BackgroundOffice blood pressure (BP) measurement is affected by the white-coat phenomenon and shows a weaker correlation with the gold standard ambulatory blood pressure monitoring (ABPM). To overcome this limitation, 24-hour ABPM is recommended by the guidelines for the diagnosis of hypertension. However, 24-hour ABPM is expensive and cumbersome, which limits its use in low to middle-income countries like Pakistan. We aimed to assess if an abbreviated ABPM interval can be utilized to diagnose hypertension effectively in our population.MethodsA cross-sectional study, involving 150 participants as part of the Post Clinic Ambulatory Blood Pressure (PC-ABP) study, was conducted in the cardiology clinics. Participants ≥18 years of age, who were either hypertensive or referred for assessment of hypertension, were included. Blood pressure (BP) readings were taken with an ambulatory BP monitor over a 24-hour period. After excluding the first hour called the ‘white-coat window,’ the mean of the first six systolic readings taken every half hour during the daytime was calculated and was called systolic three-hour ABPM. Pearson correlation coefficients were calculated and Bland-Altman plots were constructed to determine the correlation and limits of agreement between mean systolic three-hour ABPM and daytime-ABPM. Receiver operating characteristic (ROC) curve for systolic and diastolic three-hour daytime ABPM and area under the curve (AUC) were analyzed for the level of accuracy in predicting hypertension.ResultsOf the 150 participants, 49% were male, and 76% of all were hypertensive. The mean age of participants was 60.3 ± 11.9 years. The mean systolic three-hour ABPM was 135.0 ± 16 mmHg. The mean systolic daytime ABPM was 134.7 ± 15 mmHg. Pearson correlation coefficient between mean systolic three-hour ABPM and mean systolic daytime ABPM was 0.85 . The limits of agreement were 18 mmHg to −17 mmHg between the two readings on Bland-Altman plots and the area under the curve of the receiver operating characteristic (ROC) was 0.96, suggesting that three-hour systolic ABPM is a good predictor of hypertension.ConclusionThree-hour ABPM correlates well with 24-hour ABPM in the Pakistani population. We recommend considering the use of this abbreviated ABPM to screen hypertension where a full-length ABPM cannot be used. Further studies can be conducted on a larger sample size to determine the prognostic implications of this shortened ABPM. Office blood pressure (BP) measurement is affected by the white-coat phenomenon and shows a weaker correlation with the gold standard ambulatory blood pressure monitoring (ABPM) . While AStudy site, population, and sample sizeThis was a sub-study of the Post Clinic Ambulatory Blood Pressure study (PC-ABP), therefore the methodology including sample size calculation has been published previously . In brieAmbulatory Blood Pressure MeasurementAfter the clinic measurements were taken by the consulting physician using an automated and validated BP device , utilizing a standardized protocol ,9, a 24-Participants returned to the clinic after their 24 hours of the ABPM was complete and the data were then analyzed. All participants were given cash compensation to cover their logistics and travel costs. Since the study was conducted on actual patients visiting the cardiology clinic, an earlier clinic follow-up was scheduled if a major discrepancy was found between clinic readings and ABPM readings.Three-Hour Ambulatory Blood Pressure MeasurementsThe ABPM was considered valid when ≥85% of readings were recorded . The firStatistical AnalysisStata version 12  was used for data analysis. For continuous variables, mean and standard deviations were calculated whereas, for categorical variables, frequency and percentages were calculated. Mean in-clinic BP, 24-hour ABPM, daytime ABPM, nighttime ABPM, and one-, two-, and three-hour ABPM were calculated. Pearson correlation coefficients were calculated to determine the correlation between the mean one-, two-, and three-hour ABPM (systolic and diastolic) with the three systolic and diastolic components of 24-hour ABPM . The abbreviated reading with the highest correlation with daytime systolic ABPM was used in the final analysis. The Bland-Altman plots were constructed to determine the limits of agreement between three-hour ABPM (systolic and diastolic) and the daytime ABPM (systolic and diastolic). We categorized daytime ABPM into hypertension (SBP/DBP: ≥135/85 mmHg) and non-hypertension (<134/84 mmHg) based on the European Society of Hypertension guideline daytime ABPM value for the diagnosis of hypertension [Of the 162 patients who fulfilled our inclusion criteria, 150 agreed to participate in the study. The mean age of the participants was 60.3 ± 11.9 years. Hypertensive patients were 76% of the total participants and 49% were males. The baseline characteristics of the population are listed in Table The white-coat effect was found in 38% (n = 43) hypertensive participants and 25% (n = 36) of the participants who were referred for the assessment of hypertension had white-coat hypertension.The mean ± standard deviation (±SD) in-clinic SBP, DBP, and pulse readings were 152.3 ± 21 mmHg, 90.9 ± 12 mmHg, and 74.1 ± 15/min, respectively. The mean (±SD) overall 24-hour ambulatory SBP, DBP, and pulse readings were 130.9 ± 13 mmHg, 74.8 ± 9 mmHg, and 70.7 ± 13/min, respectively. The mean (± SD) daytime ambulatory SBP, DBP, and pulse readings were 134.7 ± 15 mmHg, 78.7 ± 15 mmHg, and 72.6 ± 12/min, respectively. The mean (±SD) nighttime ambulatory SBP, DBP, and pulse readings were 121.9 ± 18 mmHg, 68.8 ± 9 mmHg, and 63.8 ± 10/min, respectively. The mean (±SD) one-hour ambulatory SBP, DBP, and pulse readings were 142.2 ± 18 mmHg, 81.6 ± 12 mmHg, and 75.0 ± 16/min, respectively. The mean (±SD) two-hour ambulatory SBP, DBP, and pulse readings were 139.0 ± 16 mmHg, 80.6 ± 11 mmHg, and 74.6 ± 14/min, respectively. The mean (±SD) three-hour ambulatory SBP, DBP, and pulse readings were 135.0 ± 16 mmHg, 78.3 ± 11 mmHg, and 74.6 ± 14/min, respectively.Pearson correlation coefficients between one-, two- and three-hour ambulatory BP, the three components of 24-hour ABPM, and in-clinic BP are shown in Table Based on the highest correlation shown between the three-hour ambulatory BP and the daytime ambulatory BP values, we chose three-hour ambulatory BP for the final analysis. Bland-Altman plots were constructed to show the limits of agreement between mean three-hour systolic and diastolic ABPM and daytime ABPM as shown in Figure Keeping daytime systolic and diastolic ABPM as the reference standard, the AUC of ROC was 0.96  for systolic three-hour ABPM and 0.93  for diastolic readings three-hour ABPM, suggesting three-hour ABPM to be a good predictor of daytime hypertension captured on a 24-hour ABPM, as shown in Figure In our population, three-hour ABPM has a strong correlation with daytime ambulatory BP, thereby making it a good predictor of daytime hypertension. Our results were similar to the study by Mas-Heredia et al. where they demonstrated that one-hour ABPM showed a good correlation with daytime ABPM . SimilarThree-hour ABPM can offer several advantages in a resource constraint region. It can be useful in medical centers with limited resources where a single ABPM device can diagnose daytime hypertension according to the guideline-based recommendations in more than one patient per day, lowering the upfront cost of providing an accurate diagnosis. Furthermore, in patients who are unable to carry the ABPM for the entire day or find it uncomfortable, these patients can be advised three-hour ABPM to assess daytime BP levels. Physicians can quickly analyze the results of this shortened ABPM to make appropriate changes in medications within the same day. The three hours of ambulatory assessment can be spent outside the medical environment, thereby aiding the diagnosis of white-coat phenomenon and masked hypertension, as was possible with one-hour ABPM in Mas-Heredia et al.’s study .LimitationsThree-hour ABPM may not be able to identify nocturnal dipping patterns, nocturnal hypertension, and the circadian variations in the BP, which may miss prognostically important information. However, the same information cannot be acquired with clinic BP or home BP readings as well. We have shown a good correlation between three-hour ABPM and daytime systolic ABPM. Thereby, we were able to determine a representative BP value within a shorter duration of monitoring to facilitate decision-making for the patient.Despite the fact that a shorter interval of ABPM has shown reproducibility with daytime ABPM, it has not been studied for its prognostic value in predicting cardiovascular outcomes. Long-term follow-up studies with a larger sample size are needed to demonstrate the prognostic significance of a shorter interval ABPM and its utility in identifying patients who may