the long-term reproducibility has to be questioned and repetitions of diurnal pressure profiles can be useful in clinical routine.These results confirm results of the study of Aptel et al. In the comparison of IOP values on four diurnal pressure profiles at an interval of six months, the authors could not find long-term reproducibility by building the ICCs . PossiblPerforming inpatient diurnal IOP profiles is an important part of glaucoma diagnostics to detect individual IOP fluctuations. Short and long-term repeatability of IOP measurements during diurnal IOP profiles is overall moderate to good. This is to the best of our knowledge the first study evaluating agreement of IOP over a period of 48-hours including nighttime measurement at 12 midnight. Due to mostly moderate agreements we conclude that it is required to perform 48-hours IOP profiles to get a better overview of the individual IOP fluctuations. The comparisons of IOP values between nighttime measurements around 12 midnight with lowest ICC values for these time points demonstrate that nighttime measurements are useful. To detect more IOP variations additional measurements at nighttime could be performed in the future.


On the other hand, the presence of ATRH at any one of the time points was not statistically significant. In conclusion, persistent ATRH is more important for the prognosis of renal disease than the initial ATRH status. Continuous follow-up and appropriate treatment are important to improve the renal outcomes.Apparent treatment-resistant hypertension (ATRH) is closely related to chronic kidney disease (CKD); however, the long-term outcomes and the effects of improvement in ATRH in patients with CKD are not well understood. We evaluated the relationship between the persistence of ATRH and the progression of CKD. This cohort study enrolled 1921 patients with CKD. ATRH was defined as blood pressure above 140/90 mmHg and intake of three different types of antihypertensive agents, including diuretics, or intake of four or more different types of antihypertensive agents, regardless of blood pressure. We defined ATRH subgroups according to the ATRH status at the index year and two years later. The prevalence of ATRH at baseline was 14.0%. The presence of ATRH at both time points was an independent risk factor for end-point renal outcome (HR, 1.41; 95% CI, 1.04–1.92;  Hypertension (HTN) is a major risk factor for cardiovascular disease, cerebrovascular accidents, and chronic kidney disease (CKD) ,2. It isATRH is often refractory to treatment and can remain unresolved for many years . The proThe KoreaN cohort study for Outcome in patients with CKD (KNOW-CKD) is a prospective, multicenter, observational cohort study to clarify the natural course, complication profile, and risk factors for the progression of renal disease and complications in patients with CKD. The detailed design and methods of the KNOW-CKD have been published previously . The stu2 were also excluded because they were CKD stage 5 [The KNOW-CKD enrolled 2238 patients with CKD between 2011 and 2016 from nine major university-affiliated tertiary care hospitals throughout South Korea. The participants were followed up until 2020. This study had an ethnically homogenous population group consisting of Koreans aged 20 to 75 years with CKD stages 1 to 5 who were not on dialysis and had not undergone kidney transplantation. A total of 75 participants who did not have information of hypertension were excluded. A further 114 participants were excluded because of inadequate information about their BP or anthropometric or laboratory data at baseline, or lack of follow-up records. A total of 128 participants with an estimated glomerular filtration rate (eGFR) less than 15 mL/min/1.73 m stage 5 . FinallyThe baseline socio-demographic data, including smoking history, current medication, comorbidities, and anthropometric measurements , were collected. Blood samples were obtained after more than 8 h of fasting. A random mid-stream urine sample was collected to measure the urine creatinine, albumin, and protein levels. Serum and random urine creatinine levels were measured using isotope dilution mass spectrometry. Participants visited the clinic 6 months and 12 months after the first visit and annually thereafter. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation .ATRH was defined as follows: (1) systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg and intake of three types of antihypertensive agents, including diuretics, or 2) intake of four or more antihypertensive agents, regardless of BP. BP was measured at the nephrology center of each participating hospital at every visit and at the cardiology center at the initial visit and the fourth-year visit. BP was checked using an electronic sphygmomanometer after 5 min of resting in the seated position. The classes of antihypertensive agents were defined according to the JNC8 guidelines [ intake oThe primary end point of this study was the progression of CKD, which was defined as a composite of ≥50% reduction in the eGFR from baseline, initiation of long-term hemodialysis or peritoneal dialysis, or kidney transplantation.Patients were divided into subgroups according to ATRH status at the index year and after two years. Patients with ATRH in the index year but without ATRH in the next two years were assigned to the PRE group. Patients without ATRH in the index year but with ATRH in the