Regarding baseline BP, the group of systolic BP (SBP) 120–129 mmHg had the lowest risk of the renal outcome, which increased more than 60% in SBP ≥ 130 mmHg group. A significant increase in the renal outcome was found only in the group of diastolic BP ≥ 90 mmHg. The group of BP < 130/80 mmHg had a benefit for lowering the risk regardless of the presence of proteinuria, and it significantly reduced the risk in patients with proteinuria. Achieving SBP level < 130 mmHg after one year resulted in a 42% risk reduction in patients with SBP level ≥ 130 mmHg at baseline. Targeting SBP level < 130 mmHg would be associated with the preferable renal outcome.It is well-known that hypertension exacerbates chronic kidney disease (CKD) progression, however, the optimal target blood pressure (BP) level in patients with CKD remains unclear. This study aimed to assess the optimal BP level for preventing CKD progression. The risk of renal outcome among different BP categories at baseline as well as 1 year after, were evaluated using individual CKD patient data aged between 40 and 74 years from FROM-J [Frontier of Renal Outcome Modifications in Japan] study. The renal outcome was defined as ≥ 40% reduction in estimated glomerular filtration rate to < 60 mL/min/1.73 mhttps://www.umin.ac.jp/ctr/. Unique identifier: UMIN000001159 (16/05/2008).Clinical Trial Registration-URL:  Additionally, in many countries, as well as in Japan, the prevalence of CKD has continued to rise3. CKD is an established risk factor for not only end stage renal disease (ESRD) but also cardiovascular disease (CVD) and all-cause mortality5. Given these facts, prevention of CKD progression is one of the top public health priorities.Chronic kidney disease (CKD) is a worldwide health problem, which has a high global prevalence estimated between 11 and 13%, and also has similar prevalence among the Japanese population9. In addition, blood pressure (BP) is strongly associated with kidney function and hypertension exacerbates CKD progression and incidence of ESRD, as well as the risk of CVD13. Several clinical studies have shown that BP reduction decreased those risks, however, the optimal target level of BP in patients with CKD remains unclear17. In fact, recent guidelines recommend to achieve lower BP goals, while the target BP level for patients with CKD varies depending on guidelines20. The evaluation on the relevance of the new guidelines is necessary for appropriate management of patients with CKD.Hypertension is present in approximately 80 to 85% of patients with CKD, which is much higher compared to patients in the general population21. In the FROM-J study, all patients received treatment in accordance with the CKD clinical practice guideline of Japanese Society of Nephrology, which means that all enrolled patients were treated to maintain the same BP level. Patients in the group A (standard intervention) were only instructed to follow the guideline22. On the other hand, patients in the group B (advanced intervention) received educational sessions from dieticians and a letter regarding ideal lifestyle for CKD, as well as a notification one week before the consultation21. In the FROM-J study, the association of BP levels and CKD progression has not been explored yet.The FROM-J [Frontier of Renal Outcome Modifications in Japan] study, which investigated the effect of lifestyle modification on the outcome of patients with CKD, is one of the most extensive prospective trials of patients with CKD in JapanIn the present study, we analyzed the relationship between patients’ BP levels and renal outcome. We aimed to examine the most preferable association of BP level and renal outcome in the patients with CKD.Of the 2100 patients included in these analyses, 975 (46.4%) were categorized as CKD stage 1 or 2 and 1125 (53.6%) were CKD stage 3 to 5, the mean systolic BP (SBP) (± SD) was 137 ± 16 mmHg and that of diastolic BP (DBP) was 79 ± 11 mmHg, and the prevalence of hypertension was 90.8%. The baseline characteristics of patients are shown in Table 2. The SBP 120–129 mmHg group had the lowest risk, which increased more than two folds in the SBP ≥ 130 mmHg groups.  and those with baseline eGFR ≥ 60 ml/min/1.73 m2 (n = 975), respectively. Analysis of patients with eGFR < 60 ml/min/1.73 m2 showed that the group B had a significant reduction in patients with a baseline SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg, despite no significant difference in those with baseline BP < 130/80 mmHg. We found no difference of renal outcome between the group A and B in patients with eGFR ≥ 60 ml/min/1.73 m2 .Furthermore, we compared the group A and B in accordance with their BP levels on renal outcome in patients with baseline eGFR < 60 ml/min/1.73 m2 who did not meet the BP level of < 130/80 mmHg at baseline, the group B showed a significant association of lowering risk in renal outcome compared to the group A.In the present study, we found that baseline SBP level of ≥ 130 mmHg and DBP level of ≥ 90 mmHg was associated with the increase of the risk of the renal outcome in patients with CKD. The association of baseline BP levels with the renal outcome varied by baseline proteinuria level. Among patients with proteinuria, the higher baseline BP levels significantly increased the risk of the renal outcome. Second, the renal outcome was also strongly associated with the SBP level after one year. In fact, the late achiever had a 42% reduction of the risk compared to the failure. Third, among the patients with eGFR < 60 ml/min/1.73 m28. Our analyses using baseline BP levels demonstrated that SBP level of ≥ 130 mmHg results in a significant association with increment of risk of the renal outcome: more than 60% increase in the risk among patients with all CKD stages. Moreover, the risk more than doubled in patients with eGFR < 60 ml/min/1.73 m2. The SBP 120–129 mmHg group had a lower risk of the renal outcome than the SBP < 120 mmHg group, although there was no significant difference. Thus, it is likely concluded that the optimal SBP level for better renal outcome in patients with CKD could be < 130 mmHg, rather than < 120 mmHg. Regarding DBP, as prior studies have shown, baseline DBP levels had less association with the renal outcome than baseline SBP levels29. The significantly increased risk of the renal outcome in the DBP ≥ 90 mmHg group suggests that DBP level < 90 mmHg may be better on renal outcome. Given the minor difference between the DBP 70–79 mmHg and 80–89 mmHg groups at baseline and among the groups categorized by DBP levels after one year, it is difficult to conclude that DBP level should be controlled at < 80 mmHg. Since decreased DBP level sometimes results from stiffening of the aorta, which is one of the risks of CKD progression, the benefits of DBP levels at < 80 mmHg may be obscured in patients with severe arterial stiffness30.A few observational studies have shown that SBP level was independently associated with the presence of CKD and patients with baseline SBP level of ≥ 130 mmHg had increased risk of CKD progression32. In addition, the risk of CKD progression at higher BP levels is greater in the patients with proteinuria33. In previous studies, lowering BP level reduced the risk of CKD progression among patients with a high degree of proteinuria, despite the lack of a significant reduction among patients with small degree of proteinuria 34. In the present study, among patients with proteinuria, those with BP level of < 130/80 mmHg was significantly associated with risk reduction. However, among the patients without proteinuria, the risk reduction of those with a BP of < 130/80 mmHg did not reach significant difference but the tendency of decreased risk was found. These results suggest possible benefits for patients with CKD by controlling their BP at < 130/80 mmHg, regardless of presence or absence of proteinuria.Higher degrees of urinary protein excretion are also associated with a more rapid progression of CKD38. The MDRD  and AASK (the African American Study of Kidney Disease and Hypertension) trials targeted mean arterial pressure to ≤ 92 mmHg 37. Both trials showed no significant benefit of intensive BP control on CKD progression, whereas, with extended follow-up, intensive BP control showed significant reduction of CKD progression in patients with elevated level of proteinuria. The SPRINT  and ACCORD BP (Action to Control Cardiovascular Risk in Diabetes BP) trials targeted SBP to < 120 mmHg35. In these trials, no significant difference was observed between randomized groups in ≥ 50% decline in eGFR or ESRD. A few studies showed that intensive BP lowering had adverse effects on CKD progression35. Distinct from previous