have nocturnal hypertension.Being a single-center study conducted in cardiology clinics, a generalization of our results may be limited. However, all the participants were Pakistani in origin so the results can be applicable to people of this region. Furthermore, our results were not stratified according to different antihypertensive medications, age, and gender of the participants, or the exact time of the day on which the ABPM was attached, which may show variable results.Three-hour ABPM shows a high correlation with daytime ABPM amongst the Pakistani population, making it a good predictor of hypertension. This shortened ABPM can be considered to screen and manage hypertension, especially where a full-length ABPM is undesirable due to cost or logistic constraints. Further studies can be conducted on a larger sample size to determine the prognostic implications of this abbreviated three-hour ABPM in hypertension management.


Firmicutes was found to be remarkably decreased in severe CHF patients, and the phylum Proteobacteria was the second most abundant phyla in severe CHF patients instead of phylum Bacteroides strangely. Secondly, the α diversity indices such as chao1, PD-whole-tree and Shannon indices were significantly decreased in the severe CHF versus the control group, as well as the notable difference in β-diversity between the two groups. Thirdly, our result revealed a remarkable decrease in the abundance of the short-chain fatty acids (SCFA)-producing bacteria including genera Ruminococcaceae UCG-004, Ruminococcaceae UCG-002, Lachnospiraceae FCS020 group, Dialister and the increased abundance of the genera in Enterococcus and Enterococcaceae with an increased production of lactic acid. Finally, the alternation of the gut microbiota was presumably associated with the function including Cell cycle control, cell division, chromosome partitioning, Amino acid transport and metabolism and Carbohydrate transport and metabolism through SCFA pathway. Our findings provide the direction and theoretical knowledge for the regulation of gut flora in the treatment of severe CHF.Chronic heart failure (CHF) is the final outcome of almost all forms of cardiovascular diseases, remaining the main cause of mortality worldwide. Accumulating evidence is focused on the roles of gut microbial community in cardiovascular disease, but few studies have unveiled the alterations and further directions of gut microbiota in severe CHF patients. Aimed to investigate this deficiency, fecal samples from 29 CHF patients diagnosed with NYHA Class III-IV and 30 healthy controls were collected and then analyzed using bacterial 16S rRNA gene sequencing. As a result, there were many significant differences between the two groups. Firstly, the phylum  Chronic heart failure (CHF) is a major health problem worldwide. It is the final outcome of almost all forms of cardiovascular diseases. CHF is recognized not only as a deregulation of hemodynamic disorder and neurocrine activation, but also an uncontrolled elevation of inflammatory responses and oxidative stress . CHF is The gut microbiota, comprising the trillions of bacteria in the gastrointestinal tract, is essential for maintaining human health in many aspects, digesting the indigestible nutrients of the host, producing vitamins and hormones, shaping the development of the mucosal immune system, and preventing the colonization of pathogenic bacteria . Host-miIn order to define a more robust HF-related gut microbiota signature, we conducted this cross-sectional cohorts investigation. In this study, we collected stool samples from severe CHF patients and healthy controls, amplified the variable region of intestinal bacteria 16S rRNA, constructed a DNA library, and then assessed the taxonomic composition of the gut microbiota in patients with severe CHF.n = 29) were recruited from the First Affiliated Hospital of Harbin Medical University and the Fourth Affiliated Hospital of Harbin Medical University between April 2020 and August 2020, as well as 30 asymptomatic persons undergoing physical examinations as healthy controls. Patients who were recruited represent multiple stages of HF progression, as defined by NYHA Class III-IV. The inclusion criteria were as follows: (1) the subjects had not received antacids, probiotics, antibiotics, or antimicrobial agents within 30 days before sample collection; (2) there was no organic disease of the digestive system; and (3) they had no