next two years were assigned to the POST group. Patients with ATRH both in the index year and after two years were assigned to the BOTH group.p-values were two-sided, and p < 0.05 was defined as statistically significant.The baseline demographic and clinical characteristics were analyzed using the chi-square test or Fisher’s exact test for categorical variables and the Kruskal–Wallis test or one-way analysis of variance for continuous variables. Baseline characteristics are described as numbers and percentages or means with standard deviations. Logistic regression models were used to evaluate the risk factors associated with ATRH. Unadjusted odds ratios (ORs) between ATRH and the predictive factors, including all baseline characteristics, were calculated, and the variables with statistical significance were selected for multivariate logistic regression. Renal outcomes in patients with ATRH were analyzed using the Kaplan–Meier method and Cox proportional hazards model. The results are presented as hazard ratios (HRs) and 95% confidence intervals (CIs). We performed subgroup analysis by sex, age, body mass index (BMI), presence of diabetes mellitus (DM), primary renal outcome, and eGFR using the Cox regression model. These statistical analyses were conducted using the SPSS  and R  software. All n = 268). A higher prevalence of ATRH was observed in men. Additionally, participants with ATRH were older; more likely to be obese; more likely to be past smokers; had lower eGFR, hemoglobin, and high-density lipoprotein levels; and a higher BUN and random urine protein creatinine ratio (PCR). Participants with ATRH were more likely to have a medical history of coronary artery disease, DM, and diabetic kidney disease. Renin-angiotensin system blockers were the most common choice of antihypertensive agents, followed by calcium channel blockers, beta-blockers, diuretics, alpha-blockers, nitrates, and minoxidil. We also present the baseline characteristics of the ATRH subgroups in The baseline characteristics of the population are presented in p = 0.001), lower eGFR , higher BMI , DM , higher uric acid OR, 1.15; 95% CI, 1.06 to 1.24; p < 0.001), and higher random urine PCR  were independent risk factors for ATRH.The risk factors associated with ATRH at baseline are shown in As shown in p = 0.027). The PRE group  and POST group  were not statistically significant.Adjusted Cox proportional hazard models were used to determine whether ATRH subgroups were independent risk factors for end-point renal outcome . In the p < 0.001)  . End-poi2 and eGFR < 30 mL/min/1.73 m2. eGFR ≥ 30 mL/min/1.73 m2 was associated with a significantly higher OR  than eGFR < 30 mL/min/1.73 m2  (p = 0.048).We further evaluated the association between ATRH and the end-point renal outcome in several subgroups . There wThe present study showed that unlike the PRE and POST groups, the presence of ATRH at both time points, that is, the BOTH group was an independent risk factor for the end-point renal outcome. This indicates that the persistence of ATRH is more associated with the progression of renal disease than the initial ATRH status. Patients with CKD in whom ATRH resolved within 2 years showed better outcomes than those in whom ATRH persisted. Our study reinforces the importance of continuous patient follow-up. In addition, appropriate treatment can improve renal outcomes. The patients’ BP status, drug compliance, and lifestyle factors should be monitored and discussed with the patient regularly.2, and 303 (15.8%) had a baseline eGFR > 90 mL/min/1.73 m2. These patients were enrolled because of proteinuria or structural abnormalities of the kidney, such as autosomal dominant polycystic kidney disease or glomerulonephropathy. Furthermore, the homogenous ethnic composition of the study population might also be the cause for the difference in prevalence.The KNOW-CKD is the largest cohort study to investigate the clinical course and complications in patients with CKD in South Korea. In this study, the prevalence of ATRH was relatively lower than that in cohorts of CKD patients from other countries; it was more similar to that in the general hypertensive population. In a comparative study, the prevalence of ATRH was higher in the European population and lower in cohorts from North America, high-income Asian countries, and Australia . MoreovePrevious studies have suggested that advanced age, male sex, lower baseline renal function, a higher degree of proteinuria/albuminuria, DM, and a higher BMI are independently associated with the prevalence of ATRH ,22,23. OSeveral large studies have shown an association between the severity of HTN and progression of CKD. In a cohort of more than 470,000 patients with HTN followed up over 5 years, ATRH was an independent risk factor for end-stage renal disease (ESRD) . There aOur study had some limitations. First, the study population was enrolled only from tertiary care hospitals, and we could not enroll patients with hypertension from primary clinics. The prevalence of ATRH might be underestimated in tertiary care hospitals. Second, drug compliance was not measured accurately. Poor compliance to medications is a major cause of failure to achieve normal BP . HoweverIn conclusion, the persistence of ATRH is associated with adverse renal outcomes. This finding suggests that continuous follow-up and appropriate treatment are important to prevent the progression of renal disease.