intervention trials, in the present study, all enrolled patients had the same BP target level of < 130/80 mmHg. The analyses on the management of SBP levels after one year suggests that achieving the target SBP level after one year could significantly retards CKD progression among patients with SBP level of ≥ 130 mmHg at baseline. In addition, the analyses imply the possibility that failing to meet the target SBP level after one year would exacerbate CKD progression even though it was achieved at baseline. In fact, the difference in the risk between the late failure and the achiever increased over the follow-up period, and the former had 80% increased risk compared to the latter. A post hoc analysis of SPRINT showed an increase in acute kidney injury events in the intensive treatment arm among the patients with eGFR < 45 ml/min/1.73 m239. However, in the present subgroup analysis of patients with eGFR < 45 ml/min/1.73 m2, the late achiever was also associated with reduction of the risk of renal outcome compared to the failure. Moreover, the association of the reduction was even stronger than the analysis which included patients with eGFR ≥ 45 ml/min/1.73 m2. This fact may suggest that targeting a slightly moderate SBP level to < 130 mmHg, rather than to < 120 mmHg, would minimize adverse effects and maximize benefit for the renal outcome.Varying target levels have been used for patients undergoing intensive BP control group and the results have been inconsistent21. On the contrary, the average body mass index and hemoglobin A1c were significantly lower after one year in the group B compared to the group A. A significantly lower rate of absence from regular clinical visits and higher co-treatment rate with nephrologists were observed in the group B21. In the current study, the group B demonstrated a significantly reduced risk of renal outcome among the patients with baseline eGFR < 60 ml/min/1.73 m2 who did not meet the BP level of < 130/80 mmHg at baseline. The lack of a significant difference in BP levels between the group A and B suggests that treatment of comorbidities, such as diabetes and obesity, as well as lifestyle modifications, may have further benefits to improve renal prognosis in patients with reduced kidney function who do not achieve the target BP level.In the FROM-J study, BP levels during the study period and the anti-hypertensive medication were almost identical between the groupsOur analysis has several limitations. First, since this was a post hoc analysis of the FROM-J study, unknown risk factors, which may have affected the results, were not completely excluded. Second, patients aged ≥ 75 years were excluded from the present study; therefore, our findings are unable to be applied to patients aged ≥ 75 years. Third, the assessment for the potential adverse effects associated with SBP level of < 110 mmHg or DBP level of < 60 mmHg was not performed, due to the lack of the applicable patient’s number. Fourth, we lacked data on some potentially important unmeasured confounders such as duration of hypertension or BP levels before recruitment into the study. Fifth, the presence of proteinuria was based on the results of dip-stick test, which has the possibility of a false negative or false positive. However, dip stick test is simpler and less expensive and more commonly used than the quantitative test. It is therefore convenient for non-specialists and general practitioners (GPs).In conclusion, the significant association of the SBP ≥ 130 mmHg and DBP ≥ 90 mmHg groups at baseline with the renal outcome was found. Taking the result of BP levels at baseline and after one year together, targeting the SBP level to < 130 mmHg would be preferable for preventing CKD progression. The current guidelines which recommend a target BP level of < 130/80 mmHg for CKD patients appears to be appropriate.40. The study was a Central Institutional Review Board Program; the Committee on Ethics in Strategic Research of the Kidney Foundation, Japan, and the institutional review board at the University of Tsukuba examined and approved the implementation plans and their revision40. In brief, the local medical associations were randomly assigned to two intervention groups. All patients received treatment in accordance with the CKD clinical practice guideline of Japanese Society of Nephrology, and patients in the group A (standard intervention) were only instructed to follow the guideline22. On the other hand, patients in the group B (advanced intervention) received three additional interventions. Firstly, the group B patients received 30-min educational sessions from dieticians upon visiting their local GP offices every 3 months. Secondly, the group B patients received a CKD treatment report from the coordinating center bimonthly to learn about CKD and their ideal lifestyle to prevent progression. In addition, they received a notification 1 week before the consultation in order to prevent their withdrawal from treatment. Thirdly, the group B GPs received comments about their patients’ data, focusing on the gap between target and practice, from the coordinating center.The FROM-J study was a prospective cluster-randomized trial, and enrolled patients with CKD who were under consultation with GPs. Details of the study design have previously been published41. In both groups, the BP target level of < 130/80 mmHg was applied for patients with all CKD stages, and that of < 125/75 mmHg was applied for patients with proteinuria > 1.0 g/day. The study was conducted in accordance with Ethical Guidelines for Clinical Studies  and the Ethical Guidelines for Epidemiological Studies .Patients’ BP level was measured by physicians or certified staff with the arm-cuff position at the heart level during rest in a seated position. The measurement was performed two times at intervals of 1–2 min by the auscultation method or by using an automatic sphygmomanometerIn FROM-J study, a total of 2379 patients aged 40 to 74 were enrolled. Eligible participants were those who had Stage 1, 2, 4 or 5 CKD, or Stage 3 CKD with proteinuria  and diabetes or Stage 3 CKD with proteinuria (ratio of urinary protein/urinary creatinine > 0.3 g/gCr or proteinuria > 1 +) and hypertension, who were under consultation with GPs. Dialysis patients, renal transplant patients, and those who did not consent were excluded from the study. Participant recruitment was from April 1, 2008 to October 19, 2008. On October 20, 2008, the local medical associations were randomly assigned at a ratio of 1:1 to group A or group B. Randomization was performed centrally by means of a com- puter-generated random-number sequence. The primary intervention study and follow-up duration lasted from October 20, 2008, to March 31, 2012. For our analyses, 104 patients who chose to withdraw, 74 patients without BP or eGFR data at baseline, 23 patients who had only one measurement of BP in the first 6 months, and 78 patients who had only one measurement of eGFR during the study period, were excluded, resulting in the final number of participants of 2100  to assess the benefit of low BP level, which was < 130/80 mmHg at baseline, on renal outcome.Second, we investigated the association of BP at baseline and after 1 year with the renal outcome. In patients without measurement of BP just 12 months later, the BP of the 2 months before and after was taken as the BP of 1 year later. With a target SBP level of < 130 mmHg and a target DBP level of < 80 mmHg, patients were divided into four groups based on the achievement of the target SBP and DBP levels at baseline and after 1 year, respectively. We intended to confirm whether achievement of the target BP level after 1 year was associated with reduction of the risk of the renal outcome.44:Furthermore, we compared the group A with B to assess the benefit of lifestyle modification in terms of preventing CKD progression. We examined the difference between the two groups stratified by baseline eGFR and BP levels. eGFRs in this study were calculated using the following formulaCumulative probability of the renal outcome was traced using the Kaplan–Meier curves and analyzed using a log-rank test. The effects of BP levels on the renal outcome were evaluated using Cox proportional hazards regression models with adjustment for age, sex, body mass index, current smoking, presence of diabetes mellitus, presence of dyslipidemia, intervention arm, presence of hyperuricemia and use of anti-hypertensive medication. We calculated the risk ratios of renal outcome for each stratified baseline BP level. A two-tailed value of P < 0.05 was defined as the statistically significant. All analyses were performed using JMP, version 15 .Supplementary Information.