gastrointestinal surgery. NYHA classification was performed by patients’ treating cardiologist and adjudicated by 2 HF specialists who were blinded to the results. All patients with HF were treated according to current HF management guidelines. Associated clinical information was collected from electronic medical records. All participants (or their direct relatives) gave written informed consent, and the First Affiliated Hospital of Harbin Medical University and the Fourth Affiliated Hospital of Harbin Medical University approved all study protocols.Chronic heart failure patients  from all the participants 1–2 days after admission, then transferred into sterile collecting pipes and frozen at −80°C immediately.The bacterial DNA was extracted from the fecal samples using the Tiangen stool mini kit  according to the manufacturer’s instructions. The extracted DNA from each sample was used as the template to amplify the V3–V4 region of 16S rRNA genes using PCR. PCR amplification, sequencing of the PCR amplicons and quality control of raw data were performed. A sequencing library of the V3–V4 regions of the 16S rRNA gene was prepared as described previously . The pur1 firstly. Next we obtained the clean data for subsequent analysis after removing the Chimera Sequence using QIIME2.2 Third, operational taxonomic units (OTUs) were delineated at the cutoff of 97% also using QIIME2, and the sequencing results were compared and analyzed to obtain the family and genus annotations of OTUs based on the Silva database.3 Then α- and β-diversity analyses were performed using QIIME2 fourthly. Shannon-wiener diversity index, Simpson diversity index, the observed OTUs, PD (phylogenetic diversity)-whole-tree and Chao1 index were evaluated. A normalized OTU abundance table was used for the β-diversity analysis, including principal coordinate analysis (PCoA) based on weighted UniFrac, and unweighted UniFrac distances. Next, we performed Lefse analysis to clarify the dominant bacteria. LEfSe is a software for discovering high-dimensional biomarkers and revealing genome characteristics. LEfSe uses linear discriminant analysis (LDA) to estimate the impact of the abundance of each component (species) on the difference effect. At last, the gene function of the sample was inferred based on the species composition obtained by sequencing, and the functional difference between different groups was analyzed using PICRUSt.4 Subsequently, the Welch’s t-test method of two groups was performed using the STAMP software to filter the parts with P-value > 0.05, and Heatmap Plot, PCA plot, and Extented error bar graphs were drawn to reveal significant differences in species abundance between different samples.We evaluated the quality of sequencing data using the Fast-QC softwareThe baseline characteristics of all the participants are shown in Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria. The phylum Firmicutes was found with the highest abundance of reads in CHF patients, accounting for 59.5% in total, which was significantly decreased versus that of an abundance of 72.4% in the controls. The second was the phylum Proteobacteria, accounting for 21.3% in total, which was much more abundant versus that of an abundance of 6.9% in the controls. Likewise, bacteria belonging to the phyla Actinobacteria were more abundant in CHF patients than that in the healthy controls (2.7 vs. 0.9%), While bacteria belonging to the Bacteroidetes phyla were slightly less abundant in HF patients than that in the healthy controls (14.9 vs. 17.7%).The different distribution of relative abundance of top 19 at the phylum level in the two groups is presented in Faecalibacterium (10.5 vs. 22.8%), as well as more abundant of Escherichia-Shigella (10.3 vs. 4.6%), Enterococcus (7.7 vs. 0.0%), and Klebsiella (6.9 vs. 1.1%) than that in the healthy controls  and KEGG orthologs (KOs). Some of these COs and KOs were indicated to be significantly different in fecal microbiomes between the CHF and healthy control group . Most of the phylum Proteobacteria are pathogenic bacteria, as a result, it is considered to be a microbial signature of dysbiosis in gut microbiota  through the fermentation of dietary polysaccharides. In addition, we firstly reported that the decrease of genra Dialister and the increase of the genera in Enterococcus and Enterococcaceae were also the most notable features in CHF patients. Dialister is one of the most representative types of intestinal