The time-to-graft failure corresponded well to the time from the renal biopsy of native kidney to end-stage renal disease (5.9 versus 0.4 years). Body mass index, proteinuria, microscopic hematuria, histological evaluation of fibrosis, and crescents at the time of renal biopsy of native kidney were the main variables for the differentiation of the two groups. Higher age of kidney-transplant donor, histological recurrence of IgAN, antibody-mediated rejection, and the onset of microscopic hematuria and proteinuria within 1 year after kidney transplant were also associated with worse graft survival in multivariate Cox regression analysis.The recurrence of IgA nephropathy (IgAN) after kidney transplantation occurs in 20–35% of patients. The main aim of this study is to evaluate risk factors affecting the course of IgAN after renal biopsy of native kidney and kidney transplant. We evaluated clinical parameters and histological findings at the time of biopsy of native kidney and after kidney transplantation in 313 patients with IgAN with a follow-up of up to 36 years. Using hierarchical clustering method, patients with graft failure (n=50) were divided into two groups based on the mean time from kidney transplant to graft failure (11.2  IgA nephropathy (IgAN) is the most common primary glomerulonephritis with potentially serious outcome leading to end-stage renal disease in 30% to 50% of patients within 20 to 30 years from diagnosis. The diagnosis of IgAN requires evaluation of a renal biopsy specimen and finding of IgA immunodeposits . A multiDue to the young age and minimal comorbidities, patients with IgAN are optimal candidates for kidney transplantation. However, the recurrence of the original disease in the graft is a known complication in patients with IgAN and an often cause in the decline of graft function. Other glomerular or vascular lesions secondary to acute or chronic graft rejections might also negatively affect the graft function.To better understand the graft function, we evaluated in 313 patients with IgAN who received kidney transplant clinical parameters and histological findings at the time of biopsy of native kidney performed in 1991–2013 and after receiving the kidney transplant in 1996–2017. The main aim of our study is to assess the outcome of renal transplants in this cohort. We identified risk factors for disease progression after kidney transplantation and assessed the correlation with the previous rate of decline of renal function in the native kidneys.Our study is a retrospective, multicenter, observational study of patients with biopsy-confirmed IgAN who received kidney transplant at the Institute for Clinical and Experimental Medicine, Prague, Czech Republic. We retrieved all patients with biopsy-confirmed IgAN from Czech registry of renal biopsies  performed in 25 hospitals in the Czech Republic between 1991 and 2017, and all patients transplanted between 1996 and 2017 at the Institute for Clinical and Experimental Medicine (n=523) and their overlap resulted in a final cohort of 313 patients.Clinical parameters  were retrieved at the time of native kidney biopsy. In addition, crescents and fibrosis were evaluated in biopsy with native IgAN. After kidney transplantation, all transplant parameters  were extracted from the hospital database. The occurrence of rising proteinuria (>0.5 g/24 h) and erythrocyturia (>10 erythrocytes/1 µl of urine sediment) and all kidney-biopsy findings were also included in analyses. Kidney-biopsy findings for each case were evaluated independently by two specialized nephropathologists. Any unclear cases were discussed with an additional nephropathologist to reach a consensus.Native kidney biopsies were performed in local hospitals indicated due to impaired renal function and/or urinalysis and evaluated centrally by pathologists from the Institute for Clinical and Experimental Medicine. After transplantation, besides indication biopsies, the center standard-of-care 3-month protocol biopsies were performed for all kidney-transplant recipients. Indication biopsies were performed based on observed deterioration of graft function and/or proteinuria. The decision for renal biopsy after kidney transplantation was made by the medical team of at least six nephrologists. Only 8% (25/313) patients never had allograft biopsy.The evaluation of patients with performed renal biopsies was approved by the Ethics Committee of the General University Hospital in Prague, Czech Republic . Written informed consent was obtained from all subjects involved in the study who underwent renal biopsy.www.xlstat.com), Continuous variables were compared by the Mann–Whitney U test and categorical variables by Pearson’s chi-squared test. The death-censored graft survival was evaluated by Kaplan–Meier analysis using the log-rank test. To investigate the significance of each prognostic factor for allograft loss, univariable Cox proportional hazards models were calculated for clinical parameters