Dialysis patients have an increased risk of mortality. Recently treatment with haemodiafiltration (HDF) has been reported to reduce mortality, particularly cardiovascular mortality, compared to standard high-flux haemodialysis (HD). However, why HDF may offer a survival advantage remains to be determined. So, we conducted a pilot study to explore differences in middle-molecules, inflammation and markers of vascular disease in patients treated by HD and HDF.Observational cross-sectional study measuring serum β2-microglobulin (β2M), Advanced Glycosylation End Products (AGEs) by skin autofluorescence (SAF), oxidative stress with ischaemia modified albumin ratio (IMAR) and peripheral vascular disease assessment using Ankle-Brachial Index (ABI), and arterial stiffness using Cardio-Ankle Vascular Index (CAVI).2M (31±9.9 vs 31.2±10 ug/mL) and SAF (2.99±0.72 vs 3.0±0.84 AU), ABI (1.06±0.05 vs 1.07±0.10) and CAVI (9.34±1.55 vs 9.35±1.23) were not different, but IMAR was higher in the HD patients We studied 196 patients, mean age 69.1 ± 12.4 years, 172 (87.8%) treated by HD and 24 (12.2%) by HDF. Age, body mass index, co-morbidity and dialysis vintage were not different between HD and HDF groups. Middle molecules; βIn this pilot observational study, we found patients treated by HDF had lower oxidative stress as measured by IMAR, with no differences in middle molecules. Lower oxidative stress would be expected to have diverse protective effects on the cardiovascular system Although we found no differences in ABI and CAVI, future studies are required to determine whether reduced oxidative stress translates into clinically relevant differences over time. Although haemodialysis (HD) is life-sustaining for patients with chronic kidney disease (CKD) stage 5, mortality remains high, with an increased risk of cardiovascular disease (CVD) . PatientIn clinical practice PVD can be assessed by measuring the ankle-brachial index (ABI) and arterial stiffness can be measured using the cardio ankle vascular index (CAVI). The ABI is the ratio of systolic blood pressure (SBP) between the ankle and brachial arteries, and the lower the ABI the greater the reduction in peripheral blood supply and risk of mortality . WhereasAfter adjusting for traditional risk factors including age, gender, smoking history and lipid profiles, then inflammation is reported to be a significant prognostic factor associated with PVD in patients with CKD . Althoug2 microglobulin and SAF), IMA, assessments of PVD and arterial stiffness in dialysis patients treated by high-flux HD and HDF.Haemodiafiltration (HDF) is gaining popularity in Europe, and an individual patient analysis of four recent major clinical trials reported that all-cause survival was greater for dialysis patients treated with HDF compared to treatment with standard high-flux HD , with a 2M), were obtained from hospital records. All patients dialysed 2 or 3 times a week, for a minimum of 4 hours per session. The target dialysis session Kt/V was >1.2 for thrice weekly HD and >2.0 for twice weekly HD. This was designed so that patients with different dialysis schedules would receive the same weekly equilibrated dialyser clearance (Kt/V). If patients failed to achieve the sessional target Kt/V with 4 hours, then the dialysis session time was increased appropriately. For those patients treated by HDF, then the target for convective clearance was more than 20 L per session, and again if required dialysis session times were extended to ensure targets were achieved. All HD and HDF treatments used a high flux dialyser and ultrapure quality dialysis water. The decision as to whether patients had been treated by HD or HDF was at the discretion of the supervising renal clinician. All patients had been treated by either high-flux HD or HDF for a minimum of three months prior to study entry, and within that period no HDF patient had been treated by high-flux HD, and vice-versa.We enrolled HD patients dialysing in 3 centres in the central Bangkok region in our pilot observational study between November 2015 and March 2016 . MedicalAlbumin is structurally altered by oxidative stress and then is unable to bind cobalt at the metal binding site. By adding cobalt, then cobalt not bound by albumin can be detected by a yellow/brown colourimetric reaction between free cobalt and dithiothreitol . We testSAF measurements were made using an AGE reader , which uses ultraviolet light range 300–420 nm for excitation of AGEs deposited in subcutaneous tissues and then measures the reflected autofluorescence light by spectrophotometer . SAF wasCAVI and ABI were measured using the vascular screening system . Four cuffs were placed on the limbs and CAVI measured as to the difference in the pulse wave velocity arriving to the ankles relative to the heart . All meawww.r.project.org).Normally distributed numeric data are presented as mean and standard deviation and non-parametric data as median and interquartile range. The student t test or Mann-Whitney U-tests were used to compare continuous variables for analysing parametric and non-parametric variables respectively, with appropriate post-hoc testing. Categorical data is presented as number (%) and Chi-squared or Fisher’s exact test were used to analyse categorical variables, with appropriate adjustments for small numbers. Factors associated with IMAR were analysed initially in a univariate linear regression model and those variables with a p value < 0.1 were then included in multivariate linear regression model . Variables which were not normally distributed were log transformed prior to inclusion. Statistical significance was taken with a p value <0.05. The graph was plotted using R statistic  and conducted according to the principles of the declaration of Helsinki, with patients providing written informed consent, and registered with the Thai Clinical Trials Registry (TCTR20200306001).2M or SAF. IMAR for the whole group was 37.5±15.2, and IMAR was significantly lower in the HDF group Click here for additional data file.S1 FigRed triangular symbols represent mean for treatment group (P = 0.42).(PNG)Click here for additional data file.S2 FigRed triangular symbols represent mean for treatment group (P = 0.99).(PNG)Click here for additional data file.S3 FigRed triangular symbols represent mean for treatment group (P = 0.79).(PNG)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Blood pressure measurement is a marker of antenatal care quality. In well resourced settings, lower blood pressure cutoffs for hypertension are associated with adverse pregnancy outcomes. We aimed to study the associations between blood pressure thresholds and adverse outcomes and the diagnostic test properties of these blood pressure cutoffs in low-resource settings.NCT01911494) in India (n=6), Mozambique (n=6), and Pakistan (n=10). We included pregnant women aged 15–49 years (12–49 years in Mozambique), identified in their community by trained community health workers, who had data on blood pressure measurements and outcomes. The trial was unmasked. Maximum blood pressure was categorised as: normal blood pressure (systolic blood pressure [sBP] <120 mm Hg and diastolic blood pressure [dBP] <80 mm Hg), elevated blood pressure (sBP 120–129 mm Hg and dBP <80 mm Hg), stage 1 hypertension , non-severe stage 2 hypertension , or severe stage 2 hypertension . We classified women according to the maximum blood pressure category reached across all visits for the primary analyses. The primary outcome was a maternal, fetal, or neonatal mortality or morbidity composite. We estimated dose-response relationships between blood pressure category and adverse outcomes, as well as diagnostic test properties.We did a secondary analysis of data from 22 intervention clusters in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials (vs those with blood pressure in any lower category), dose-response relationships were observed between increasing thresholds and adverse outcomes, but likelihood ratios were informative only for severe stage 2 hypertension and maternal CNS events (likelihood ratio 6·36 [95% CI 3·65–11·07]) and perinatal death (5·07 [3·64–7·07]), particularly stillbirth (8·53 [5·63–12·92]).Between Nov 1, 2014, and Feb 28, 2017, 21 069 women  contributed 103 679 blood pressure measurements across the three CLIP trials. Only women with non-severe or severe stage 2 hypertension, as discrete diagnostic categories, experienced more adverse outcomes than women with normal blood pressure (risk ratios 1·29–5·88). Using blood pressure categories as diagnostic thresholds (women with blood pressure within the category or any higher category In low-resource settings, neither elevated blood pressure nor stage 1 hypertension were associated with maternal, fetal, or neonatal mortality or morbidity adverse composite outcomes. Only the threshold for severe stage 2 hypertension met diagnostic test performance standards. Current diagnostic thresholds for hypertension in pregnancy should be retained.University of British Columbia, the Bill & Melinda Gates Foundation. Hypertension in pregnancy has traditionally been defined as a systolic blood pressure (sBP) of at least 140 mm Hg or a diastolic blood pressure (dBP) of at least 90 mm Hg, or both.In 2017, the American College of Cardiology and American Heart Association recommended lowering the blood pressure thresholds for diagnosing hypertension outside of pregnancy, classified as: elevated blood pressure , stage 1 hypertension , and stage 2 hypertension .Evidence before this studyWe searched MEDLINE, PubMed, Embase, CINAHL, CNTRAL, LILACS, Web of Science, and Google Scholar databases, including reference lists of eligible studies, for studies published in English between Jan 1, 2017, and Dec 31, 2020, using the search terms “human” AND  AND (“American College of Cardiology” OR “American Heart Association”) AND (“stage 1 hypertension” OR “prehypertension”) AND .In 2017, the American College of Cardiology and American Heart Association recommended lowering blood pressure thresholds for diagnosing hypertension outside of pregnancy. Several studies have examined the risk of adverse pregnancy outcomes associated with these lower blood pressure values in pregnancy, compared with the established cutoff of 140/90 mm Hg or greater.Added value of this studyNearly all evidence for using the American College of Cardiology and American Heart Association thresholds to diagnose hypertension in pregnancy are from high-income settings and rely on retrospective, routinely collected clinical data. Furthermore, these studies have focused exclusively on associative measures (such as risk ratios) between blood pressure thresholds and adverse outcomes. By contrast, this study provides prospective blood pressure data from more than 20 000 pregnant women, in three low-income and middle-income countries (LMICs), using standardised measurement technique and a validated device, and examines not only associations between blood pressure thresholds and adverse outcomes, but also the diagnostic test properties of those thresholds. Associations were dependent on blood pressure greater than or equal to 160/110 mm Hg.Implications of all the available evidenceOur findings suggest that there is an association between the American College of Cardiology and American Heart Association blood pressure thresholds and adverse pregnancy outcomes in LMIC settings, but there is no