flora associated with irritable bowel syndrome , we were still unable to completely account for the influence of diet on gut microbiota. Second, the enrolled cohort was a small sample size and predominantly male in patients with severe CHF. Further studies informing the generalizability of gut microbiota in patients with CHF are warranted. Third, it is also necessary to address temporality of associations between gut dysbiosis and CHF. Finally, multiple omics data, such as metabolomics and proteomics, will be warranted to confirm the suppose that SCFAs produced by the gut microbiota participating the pathophysiological processes of CHF and explore the exact mechanisms.Ruminococcaceae UCG-004, Ruminococcaceae UCG-002, Lachnospiraceae FCS020 group, Dialister and the increased abundance of the genera in Enterococcus and Enterococcaceae with an increased production of lactic acid. Moreover, the alternation of the gut microbiota was presumably associated with the function including cell cycle control, cell division, chromosome partitioning, amino acid transport and metabolism and carbohydrate transport and metabolism through SCFA pathway. This information may not only improve our understanding of the pathogenesis of severe CHF, but also suggest that the regulation of the composition of gut microbiota may represent a promising therapeutic target.In conclusion, the current results firstly exhibited remarkable differencesion the composition and diversity of the gut flora of severe CHF patients and healthy controls using bacterial 16S rRNA gene sequencing. The microflora of severe CHF patients was characterized by the decreased abundance of the SCFA-producing bacteria including genera The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.The studies involving human participants were reviewed and approved by The First Affiliated Hospital of Harbin Medical University and The Fourth Affiliated Hospital of Harbin Medical University approved all study protocols. The patients/participants provided their written informed consent to participate in this study.YH, PL, and HJ conceived and designed the experiments. YH and TF analyzed data and drew the pictures. WS and DD wrote this manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease. Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and worldwide ,2.The renin–angiotensin–aldosterone system (RAAS) blockade, with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB), was the sole treatment option for diabetic kidney disease (DKD) for about 20 years. This review discusses the current landscape of treatment options for DKD, including an RAAS blockade with ACE-I or ARB, and newer therapies such as sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), along with a summary of landmark trials that support the use of these agents .The renin–angiotensin–aldosterone system is strongly linked with kidney and cardiac disease. The angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II, which has pro-inflammatory and pro-fibrotic effects , increasACE inhibition and the angiotensin blockade in the form of ACE inhibitors and angiotensin receptor blockers have been proven to be useful in patients with kidney and cardiac diseases. The effects of angiotensin on kidney autoregulation was described as early as 1983 . Over thACE-Is and ARBs have been well described in the literature, with landmark trials proving the therapeutic utility of this class of drugs for patients with DKD, and remain the mainstay of management of DKD . The “CSG Captopril trial” compared captopril with placebo in patients with insulin-dependent diabetes mellitus, proteinuria ≥500 mg/day and creatinine ≤2.5 mg/dL, and showed that captopril was effective in slowing the deterioration of kidney function, independent of blood pressure control alone . This paThe RENAAL trial (reduction of end-points in non-insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan) randomized participants to losartan 50–100 mg/day vs placebo, in addition to conventional hypertension (HTN) therapy including calcium channel blockers, diuretics, alpha blockers, and beta blockers. The primary end-point of this study was the doubling of creatinine, ESKD, or death. The losartan arm had a 25% risk reduction for creatinine doubling, and a 28% risk reduction for ESKD but no effect on death . The Irbesartan Diabetic Nephropathy Trial (IDNT) had three arms: irbesartan, amlodipine, and placebo, with a primary end-point