at the time of native kidney biopsy , and clinical variables related to kidney transplantation  were assessed in a univariable model. Potential predictors of graft loss were included in the multivariable model based on their significance in the univariable analysis. P values of <0.05 were considered significant. Statistical analysis was performed using IBM SPSS Statistics, Version 24  and GraphPad Prism 5, Version 5.03 .Agglomerative hierarchical clustering was used for the differentiation of primary data  into two groups. Discriminant analysis with transformed  variables was used to predict the membership of the other variables to the group. The verification of membership was confirmed by Mann–Whitney nonparametric test. Logistic regression was used for the validation of the results of the discriminant analysis and for the calculation of ROC curves in the case of two groups. Response type for logistic regression was binary; prediction accuracy was nearly 100%. All calculations were done by the program XLSTAT  correlated well with the distribution of the two groups based on the time from renal biopsy of native kidney to end-stage renal disease (6.8 versus 1.1 years).Subsequently, we evaluated 50 patients (16%) with graft failure after the first kidney transplant. Erythrocyturia occurred in 31 (62%) of these patients. Histologically verified recurrence of IgAN was confirmed in 23 individuals (46%). According to the hierarchical clustering method, 50 patients were divided into two groups that were compared using Mann–Whitney test Table 3.versus 0.22). Other risk factors, such as body mass index, proteinuria, microscopic hematuria, and histological evaluation of fibrosis and crescents at the time of renal biopsy of native kidney, were also confirmed, but additional factors, including age, renal parameters, and blood pressure at the onset of renal biopsy of native kidney, did not affect the differentiation into two groups , antibody-mediated rejection, or combination of recurrence of IgAN with antibody-mediated rejection on graft survival Figure 5Microscopic hematuria is not a reliable manifestation of IgAN recurrence after kidney transplantation. In an Italian cohort of 190 transplanted patients with IgAN, microscopic hematuria was not present at diagnosis of the recurrence in 25% of the patients , similarThe incidence of IgAN recurrence in biopsies diagnosed based on clinical parameters is approximately 30%, ranging from 9% to 53% among different centers with regard to protocol and clinical biopsies Table 7.The rate of recurrence after kidney transplant might be undervalued in the absence of a histological diagnosis of the original disease in native kidneys or in the case of short follow-up after kidney transplant  and/or iThe conversion of the histological recurrence into clinical recurrence might be associated with the activation of complement and cytokines production . NeverthIn our cohort of 313 patients, 10-year renal survival was unfavorable in patients with histologically recurrent IgAN compared to patients without recurrent IgAN Figure 3Which predictors of graft failure due to IgAN recurrence in kidney transplant are known? In a cohort of 71 transplanted IgAN patients, cellular or fibrocellular crescents were confirmed in 14% of graft biopsies and were related to higher interstitial inflammation with a significantly worse graft survival . The OxfThe crescents in histological evaluation of native biopsies were an unfavorable factor for renal function of native kidney and for graft survival in our cohort of 313 Czech patients. This finding is in agreement with the results of Columbia University Medical Center from 2001 to 2012 , 31, 32 We confirmed the expected clinical risk factors predicting poor outcome in patients with native IgAN, such as proteinuria, erythrocyturia, and body mass index Table 4.It was suggested that an increased risk of recurrences and graft loss in patients with IgAN with the first graft loss was due to recurrence , 36, 37,Do living-donor kidneys have a more frequent risk of recurrence and graft failure compared to the kidneys from deceased donors? In our cohort, histologically verified recurrence of IgAN as well as the rate of graft survival in recipients from living-related donors was similar to that of recipients from deceased donors. Some studies showed an unfavorable effect of living donors on the graft outcome , 38–41, We would like to emphasize that our study involves a retrospective analysis of a large cohort of IgAN patients after kidney transplant, comprising data for native kidney biopsies and regular protocolar biopsies of grafts from one center, which, until now, was an underreported area of central Europe regarding this theme. The limitation of our study includes the lack of serum or urinary biomarkers for the assessment of the activity of disease at the time of diagnosis or relapse and/or in association with treatment. Serum IgA levels or serum levels of autoantibodies