antenatal blood pressure threshold that is sensitive with regards to the adverse maternal, fetal, or neonatal outcomes studied, including data-driven cutoffs. However, severe stage 2 hypertension (blood pressure ≥160/110 mm Hg) is associated with a substantially increased risk of adverse maternal CNS outcomes and fetal or neonatal death, particularly stillbirth, and should be treated as per international guidance. Antenatal care must aim to provide more than accurate blood pressure measurement to achieve the Countdown 2030 goals.We aimed to analyse the relationship between blood pressure thresholds to define hypertension in pregnancy and adverse maternal, fetal, or neonatal outcomes, as well as the diagnostic test properties of these cutoffs, in low-resource settings.NCT01911494) in India (n=6), Mozambique (n=6), and Pakistan (n=10).We did a secondary analysis of data from 22 intervention clusters in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials  and relevant in-country research ethics boards .First, community engagement addressed barriers and facilitators to accessing care. Second, existing cadres of community health workers were trained to task-share pregnancy hypertension-oriented care at CLIP contacts in women's homes, using the CLIP Pre-eclampsia Integrated Estimate of Risk Score (PIERS) On-the-Move (POM) digital health app for risk stratification.Blood pressure measurement for all women in the intervention clusters  was standardised and taken by trained community health workers, using a semi-automated pregnancy-validated and pre-eclampsia-validated oscillometric device .Trained surveillance teams did regular household surveys (every 3–6 months) in Mozambique and Pakistan; in India, a prospective population-based surveillance system was established. The PRE-eclampsia Eclampsia Monitoring, Prevention, and Treatment (PRE-EMPT) research group, University of British Columbia, Canada, was responsible for overall trial coordination and data management.The primary CLIP composite outcome was a composite of maternal, fetal, and neonatal mortality and morbidity, and all outcomes were adjudicated by an in-country team of clinicians. Maternal death and morbidity were assessed during pregnancy or within 42 days after pregnancy; morbidity was defined as one or more life-threatening pregnancy complications . This analysis also included a maternal CNS composite outcome of one or more of maternal eclampsia, stroke, coma, or mortality. Fetal or neonatal death included stillbirth, early neonatal mortality, or late neonatal mortality .In this analysis, we included CLIP trial participants who were from intervention groups and had at least one POM app-guided antenatal contact with blood pressure measurement done by community health workers at a clinically estimated gestation of 44 weeks or less. Analyses including post-partum and perinatal outcomes were restricted to women who had delivered and provided outcome information.We classified the antenatal blood pressure readings for each woman at each visit, on the basis of the American College of Cardiology and American Heart Association criteria,vs ≥20 weeks).Descriptive statistics were used to summarise baseline maternal characteristics, and maximal blood pressure categories overall and according to gestational age at measurement  between normal blood pressure and each category, using generalised estimating equations with a Poisson link function.The diagnostic test properties of blood pressure categories were assessed using sensitivity, specificity, and positive and negative likelihood ratios (LRs). Positive LR was calculated as: sensitivity / (1 – specificity). Negative LR was calculated as: (1 – sensitivity) / specificity. CIs were calculated by standard methods.In a sensitivity analysis to determine if the sensitivity of blood pressure categories for adverse outcomes improved closer to term, we re-classified women according to the maximum blood pressure category reached within predefined gestational age categories . Also, we estimated the optimal sBP and dBP cutoffs to maximise sensitivity of blood pressure for fixed false-positive rates of 5%, 10%, and 20%. All analyses were done using R version 4.0.2.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Between Nov 1, 2014, and Feb 28, 2017, 21 069 women  contributed 103 679 blood pressure measurements across the three CLIP trials . Most woBlood pressure values overall were stable, without a clinically important mid-trimester decrease, until about 30 weeks of gestation, after which both sBP and dBP increased with advancing gestational age . MaximalThere was a dose-response relationship between higher blood pressure category and greater RR for adverse outcomes compared with normal blood pressure, for most outcomes with non-severe stage 2 hypertension and for all outcomes with severe stage 2 hypertension, which increased risk by at least two times and up to six times . When thThe only blood pressure category that was useful as a diagnostic test for the outcomes examined was severe stage 2 hypertension; sensitivity was low, but the positive LR was good for the maternal CNS composite outcome and fetal or neonatal death, particularly stillbirth . All othIn sensitivity analyses restricted to blood pressure measurements in specific gestational age ranges within the third trimester, sensitivity remained low for all blood pressure categories, including the elevated blood pressure category, although sensitivity was slightly higher for measurements from 32 weeks to less than 37 weeks . Also, sIn the CLIP trial clusters in low-resource settings, women classified as having elevated blood pressure or stage 1 hypertension did not have an increased risk of adverse maternal, fetal, or neonatal outcomes compared with women with normal blood pressure (<120/80 mm Hg). Risk of adverse outcomes was increased with stage 2 hypertension, particularly with severe stage 2 hypertension, which was associated with a two to six times increased risk compared with normal blood pressure. When blood pressure categories higher than normal were used as diagnostic cutoffs for abnormal blood pressure (how 140/90 mm Hg is currently used), the risk of adverse outcomes was increased; however, this increase was driven by the risks associated with severe stage 2 hypertension. In addition, sensitivities for adverse outcomes were low (<45%), and no category other than severe stage 2 hypertension showed useful diagnostic test properties. Using optimal cutpoint analyses for false-positive rates considered clinically reasonable led to poor sensitivity (<30%) for all outcomes.If elevated blood pressure was used as a diagnostic cutoff, an additional 28% of women would be labelled as having an abnormal blood pressure; if stage 1 hypertension was used, this would be an additional 11% of women, in addition to women already identified as having hypertension by current criteria . In our study population, the prevalence of hypertension was previously found to be 14·0% in India, 16·8% in Mozambique, and 11·6% in Pakistan, after inclusion of hypertensive diagnoses from household survey and facility records.To our knowledge, this is the first study to report on the diagnostic properties of using revised blood pressure thresholds for the diagnosis of hypertension in pregnancy, and the first to report on outcomes by specific blood pressure thresholds for women in under-resourced settings.Numerous studies have reported that women with antenatal elevated blood pressure or stage 1 hypertension by American College of Cardiology and American Heart Association criteria, as used in our analyses, have an increased risk of adverse pregnancy outcomes;Importantly, none of the aforementioned studies have reported the diagnostic test properties of various blood pressure categories to define abnormal blood pressure in pregnancy. As blood pressure measurement in pregnancy is a screening test, it should have high sensitivity for the adverse outcomes of interest, which can then lead to the established therapeutic care pathways for hypertension in pregnancy. However, blood pressure measurement is not sensitive, whether American College of Cardiology and American Heart Association categories are used (even elevated blood pressure) or an optimal blood pressure cutoff is estimated from the data and chosen. Perhaps this poor sensitivity is unsurprising, as the hypertensive disorders of pregnancy are one of three leading causes of adverse maternal outcomes , including spontaneous preterm birth, fetal growth restriction, and intrapartum complications for fetal or neonatal outcomes,The one blood pressure category that was useful in identifying women at increased risk of adverse outcomes  was severe stage 2 hypertension. This finding endorses severe stage 2 hypertension as a condition that should be avoided, as have previous data from well resourced settings,Our study has several strengths, including our large sample size, community-based recruitment of unselected pregnant women in south Asia and sub-Saharan Africa, and the standardisation of blood pressure readings across the sample, using a pregnancy-validated device.This study has several limitations. First, many women in Pakistan and Mozambique were enrolled after 20 weeks of gestation, consistent with timing of booking for antenatal care in these settings; therefore, a diagnosis of chronic hypertension could not be evaluated when blood pressure was measured after 20 weeks of gestation. Second, only basic maternal characteristics were available for our adjusted analyses. Third, many women did not have weekly blood pressure measurements from 36 weeks of gestation to delivery as specified in the CLIP protocol, so although the household survey and facility records ultimately informed diagnoses of hypertension, we did not have all relevant blood pressure values for this analysis, particularly from close to term. Women with stage 2 hypertension, whether severe or non-severe, were referred to facilities for antihypertensive treatment (about which we have no further information) and facility care; although not the focus of our analyses, such management is likely to have attenuated the relationship between stage 2 hypertension and outcomes and overestimated the strength of association between lower levels of blood pressure and adverse outcomes. Finally, we did not include in our analysis the outcome of pre-eclampsia given our community setting, and so could not evaluate this as an outcome with the revised hypertension definitions embedded in it.Pregnant women in under-resourced settings with higher-than-normal blood pressure are at increased risk of adverse outcomes, due to the risks associated with blood pressure of 140/90 mm Hg or higher, particularly with severe stage 2 hypertension. No antenatal blood pressure threshold is sensitive with regards to the adverse maternal, fetal, or neonatal outcomes studied, including data-driven cutoffs. However, the occurrence of severe stage 2 hypertension (≥160/110 mm Hg) is associated with a substantially increased risk of adverse maternal CNS outcomes and fetal or neonatal death, particularly stillbirth, and should be treated as per international guidance.A data sharing statement for the CLIP trials is provided in the LAM and PvD report grants from the Bill & Melinda Gates Foundation, during the conduct of the study. All other authors declare no competing interests.