of doubling creatinine, development of ESKD, and death. When compared with the placebo, irbesartan had a lower relative risk for the primary end-point, and also specifically for the doubling of creatinine . With the benefits of RAAS inhibition firmly established, the next obvious question was whether combining ACE-I and ARB could provide an additional benefit. The ONTARGET trial, which compared telmisartan, ramipril, or both, in patients with high risk for vascular events, showed that a combined RAAS blockade with ACE-I and ARB was not associated with an improvement in outcome, but was associated with an increase in adverse events, including hypotensive episodes, syncope and renal impairment . Although these medications have been used for decades for patients with DKD, there are some practical considerations to keep in mind when starting a patient on an ACE-I or ARB. When starting one of these medications, it is important to monitor the serum creatinine and potassium within 2–4 weeks after starting this medication or changing the dose. One should monitor for a medication-induced change in serum creatinine that is >30%, or a medication-induced hyperkalemia . Initial studies with SGLT2 inhibitors explored their utility in improving blood sugar control in patients with type II diabetes mellitus (T2DM) by virtue of increased urinary glucose excretion ,17. The beneficial effect of this class of medications are now known to go beyond their glucosuric effect, with independent cardiovascular and kidney benefits. Glomerular hypertension is one of the maladaptive mechanisms of the pathogenesis of DKD. The impact of SGLT2 inhibitors on this process remains the most widely accepted mechanism resulting in kidney protection. By blocking SGLT2 in the proximal tubule, SGLT2 inhibitors produce a natriuretic effect, which induces tubulo-glomerular feedback resulting in vasoconstriction in the afferent arteriole, reducing glomerular hyperfiltration . The redAside from their effect on glomerular pressure, it has also been hypothesized that excessive glucose uptake in the tubules can potentially contribute to proximal tubule production of extracellular matrix proteins, which may slow the progression of CKD . In addiAnother hypothesis is that SGLT2 inhibitors can induce a low ketotic state through the increased production of ketone bodies and their decreased urinary excretion. This “thrifty substrate” theory hypothesizes that the level of ketones can be preferentially oxidized over free fatty acids, which play a role in the decreased oxidative stress on the kidneys and heart ,23.Numerous trials have now established the cardiovascular and kidney benefits of SGLT2 inhibitors, and solidified their role in the management of patients with DKD and, most recently, proteinuric CKD in general . The landmark trials involving SGLT2 inhibitors were initially designed to evaluate cardiovascular (CV) benefits, and their kidney benefits soon became apparent. In trials examining kidney benefits, patients were on clinically appropriate doses of RAAS inhibition, in the form of ACE-I or ARB, prior to being started on SGLT2 inhibitors. The CANVAS trial randomized patients to canagliflozin or placebo groups; the primary outcomes were death from CV causes, nonfatal myocardial infarction (MI) and nonfatal stroke. Amongst the patients in this study, 17.2% had a history of DKD, and in the final analysis there was reduction in the kidney composite outcome ; hazard ratio HR 0.60 (95% CI of 0.47–0.77). The hazard ratio for progression of albuminuria was also statistically significant at 0.73 (95% CI of 0.67–0.79) .2 and the median urinary albumin–creatinine ratio (UACR) was 927 mg/g. The primary outcome, defined as ESKD, a doubling of the serum creatinine or death from kidney or cardiovascular cause, was lower in the canagliflozin group  [In order to further investigate the potential kidney benefits of canagliflozin, the CREDENCE trial examined kidney outcomes as the primary end-point in patients with albuminuric CKD, randomized to canagliflozin or placebo. The average eGFR was 56.2 mL/min/1.73m59–0.82) .2, ESKD or death from kidney or cardiovascular cause. The hazard ratio for the renal composite was 0.76 (95% CI 0.67–0.87). The HR with individual components of renal composite improved even further to 0.53 (95% CI 0.43–0.66) [The Dapagliflozin Effect on Cardiovascular Events trial  was designed to further investigate kidney and cardiovascular