specific for galactose-deficient IgA1 after kidney transplant or native-kidney biopsy were assessed as the risk factor of IgAN recurrence in other studies , 12. AnoMicroscopic hematuria with histologically verified recurrence of IgAN predicts an unfavorable renal survival in a cohort of 313 Czech patients with IgAN who received kidney transplant (p < 0.001). Significantly better renal function was found in female graft recipients. We confirmed that higher BMI, male gender, clinical activity , and histological findings, including crescents and enlarged interstitial fibrosis, are risk factors for progressive loss of renal function in patients with IgAN. Furthermore, higher age of donor of the kidney predicted worse prognosis of graft survival of patients with IgAN.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the ethics committee of 1st Medical Faculty, Charles University, Prague, General Teaching Hospital, Prague. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors received funding from grants PROGRES Q25/LF1, DRO VFN 64165, IKEM IN 00023001 from the Ministry of Health of the Czech Republic and NanoEnviCz No. LM2015073 from the Ministry of Education Youth and Sports.JN is a co-founder and co-owner of and consultant for Reliant Glycosciences, LLC, and a co-inventor on US patent application 14/318,082 (assigned to UAB Research Foundation).The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In the very elderly, “the lower the better” hypothesis has constantly been contradicted by randomized control trials and various cohort studies, but inconsistency in results led to unclear blood pressure treatment targets. This study aimed to assess the relationship between baseline blood pressure (BP) and ischemic stroke, myocardial infarction, and all-cause mortality in very elderly people treated for hypertension.This large population-based retrospective cohort study was based on the national claims database of the Korean National Health Insurance System, which covers the entire Korean population. 374,250 participants aged ≥ 75 years taking antihypertensive agents were recruited, excluding patients with a history of previous ischemic stroke or myocardial infarction.Systolic BP (SBP) followed a J curve for ischemic stroke and a U curve for all-cause mortality, with nadir ranges of 120 to 129 mmHg and 140 to 149 mmHg, respectively. While increasing diastolic BP (DBP) generally resulted in higher HRs for ischemic stroke, HRs for myocardial infarction and all-cause mortality significantly increased only when DBP was ≥ 80 mmHg and ≥ 90 mmHg, respectively. The SBP/DBP combination analysis showed that even with SBP < 130 mmHg, higher DBP ≥ 90 mmHg had higher HRs for all three outcomes compared to the reference group (130 to 149 / < 80 mmHg).There were no further benefits or even harm below certain BP levels for ischemic stroke, myocardial infarction, and all-cause mortality in very elderly hypertensive patients. Hypertension is a major risk factor for cardiovascular disease and stroke, and nearly 9.4 million people around the globe die from its complications annually . HyperteLike the younger population , very elTo address the inconsistency of results on the effects of blood pressure in the very elderly, this study used the National Health Insurance Service (NHIS) database, which covers the entire Korean population. We evaluated Koreans 75 years or older treated for hypertension, examining the association between baseline blood pressure and ischemic stroke, myocardial infarction (MI), and all-cause death. Beyond looking at SBP and DBP individually, we also analyzed SBP/DBP combination groups to examine the real-world situation where the two parameters are controlled not separately, but rather together and may interact. The importance of this study lies in the large population size of nationwide claims data and its focus on the clinically relevant population undergoing antihypertensive treatment. This study will also add reliable evidence to the limited knowledge currently available for hypertension in the very elderly Asian population. Moreover, beyond all-cause mortality which has been the key focus of previous large population cohort studies, we also addressed ischemic stroke and MI, which are representative of the coronary and cerebrovascular complications of hypertension. Lastly, the SBP/DBP combination analysis may provide evidence to further our understanding of BP parameters and suggest potential aspects to consider for managing BP in the real-world clinical setting.In this retrospective cohort, we used the national claims database established by the NHIS of Korea. In Korea, the entire population has mandatory coverage under NHIS, and every two years they are recommended to receive a medical checkup . The NHIParticipants’ blood pressure measured at their initial medical checkup between 2009 and 2012 was set as the baseline BP. It was recommended to measure blood pressure on the right arm after resting for 