Compartment syndrome (CS) is a pathological event caused by elevated intracompartmental pressure (ICP); however, changes from the onset of inducing atraumatic CS remained unclear. The study aimed to investigate the physiological changes in a newly developed in vivo porcine acute atraumatic CS model. CS was induced by ischemia–reperfusion injury in the left hind leg of fourteen pigs divided into an echogenicity group (EG) and a shear wave elastography group (SEG). Echogenicity was measured in EG, and shear elastic modulus (SEM) was measured in SEG seven times before, at the onset of inducing CS, and every 30 min after the onset over eight hours. Simultaneously, ICP, blood pressure, and muscle perfusion pressure (MPP) were also measured in both groups. Our results indicate that SEM of the experimental leg in SEG significantly increased as CS developed compared to the control leg (p = 0.027), but no statistical difference in the echogenicity in EG was found between the experimental leg and control leg. There were also significant correlations between SEM and ICP (p < 0.001) and ICP and MPP (p < 0.001). Our method and findings can be a basis to develop a non-invasive diagnostic tool using a shear wave elastography for atraumatic CS. Untreated CS can lead to irreversible muscle damage and disability. Prompt recognition of CS is the most significant procedure to prevent irreversible changes2. Nevertheless, CS is typically induced by a traumatic event3; however, it can also occur due to atraumatic causes like excessive physical training, medical history of anticoagulants, bleeding disorders, vascular obstruction, recovered hypovolemia, and prolonged cardiac or vascular surgery2. Especially, in acute atraumatic CS, ischemia–reperfusion injury of a limb is the occasional and representative cause of acute atraumatic CS in general hospitals7. This can occur anytime in hemodynamically unstable conditions such as shock, prolonged vascular surgery, heart surgery, and so on. Most patients suffering from these conditions should be managed in the intensive care unit (ICU) and may not complain about their symptoms due to poor general conditions or unconsciousness11. The favorable prognosis of CS can be achieved through accurate and timely diagnosis. Patients with CS suffer pallor , pain, pulselessness (faint pulse), paresthesia (numbness feeling), and paralysis (weakness with movements) of the affected extremity (5P), and 5P traditionally has been used to diagnose CS15. The clinical diagnosis with only the 5Ps was inaccurate and confusing15. The current gold standard in diagnosing CS is to directly measure intracompartmental pressure (ICP) with invasive analog or digital devices14. Although invasive techniques are useful for measuring actual ICP, serious shortcomings exist19. They can induce iatrogenic injury and even elevate the ICP of the affected extremity19. Furthermore, repetitive measurement or continuous monitoring of ICP is more dangerous and impossible with these invasive techniques, although timely diagnosis is essential in cases of suspected CS to avoid delay in its diagnosis and treatment20.Compartment syndrome (CS) is defined as impaired muscle perfusion due to increased pressure in the closed muscle compartment12. Ultrasound can detect various changes, such as swelling, stiffness, and ischemia, in muscles in CS non-invasively. The swollen muscle alters echogenicity on ultrasound and increases muscle stiffness21. The increase in muscle stiffness can increase muscle elasticity that can be measured using the ultrasound image machine22. The increased ICP decreased arterial blood flow that can be measured using Doppler measurements23. Although a recent study demonstrated that there is a significant correlation between the ICP and shear modulus obtained from shear wave elastography (SWE) among healthy individuals24, there are no comprehensive studies simultaneously investigating echogenicity, muscle elasticity, and arterial blood flow in an in vivo acute atraumatic CS model. There is only one study in CS that investigated the relationship between the ICP and muscle elasticity using SWE for the first time using a dead turkey limb model; however, the absolute muscle stiffness has not been investigated25. Understanding comprehensive physiological changes associated with CS can be further possible by measuring these values simultaneously since there can be a significant relationship between the muscle perfusion pressure associated with blood pressure and ICP. Thus, the authors devised a physiologic porcine leg model for acute atraumatic CS and intended to investigate the correlations of ICP and changes in muscle echogenicity, elasticity, and arterial blood flow velocity on ultrasound during acute CS. Our findings and methods in this study can be used to further develop a new non-invasive sonographic technique that is safe, accurate, and reproducible in measuring and monitoring ICP in the future.The increased ICP can cause sequential physiologic alterations of muscle like decreased muscle perfusion, muscle ischemia, muscle necrosis, inflammatory muscle swelling, and subsequent increased ICPWilcoxon rank-sum tests revealed that there were no significant differences in the ICP and perfusion pressure of the experimental legs between the Echogniecity Group (EG) and Shear wave elastography group (SEG) at each time point. As seen from Fig. Two-way repeated measure ANOVA analysis of the ranked data revealed that the maximum blood flow velocity showed a significant effect of condition p=0.012), and interaction of time and condition (p < 0.001) and the minimum blood flow velocity showed a significant effect of condition (p = 0.001), and interaction of time and condition (p =0.019). As seen from Table 2, and inRepresentative SWE images at each time point between the experimental leg and the control leg are illustrated in Fig. Two-way repeated measure ANOVA analysis of the ranked data revealed that the shear elastic modulus showed a significant effect of condition (p=0.027) and time (p=0.003). As seen from Fig. 27. Our results indicate that shear elastic modulus significantly increases as CS develops compared to the control leg. There were also significant correlations between the shear elastic modulus and the ICP. Although the pattern of higher echogenicity was observed in the experimental leg compared to the control leg after reperfusion, it was not sensitive enough compared to the shear elastic modulus value to detect the CS.This is the first study to investigate comprehensive measurements related to detecting CS using an in vivo porcine acute atraumatic CS leg model. Our developed model is unique and novel since the induced CS is physiologically quite similar to an acute atraumatic CS of a human limb30. Therefore, our animal model is favorable for measuring the ultrasonographic changes in pure muscle properties during CS. Thereby, our model shows a significant difference from others30. Reperfusion after tissue ischemia generates reactive oxygen species and activates neutrophils32. They cause muscle necrosis, swelling, and finally elevate ICP32. This model has pathophysiology similar to that of CS after revascularized limb. Based on our results in the EG, as demonstrated in Table In the present study, the CS was triggered by ischemia-reperfusion injury of the porcine leg muscle without any artificial manipulation into the target compartment, whereas in previous studies the CS was made by various controls, such as direct infusing fluid into a target compartment or deliberate mechanical damage of muscle33. In our study, perfusion pressure was calculated by subtracting the ICP from the diastolic blood pressure. Some literature reported that perfusion pressure less than 30 mmHg is a useful clinical parameter for CS diagnosis33. Using these criteria, in our case, CS was induced for six out of seven pigs in the EG and six out of seven pigs in the SEG starting from AR_0min. No significant differences in the ICP and perfusion pressure of the experimental legs between the EG and SEG indicate that our model is valid. However, careful interpretation of our results is needed. Because ICP and perfusion pressure can also be influenced by the blood pressure of the pig throughout the long experiment, it is possible that although the ICP is not above 30 mmHg, earlier physiological changes associated with CS may be induced since the perfusion pressure after the reperfusion decreased in the experimental leg compared to the control leg. That was the reason that we also investigated measurements from the control leg and the experimental leg so that at each time point both conditions can be compared. Previous studies also reported that the variability in reported ICP thresholds inducing CS might be due to the differences in the perfusion state of the limbs33. Indeed, over seven time points, the diastolic blood pressure decreases from 53.9 ± 7.7 mmHg at the baseline to 40.0 ± 15.1 mmHg at the 120 min after reperfusion in the echogenicity group, and from 59.9 ± 10.3 mmHg at the baseline to 39.3 ± 15.4 mmHg at the 120 min after reperfusion in the shear wave elastography group. Thus, the variation of ICP might be associated with each pig’s blood pressure. Although the ICP values in our study are lower than the previous study34 reporting above 40 mmHg ICP right after ballon removal and gradual decrease until near the 40 mmHg ICP, the patterns of increase in the ICP in the experimental leg compared to the control leg were similar to our study. Considering that the diastolic blood pressure of the pigs became lower than at the beginning of the experiments, our results are valid and reasonable.Clinically, the ICP above 30 mmHg or perfusion pressure less than 30 mmHg indicates the CS is induced in humans39. A recent study investigated the possibility of ultrasound SWE for measuring the ICP of CS in a turkey hind limb model38. In this study, increased shear wave speed in the lower limbs of six turkeys was observed as the ICP was increased. In the model, the ICP was artificially induced by infusing fluid through a balloon catheter in the dead turkey’s hind limb; thus, the CS was not naturally induced and the physiological changes in muscle during real CS were not considered. Furthermore, the absolute shear modulus of elasticity was not reported. Although it is difficult to make a direct comparison of the shear wave velocity from the shear elastic modulus, the latter increases with the increase in the shear wave velocity since shear waves propagate faster through stiffer tissue41. Thereby, our finding of significant differences in shear elastic modulus in the experimental leg compared to the control leg indicated that there were changes in muscle stiffness due to the ischemia-reperfusion injury in the porcine leg. Furthermore, a significantly positive correlation between the shear elastic modulus and the ICP indicated that the shear elastic modulus could be used non-invasively to further develop a diagnostic tool for CS.Previous literature suggests SWE as a diagnostic tool for various diseases such as liver, breast, prostate, thyroid, and musculoskeletal pathologiesWhile a statistically significant positive correlation was observed between the shear elastic modulus and the ICP, no correlation was detected between echogenicity and ICP. Although there was a trend of higher echogenicity in the experimental leg compared to the control leg as CS was induced, the results were not statistically significant, while a significant increase in shear elastic modulus was observed in the experimental leg compared to the control leg. Since our experiment requires seven time points over 8 h, it is important to consistently maintain the probe pressure and angle throughout the experiments for reliable measurements. Therefore, we have considered two groups and fixed the ultrasound probe using two different setups to investigate echogenicity and SWE considering the echogenicity requires a transverse plane of probe location, while the SWE requires a longitudinal plane of probe location. Since we made comparisons throughout the time points within each group, the subject-specific variation could be considered. In this regard, we could carefully conclude that compared to the echogenicity measure, the shear elastic modulus is more sensitive in detecting CS.45. In previous studies, it has been found that muscle atrophy is associated with increased accumulation of fibrous tissues and intramuscular fat, leading to higher ultrasound echogenicity45. Previous researchers observed that when ICP increases, echogenicity increases among 50 recreational athletes following the defined exercise program22. Based on these results, the pattern of higher echogenicity in the experimental group compared to the control group after reperfusion is a reasonable result; yet, it might not be sensitive enough compared to the shear elastic modulus value for detecting the CS.Although this is the first study to investigate echogenicity in leg CS using an in vivo acute atraumatic CS porcine model, echogenicity has been extensively researched to understand muscle morphology and conditions47. Since it is invasive and dangerous, SWE can be an alternative method for safe CS diagnosis. Furthermore, ICP can be monitored continuously by the SWE, enabling physicians to detect CS at an earlier stage. This is crucial to prevent irreversible muscle damage and disability during acute atraumatic CS.In current clinical practice, a standard diagnostic method for CS is to measure the ICP by inserting a thick needle into the muscleα = 0.05; effect size d = 1.6). Therefore, a total of 14 pigs completed the study considering two groups. The 14 pigs were divided into two groups: an echogenicity group (EG) and a shear wave elastography group (SEG), considering that the ultrasound probes should stay at the same position with the same amount of compression throughout the experiments for reducing confounding factors that can be raised owing to changes in the position and contact pressure of the probe on the surface of the pig’s leg skin. The left leg was considered as the experimental leg and the right leg as the control leg for all pigs.Based on our pilot study measuring the shear elastic modulus in pigs, a sample size of seven was determined . The output of the pressure transducer was displayed on a monitor . The vital signs of the pig were continuously monitored. At the end of each experiment, the pig was euthanized with an intravenous injection of potassium chloride (2 mmol/kg).The experimental protocol was reviewed and approved by the Institutional Animal Care and Use Committee of Korea University College of Medicine before this study. All experiments were performed under relevant guidelines and regulations. Reporting is guided by the ARRIVE  guidelines. Fourteen conditioned Landrace × Yorkshire × Duroc three-way crossbred pigs were selected . Each pig was allowed to rest in a comfortable cage for 3 days before the experiment and allowed easy access to water and food except to food for 8 h before the experiment. A cervical intramuscular injection of azaperone (5 mg/kg), xylazine (2 mg/kg), atropine (0.05 mg/kg), and alfaxalone (4 mg/kg) was used for sedation before anesthesia. An intravenous (IV) catheter was inserted into the dorsal ear vein, and 0.9% NaCl was infused for fluid replacement. Alfaxalone (1.5 mg/kg)/xylazine (0.5 mg/kg) was injected into the dorsal ear vein to induce anesthesia. After induction of anesthesia, the pig was intubated and deep anesthesia was maintained by inhalation of isoflurane gas. Dissection was performed on the paratracheal area to settle a carotid arterial line for central blood pressure monitoring. The carotid arterial line was connected to a pressure-transducing device  was inserted into the carotid artery to measure the systolic and diastolic central blood pressure. It was connected to a pressure-transducing device  and continuously monitored each pig’s condition throughout the experiment using a patient monitor . A 16-gauge heparinized IV catheter  was gently inserted in the intermuscular plane between the tibialis anterior and peroneus muscles under ultrasound guidance to measure the ICP of the anterior compartment of the porcine leg, which was also connected to a pressure-transducing device and continuously monitored.A beanbag was positioned underneath each pig to maintain the supine position throughout the experiment Fig. . The tib49. Thereby, we used 6 h for the injury time using leg ischemia. No surgical procedure was performed in the right hind limb since it was considered the control condition.Each pig was placed on a surgical table in a supine position. The position was maintained by a beanbag laid beneath the pigs’ back and buttocks, and both hind limbs were restrained by an elastic band in a fully extended position. A 15 cm skin incision was made along the inguinal line in the left hind limb. After subcutaneous dissection, the vascular bundle containing the femoral artery and vein was detected at the intermuscular plane of the medial thigh. Sharp dissection was performed proximally along the femoral artery after incision of the thick inguinal ligament. In the retropelvic space, the common iliac artery (CIA) was observed and tied with a rubber sling to block the blood flow of the CIA. The proximal thigh was tied with an elastic band to block other innominate collateral arteries around the thigh. The tension of the elastic band was adjusted to block all the arterial flow, and the complete blockage of blood flow to the left hind limb was confirmed using Doppler ultrasonography. Previous studies revealed that CS was induced by reperfusion after 6 h of leg ischemia48 and Sanderson et al.49, there would not be any changes in muscle during those ischemic periods except possible edema. Thus, a total of seven measurements on both sides were obtained, as indicated in Fig. According to Gifford et al.The circular regions of interest (ROIs) were set in the color-coded box presentation (2 cm × 2 cm) in the SWE mode. Three random circular ROIs with a diameter of 5 mm were set in the color-coded box Fig. . Random Echogenicity was calculated using the ultrasound imaging machine based on the average value of the brightness in the region of interest (ROI) from the transverse image collected of the yellow trace of the tibialis anterior muscle compartment and the freehand drawing function Fig. .Figure 150 to determine the effect of condition and time on echogenicity, shear elastic modulus, ICP, and perfusion pressure. The ART is not required for data to be normally distributed and ANOVA can be performed because ART provides accurate non-parametric analysis for both main and interaction effects51. The main repeated factors were condition  and time point . The interaction between condition and time was also considered. Perfusion pressure was computed by subtracting the ICP from the diastolic blood pressure. If sphericity was violated, the Greenhouse-Geisser Correction was used for the p-value. When a significant value was found, post hoc analysis with a Bonferroni correction was performed using a paired t-test for the ranked data50 investigating the time point, which demonstrated a significant difference between the experimental and control condition by adjusting the p-value by multiplying by 7. In the SEG, Spearman's rank correlation analysis was compared to determine whether there was a correlation between the perfusion pressure and the elastic modulus, between the ICP and the elastic modulus, and between ICP and perfusion pressure using all available data points from all conditions. Similarly, in the EG, Spearman's rank correlation analysis was compared for determining whether there was a correlation between the perfusion pressure and echogenicity, between the ICP and the echogenicity, and between the ICP and perfusion pressure using all available data points from all conditions. Owing to the consistently high ICP throughout the timepoint in one sample, the result was not included in the further analysis. A P-value of less than 0.05 indicated a statistically significant value.Due to non-normal data distribution, Wilcoxon rank-sum tests were performed to compare the ICP and perfusion pressure between the experimental legs of the EG and SEG at each time point for the animal model validation. Because our data at each group in each time point were not normally distributed, data were transformed using Aligned Rank Transform (ART) for non-parametric analysis using ARTool and ranked, then two-way repeated ANOVA tests were performed