5 min or more in a sitting position using a standard mercury sphygmomanometer. In addition, it was recommended to measure systolic blood pressure and diastolic blood pressure three times at 5-minute intervals if possible, and report the average value of the second and third measurements.Rather than considering blood pressure measurements as continuous variables, we divided them into possible subgroups to find the optimal nadir for blood pressure control, and explored their relevance with key prognostic indicators. Therefore, Baseline BP was further stratified into eight subgroups in increments of 10 mmHg for SBP  and 5 mmHg for DBP .For SBP/DBP combination analysis, we set the classification points as 130 and 150 mmHg for SBP, and 80 and 90 mmHg for DBP. Through this we aimed to predict the possible real-world results of adapting the new ACC/AHA target of 130/80 mmHg, compared to the previous target of 150/90 mmHg.The outcome measures of this study were the first occurrence of ischemic stroke, MI, and death from any cause. Ischemic stroke was identified using ICD-10 codes  along with claims for one or more brain imaging studies (brain computed tomography [CT] or magnetic resonance imaging [MRI]), both prescribed during hospitalization. MI was defined by ICD-10-CM codes  recorded during hospitalization. These definitions had been validated in previous studies using NHIS data , 20.2), waist circumference and abdominal obesity . Lifestyle data were based on answers provided by subjects in standardized questionnaires conducted upon their national medical checkup.The following covariate data, considered as major risk factors for stroke or MI and also major comorbidities of hypertension, were collected and classified to establish the baseline characteristics for the cohort: age , sex, smoking , alcohol intake , physical activity , yearly income , body mass index (BMI) and obesity  along with registered anti-diabetic drug prescriptions, and dyslipidemia with total cholesterol levels ≥ 240 mg/dL, or ICD-10-CM code E78 and lipid lowering drug prescriptions. Chronic kidney disease (CKD) was identified by eGFR calculation below 60 mL/min/1.73m cohorts , 20.Baseline characteristics are presented as means with standard deviation for continuous variables and numbers and percentages for categorical variables. Annual incidence rates (IR) were calculated as the number of events per 1000 person-years. Cox proportional hazard models were used to estimate HR and 95 % confidence intervals (CI) to analyze association between baseline blood pressure subgroups and cardiovascular and mortality outcomes. Covariates  were entered into the models for adjustment. Additional analysis according to SBP/DBP combination groups was performed. Two-tailed P-values < 0.05 were considered statistically significant. Statistical analyses were conducted using SAS version 9.4 .This study included 374,250 hypertension treated Koreans 75 years or older Fig. , whose bCox regression analysis of adjusted HRs by SBP and DBP are shown in Fig. In the SBP/DBP combination analysis, HRs stratified by SBP/DBP groups were calculated Fig. . The refIn this nationwide cohort of 374,250 very old Koreans treated for hypertension, our data showed that there was a relationship between baseline blood pressure and ischemic stroke, MI, and all-cause death, after adjusting for age, sex, BMI, smoking, drinking, exercise, income status, diabetes mellitus, dyslipidemia, and chronic kidney disease.SBP followed a J-curve for ischemic stroke and a U curve for all-cause death, with nadir ranges of 120 to 129 mmHg and 140 to 149 mmHg, respectively. However, the absolute increase in stroke or death at lower blood pressure was relatively small, based on the annual incidence of the key endpoint.The HR for MI was similar to the reference group when SBP was < 160 mmHg, but was significantly increased when SBP was ≥ 160 mmHg. While a high DBP yielded a higher risk for MI and death, DBPs below 80 mmHg and 90 mmHg, respectively, had similar risks compared to the reference groups. The SBP/DBP combination analysis revealed that even with treatment SBP < 130 mmHg, higher DBP ≥ 90 mmHg had a higher HR compared to the reference group, for all three outcome measures. Within the same DBP level, the death hazard was higher for SBP < 130 mmHg than when SBP was 130 to 149 mmHg.The most important issues regarding BP control in the very elderly are: (1) is the lower the better, or is there a cutoff point below which there is no benefit or even harm? and (2) if there is a cutoff point, can it be defined? Our findings imply that very low SBP may not further reduce the risk of ischemic stroke, MI, and all-cause death in the very elderly. SBP below nadirs for ischemic stroke and death showed higher risk, and for MI, SBP < 160 mmHg represented a homogenous group with no significant difference from the reference group. Similarly, for DBP in MI and all-cause death, a DBP < 80 mmHg and < 90 mmHg had a relatively