Transplant renal artery stenosis (TRAS) is the main vascular complication of kidney transplantation. For research and treatment purposes, several authors consider critical renal artery stenosis to be greater than 50%, and percutaneous intervention is indicated in this scenario. However, there are no reports in the current literature on the evolution of patients with less than 50% stenosis.This retrospective study included data from all patients who underwent kidney transplantation and were suspected of having TRAS after transplantation with stenosis under 50% independent of age and were referred for angiography at a single centre between January 2007 and December 2014.During this period, 6,829 kidney transplants were performed at Hospital do Rim, 313 of whom had a clinical suspicion of TRAS, and 54 of whom presented no significant stenosis. The average age was 35.93 years old, the predominant sex was male, and most individuals (94.4%) underwent dialysis before transplantation. In most cases in this group, transplants occurred from a deceased donor (66.7%). The time between transplantation and angiography was less than one year in 79.6% of patients, and all presented nonsignificant TRAS. Creatinine levels, systolic blood pressure, diastolic blood pressure and glomerular filtration rate improved over the long term. The outcomes found were death and allograft loss.Age, sex and ethnic group of patients were factors that did not interfere with the frequency of renal artery stenosis. The outcomes showed that in the long term, most patients evolve well and have improved quality of life and kidney function, although there are cases of death and kidney loss. Transplant renal artery stenosis (TRAS) is the main vascular complication of kidney transplantation . TRAS usTRAS diagnosis is carried out through several exams, as evaluating clinical parameters alone does not guarantee reliability when monitoring renal perfusion. Thus, it is necessary to evaluate clinical manifestations in addition to complementary exams, such as serum creatinine, refractory hypertension, Doppler ultrasonography (US Doppler), angiotomography and angioresonance .This pathology is associated with a higher cardiovascular risk and increased mortality , 10. ForThis was a retrospective study approved by the local research ethics committee. Between January 2007 and December 2014, 6,829 kidney transplants were performed at Hospital do Rim. Patients with suspected TRAS due to refractory hypertension, renal dysfunction and/or increased PSV above 200 cm/s were referred for angiography. Patients with less than 50% stenosis were followed for a long period. Patients lost to follow-up were excluded from the analysis. The mean follow-up time of the patients was 8.5 years (5–12).Demographic and clinical data were collected from medical records. Procedure data were collected from our lab database. We used REDCap electronic data capture tools hosted at HSP – UNIFESP . REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources.Primary outcomes were defined as all-cause mortality and allograft survival. Allograft loss was defined by the need for permanent dialysis, as documented by the renal transplant team notes.Secondary outcomes were defined as serum creatinine (SCr), estimated glomerular filtration rate (eGFR) by Cockcroft-Gault, systolic blood pressure (SBP), and diastolic blood pressure (DBP) at 1 month and 1 year postarteriography.Primary outcomes were defined as all-cause mortality and allograft survival from renal angiography. Allograft loss was defined by the need for permanent dialysis as documented by the renal transplant team notes.Secondary outcomes were defined as serum creatinine (SCr), estimated glomerular filtration rate (eGFR) by Cockcroft-Gault, systolic blood pressure (SBP), and diastolic blood pressure (DBP) at 1 month and 1 year postarteriography.mice package in R) to handle missing values (MVs). We used a predictive mean matching model for numeric variables, logistic regression (logreg) for binary variables (with 2 levels) and Bayesian polytomous regression (polyreg) for factor variables (> = 2 levels). We did not impute missing values for the clinical outcomes.We used multiple imputations ]. Normality of distribution and variances were checked using histograms, Kolmogorov-Smirnoff tests, normal probability plots and residual scatter plots. Chi-square, Mann–Whitney, or two-tailed t tests were used for comparisons of baseline data.Statistical analyses included a series of logistic regression models to predict the combined endpoint of death, kidney loss or retransplantation as the main endpoint, using the odds ratio and 95% confidence intervals to estimate relative risk. Our regression models were built using a stepwise approach, limiting to 2 to 3 variables per step or per model.2 for the respective outcomes among those with high collinearity (intervariable R2 > 0.25 or variance inflation factor > 10). P values < 0.05 were considered statistically significant. Analyses were carried out using R [v4.0.0].We selected the variables with the highest partial RA total of 6,829 kidney transplants were performed at Hospital do Rim; 313 of them had clinical suspicion of TRAS, and 54 patients had no significant stenosis , and the causes of death were 50% trauma, 30% neurological disease and 10% cardiovascular disease. The ISS scheme of the majority was tacrolimus, mycophenolate, and prednisone. In this group, 100% of patients had suspected TRAS, as well as Doppler ultrasonography, and only 2 patients had PSV within the normal value, that is, up to 200 cm/s. Most had at least a 30% degree of stenosis. A total of 36.4% of patients underwent new US Doppler, and all PSVs remained within normal values. All patients used medication to control hypertension after transplantation and angiography. When we analysed the amount of medication used to treat hypertension before and after angiography, as used by this group of patients, we noticed that there was a decrease in the number of associations. Before, it was well known that patients used two or three combinations of drugs, and after angiography, this value dropped to one or two associations. In this group, only four patients showed improvement in creatinine levels. SBP, DBP and glomerular filtration rate also improved in a few patients.TRAS is the main vascular complication of kidney transplantation. Controversies in the literature about the factors that trigger stenosis in the artery of the transplanted kidney are numerous, and among them we can find type of donor, time between transplant and stenosis, and even the technique used for arterial anastomosis . In 2015Previous studies of patients with significant stenosis showed that there was no relationship between age and the degree of stenosis , 17. TheIn studies with significant stenosis, a diagnosis of systemic arterial hypertension was observed, despite the use of medications being superior to three associated types. The systolic averages found in these studies were 170 ± 30 mmHg and diastolic 105 ± 15 mmHg. After follow-up and endovascular treatment, there was an improvement in pressure, and the averages became 120 ± 20 mmHg for systolic and 75 ± 15 mm Hg for diastolic, with decreases in up to two associated medications . The aveThe Brazilian Society of Nephrology names glomerulonephritis (23.5%), hypertensive nephrosclerosis (24.1%) and diabetes mellitus (16.6%) as the main causes of chronic renal failure (16.6%) , 27. Rel. [The transplanted organs are of various origins, and according to Associação Brasileira de Transplante de Órgãos (ABTO), on average, 59% of transplants come from living donors and 41% from deceased , 28. In .  reported. .In a study published by Medina  in 2017,The time between transplantation and angiography was less than a year, as in other studies, but with patients with significant stenosis, there was no relationship between the time and the degree of stenosis , 13.The Doppler echo exam is chosen for recipients with graft dysfunction, and the increase in peak velocity suggests that the vascular flow is compromised and that when stenosis is suspected, it is necessary to perform angiography , 34, 35.To diagnose TRAS, the cut-off values are not homogeneous in the literature, with the most consensual values for direct parameters being PSV values > 180–200 cm/s –38. In tStenosis is considered significant when it compromises more than 50% of the arterial lumen, and the therapeutic approach to treatment depends on the degree of stenosis and its location. In cases of mild stenosis, that is, cases where blood pressure is controllable with medication and the creatinine level remains stable and < 3 mg/dl, conservative treatment is commonly used , 12. Aft2 is the best parameter associated with prolonged organ survival [Renal graft dysfunction of vascular aetiology is usually secondary to stenosis of the transplanted renal artery. However, high levels of serum creatinine and hypertension may also be present in patients with stenosis . In thessurvival –42. Renasurvival –46. In tsurvival , 46. Somsurvival –51. ThesThe outcomes found in this study varied mainly between allograft loss and death, while the other patients continued to evolve well with transplantation and angiography. Comparing outcome, death and allograft loss, it was found that the average age of patients who died was high compared to those who had kidney loss. One study  showed tThe percentage of patients with allograft loss was significant in the study mentioned and in the present study, at 20.7%, and the average age of these patients was over 30 years old.There were a total of 4 deceased recipients, and all were male. The majority were white, and all patients from these groups underwent haemodialysis before transplantation. Fifty percent presented with underlying diabetic nephropathy. All donors in this group were also deceased, and the causes of death were mostly neurological disease (3) and trauma (1). One hundred percent were submitted to US Doppler and were confirmed to have stenosis to any degree.Recipients with organ loss were mostly male (81.2%) and dark-skinned (45.4%). One hundred percent were submitted to haemodialysis before the transplant. The underlying diseases found were glomerulonephritis, diabetic nephropathy and indeterminate in 45.4% of patients. The majority were deceased donors, and the causes of death were trauma, neurological disease and cardiovascular disease. In 45.4% of the patients, rejection was declared, and treatment was necessary. All patients underwent US Doppler and presented any stenosis degree.In conclusion, age, sex and ethnic group of patients are factors that did not interfere with the frequency of renal artery stenosis. The outcomes showed that in the long term, death occurs in older patients with the outcome of allograft loss. Even so, most patients progress well and have improved quality of life and kidney function.It was not possible to establish significant associations between nonsignificant stenosis and factors such as DM, SAH and other underlying diseases in this study, and it was not possible to associate EART < 50% with graft type, time between transplant and angiography, degree of stenosis, time on dialysis or its type, SPV values, levels of creatinine or glomerular filtration rate, SBP and DBP. Thus, further studies are necessary in this scope because there is no previous literature on nonsignificant stenosis.In addition, this study has limitations because it is a retrospective study. There are no previous studies on patients with nonsignificant stenosis, and the search was performed in a single centre.


Peptic ulcer bleeding remains a typical medical emergency with significant morbidity and mortality. Peptic ulcer rebleeding often occurs within three days after emergent endoscopic hemostasis. Our study aims to develop a nomogram to predict rebleeding within three days after emergent endoscopic hemostasis for high-risk peptic ulcer bleeding.We retrospectively reviewed the data of 386 patients with bleeding ulcers and high-risk stigmata who underwent emergent endoscopic hemostasis between March 2014 and October 2018. The least absolute shrinkage and selection operator method was used to identify predictors. The model was displayed as a nomogram. Internal validation was carried out using bootstrapping. The model was evaluated using the calibration plot, decision-curve analyses, and clinical impact curve.Overall, 386 patients meeting the inclusion criteria were enrolled, with 48 patients developed rebleeding within three days after initial endoscopic hemostasis. Predictors contained in the nomogram included albumin, prothrombin time, shock, haematemesis/melena and Forrest classification. The model showed good discrimination and good calibration with a C-index of 0.854 . Decision-curve analyses and clinical impact curve also demonstrated that it was clinically valuable.This study presents a nomogram that incorporates clinical, laboratory, and endoscopic features, effectively predicting rebleeding within three days after emergent endoscopic hemostasis and identifying high-risk rebleeding patients with peptic ulcer bleeding.Trial registration This clinical trial has been registered in the ClinicalTrials.gov (ID: NCT04895904) approved by the International Committee of Medical Journal Editors (ICMJE).The online version contains supplementary material available at 10.1186/s12876-022-02145-9. Peptic ulcer bleeding (PUB) is the major cause of acute non-variceal upper gastrointestinal bleeding (NVUGIB), which remains an urgent medical problem with significant morbidity and mortality –4. AlthoPrevious studies developed several scoring systems to estimate the prognosis of patients with upper gastrointestinal bleeding (UGIB), including the Glasgow-Blatchford score (GBS), Rockall score (RS), and the AIMS65 score –10. HowePrior researches have been carried out to determine predictors of rebleeding in patients with PUB, and some have been incorporated into predictive models. Factors found to be predictors of rebleeding include Forrest classification, use of omeprazole, liver cirrhosis, recent surgery, systolic blood pressure below 100 mmHg, heart rate above 100 bpm, hematemesis, large ulcer size and ulcer site –20. HoweThis was a retrospective study. Patients who underwent emergent endoscopic for peptic ulcers with high-risk stigmata (Forrest Ia–Forrest IIb. Patients with more than one ulcer were classified as the most severe ulcer.) and performed endoscopic hemostasis at the Department of Gastroenterology, the First Affiliated Hospital of Nanchang University between March 2014 and October 2018 were enrolled. The exclusion criteria for this study were as follows: (1) Patients with Forrest IIc and III peptic ulcers, which did not require endoscopic therapy; (2) demographic data was incompleted. Then we collected patients’ information, including demographic information, physical examinations, clinical characteristics, auxiliary examination findings, the GBS, the RS, the AMIS65 score and clinical outcomes. The study protocol was approved by the review boards of The First Affiliated Hospital of Nanchang University center (No: 2021058).The study outcome was rebleeding within three days of the initially successful therapeutic endoscopy. Rebleeding was defined as recurrent hematemesis or melena with a decrease in hemoglobin by at least 2 g/dL within three days after the initial endoscopic treatment , and allExperienced endoscopists performed all emergent endoscopies within 12 h of hospital admission. A single-channel endoscope  was used during the procedure. The endoscopic hemostasis methods included injection therapy, thermal coagulation, mechanical therapy and combined therapy. After successfully hemostasis, the patients would receive high-dose intravenous proton pump inhibitors . Then, the patients would receive 40 mg esomeprazole once daily for 30 days.For normally distributed data, continuous variables were presented as the mean ± standard deviation (SD) and the differences between the rebleeding and no-rebleeding groups were compared using Student’s t-test. For non-normal distributed data, continuous variables were presented as the median and interquartile range (IQR) and the Mann–Whitney rank-sum test was used to analyze the difference between the two groups. Categorical variables were presented as proportions, and the chi-square test or Fisher’s exact test was used accordingly.The least absolute shrinkage and selection operator (LASSO) method, which is suitable for the regression of high-dimensional data , was useP < 0.05 was considered to be statistically significant. All the statistical analyses were performed by R statistical software 4.1.0 (www.r-project.org).Next, calibration curves and the concordance index (C-index) were calculated to evaluate the performance of the model in predicting prognosis. The values of C index of 0.5 and 1.0 respectively represent the random chance and good ability of the model to predict rebleeding. Besides, decision-curve analysis (DCA) and clinical impact curve were also used to determine the clinical net benefit associated with the use of the model . FinallyP < 0.05). While no differences were observed between the rebleeding group and non-rebleeding group concerning age, sex, alcohol use, smoking, medication use, PU bleeding history, hypertension, diabetes mellitus, systolic blood pressure, diastolic blood pressure, GBS, Rockall score, haemoglobin level on admission, blood urea nitrogen, creatinine, ulcer location, ulcer size ≥ 2 cm and methods of endoscopic hemostasis.A total of 386 patients with PUB who underwent emergency endoscopic hemostasis during the study period at our center were enrolled Fig. . Among tRebleeding within three days after emergency endoscopic hemostasis was chosen as the study outcome. In order to reduce the dimensionality and screen out the most representative risk factors for PU rebleeding within three days after endoscopic hemostasis, LASSO regression analysis was performed on the 48 collected variables using the 1-SE criteria value as the cutoff. And as a result, five variables that predict rebleeding within three days after the initially successful therapeutic endoscopy for PU screened out, including albumin, PT, shock, haematemesis/melena, Forrest classification Fig. A, B.Fig.To predict rebleeding within three days after emergency endoscopic hemostasis for PUB, we conducted multivariable logistic regression analysis using the five predictors selected by the LASSO method. And construct an accurate and stable nomogram Fig. . The equP = 0.716), showing that the model worked well. The C-index for the predictive model was 0.854, which suggested the model had a good predictive ability.The calibration curve of the predictive model showed a good fit between the prediction and observation in the primary cohort Fig. . The HosThe DCA demonstrated that this model improved patient outcomes compared with either treat-all or treat-none strategies by helping assess the risk of rebleeding in patients and informing interventions Fig. A. The DCFinally, this model was internally validated using bootstrapping resampling of the construction data set (with 1000 bootstrap samples per model). Moreover, the C-index for this nomogram was 0.830, which suggested high accuracy.PUB is the most common cause of acute non-variceal upper gastrointestinal bleeding. Although the development of endoscopic technology has effectively improved the prognosis of PUB, rebleeding is still one of the common complications . TherefoIn the present study, five predictors identified by the LASSO method were incorporated into the nomogram, and the model was proven to be of excellent performance in internal validation. The Forrest classification is mainly used to stratify ulcer bleeding patients and guide management decisions, including endoscopic and pharmacological therapy. Moreover, many studies proved that the Forrest classification had excellent predictive value for rebleeding peptic ulcers , 18, 26.There were several advantages in the present study. First, this is the first study to construct a model that incorporated variables from clinical, laboratory, endoscopic features for predicting rebleeding within three days after initial endoscopic therapy for high-risk PUB. Second, informative variables were identified using the LASSO method, which can avoid the statistical defects of overfitting compared with using univariate analysis. Third, our model had an excellent predictive ability. What is more, the model was displayed as a nomogram which was intuitive and easy to use in clinical practice.However, there were some limitations in the present study. First, the present study was a single-centre retrospective study. Second, our study only had internal validation. However, the model had a good performance in predictive ability (C-index: 0.854), and the internal verification performance was also good . This model needs to be prospectively validated on a distinct group of patients in the future.In conclusion, we established and internally validated a nomogram to predict rebleeding within three days after emergent endoscopic hemostasis. This nomogram incorporated variables from clinical, laboratory and endoscopic features and can be conveniently used to identify high-risk patients after emergent endoscopic hemostasis, which can help doctors pay more attention to or give extra intervention.Additional file 1: Patients mortality distribution.