similar risk as the reference group with DBP < 70 mmHg, suggesting there may be no further benefits below a certain DBP level. These results are in agreement with findings from previous randomized controlled trials in the very elderly, indicating that lowering BP has cardiovascular and survival benefits , but belObservational studies also suggest that there may be a cutoff point for cardiovascular benefits. In the INVEST sub-study of elderly patients aged ≥ 80 years, the primary outcome of total mortality, nonfatal stroke, or nonfatal MI followed J-curves for both SBP and DBP, with nadirs at 140 mmHg and 70 mmHg, respectively . Moreove On the contrary, results of the most recent SPRINT trial and the ACC/AHA guideline revisions seem to support “the lower the better” hypothesis. In the SPRINT trial, even in elderly patients aged ≥ 75 years, there were significant mortality benefits and coronary, cerebrovascular event reductions with a target SBP of 120 mmHg . HoweverRelatively healthy elderly patients may benefit from low SBP levels in such carefully controlled trial settings, but more caution should be taken in the actual clinical setting. The new ACC/AHA hypertension guidelines revised the target BP for non-institutionalized, community-dwelling elderly from 150/90 to 130/80 mmHg. Our SBP/DBP combination analysis, which has its division points at SBP 130, 150 mmHg and DBP 80, 90 mmHg, may in part predict the potential outcomes of this change in the BP target. For all-cause death, within the same DBP group, the HR was highest when the SBP was < 130 mmHg.The present study has its limitations in that only the initial baseline BP was collected for analysis. BP trajectory during the follow-up period could have been observed, which might have led to a deeper understanding of the results of this study. Moreover, although the models were adjusted for major covariates, other confounding factors might remain. A variety of clinical conditions, such as frailty, dementia, malnutrition and dehydration, can affect blood pressure levels in the elderly, so these factors need to be considered when interpreting the results. The fact that these additional blood pressure-related factors could not be considered together due to the retrospective cohort study design is essential when interpreting our results, and this remains a topic of study for future research.This study had also practical limitations in distinguishing between hemorrhagic stroke due to high blood pressure and intracranial cerebral hemorrhage due to trauma including traffic accidents, only based on health insurance claim data. It should be considered as an important limitation in the interpretation of the results. In addition, ischemic heart disease requiring coronary angioplasty was not considered as a major outcome variable, so it is necessary to consider this point in the design of future studies. Pulse pressure in elderly hypertensive patients is also well-known and important prognostic factor and needs to be considered as an explanatory variable in future studies.Despite these shortcomings, this study has its strengths. The strengths of this study lie in the nationally representative large population cohort and the validity of the claims data from the NHIS database. This study is also one of the first cohort studies for the very elderly Asian population, which needs to be further studied due to possible racial differences. Moreover, while SBP and DBP have been studied separately in previous reports, their combination has rarely been analyzed. This study provides evidence of the importance of considering both SBP and DBP when managing hypertensive patients. Furthermore, this study indirectly simulates the potential results to be achieved on adapting the revised ACC/AHA target of 130/80 mmHg.This may indicate that with regard to mortality, the new target may lead to unwanted outcomes. Moreover, our results show that when DBP is not controlled, a low SBP level does not always guarantee a reduction in morbidity or mortality risk. The association of generally higher HR for outcomes measures with higher DBP within the same SBP level supports that when controlling BP, not only SBP but also DBP need to be taken into consideration. In addition, when SBP exceeded 150 mmHg, the lowest DBPs < 80 mmHg had a higher risk for all three outcome measures compared to DBPs in the range of 80 to 89 mmHg. This signifies that higher pulse pressure, especially when SBP is not controlled, is particularly dangerous for the very elderly population.This nationwide cohort with a large elderly population evaluated the effects of different BP levels on ischemic stroke, MI, and all-cause mortality hazard. The nadirs, lower subgroups with no significant benefit, and higher subgroups with significant increase in HR implicate measures that might be used in the clinical setting. Further research to validate these results should be carried out in the future to set clear evidence-based standards.