outcomes related to dapagliflozin. This trial randomized its patients to receive either dapagliflozin or placebo. The kidney composite was the secondary end-point in this trial, and was defined as a ≥ 40% decrease in eGFR to <60 mL/min/1.73 m43–0.66) .2 and a UACR of 200–5000 mg/g to receive dapagliflozin or placebo, and was designed to investigate the long-term efficacy and safety profile of dapagliflozin in patients with CKD, with or without T2DM. The primary outcome in this trial was a composite of a sustained decline in the eGFR of at least 50%, ESKD, or death from kidney or cardiovascular cause. In this trial, only 67% of the patients had DM, and the trial showed a significantly lower risk for the primary outcome in patients with CKD, irrespective of whether they had DM. The primary composite outcome had an HR of 0.61 (95% CI 0.51–0.72) [2, and UACR of 1 g/g. The Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD) trial randomized patients with an eGFR of 25–75 mL/min/1.73 m51–0.72) . Study r2 initiation of kidney replacement therapy, or death from renal cause, was found to be lower with empagliflozin  [The EMPA-REG OUTCOME trial compared empagliflozin to placebo in patients with type 2 diabetes and a high risk for cardiovascular events, and had a primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke . In a se40–0.75) .2 (if baseline eGFR was ≥ 30 mL/min/1.73 m2), or <10 mL/min/1.73 m2 (if the baseline eGFR was <30 mL/min/1.73 m2). Patients with an eGFR <20 mL/min/1.73 m2 at the time of randomization were excluded from the trial. The composite kidney outcome had an HR of 0.50 (95% CI 0.32–0.77) [The EMPEROR-Reduced trial assigned patients with classes II–IV heart failure to receive empagliflozin or placebo. Composite renal outcome was one of the secondary outcomes, and this was defined as the need for chronic dialysis or kidney transplant, or a ≥40% decrease in eGFR, or a sustained eGFR <15 mL/min/1.73 m32–0.77) .2 of body surface area or an eGFR ≥45 to <90 mL/min/1.73 m2 with UACR ≥200 mg/g. The primary outcome is a composite of ESKD, sustained reduction in eGFR to <10 mL/min/1.73 m2, kidney death or a sustained decline of ≥ 40% in eGFR from randomization. The secondary outcomes in this study include CV death, hospitalizations, and all-cause mortality [The EMPA-KIDNEY trial is an ongoing study with empagliflozin for patients with CKD for at least 3 months prior to screening, which was defined as an eGFR ≥20 to <45 mL/min/1.73 mortality .With the rapidly increasing utilities of SGLT2 inhibitors, there are numerous things to keep in mind. The increased rate of genital infection caused by SGLT2 inhibitors can be addressed by education on hygiene. Peri-area cleaning after urination and before sleeping can help decrease the risk of genital infections and UTIs. Patients should also be educated to seek help if they experience genital itching. Given the diuretic effect of SGLT2 inhibitors, a “sick day protocol” can be implemented where the medication is held while a patient is ill, especially if they are experiencing symptoms such as nausea, vomiting or diarrhea. If a patient is already on a diuretic, decreasing the dose of the diuretic can also be considered at the time of SGLT2 inhibitor initiation to decrease the chance of volume depletion. Although SGLT2 inhibitors do not cause hypoglycemia, they can lead to hypoglycemia when the patient is on another agent such as insulin or a sulfonylurea; therefore, decreasing the doses of insulin and/or sulfonylurea could be appropriate when adding SGLT2 inhibitors.Finally, given the increased risk of diabetic keto acidosis (DKA), these medications should be approached with caution in patients with a history of DKA. When the medication is started, patients should be educated for the early recognition of this process.Glucagon-like peptide-1 are incretin hormones secreted from L cells in the lower gut in response to food intake and an increase in plasma glucose. These incretin hormones facilitate insulin secretion from pancreatic ß islet cells, suppress glucagon secretion, delay gastric emptying, and induce a feeling of satiety ,33. In addition to the pancreas, GLP-1 receptors are found in a variety of organs, including but not limited to the lungs, stomach and kidneys ,35. GLP-1 has also shown to have numerous kidney protective effects, including the inhibition of the inflammatory effects of angiotensin II  and the The initial use of GLP-1 agonism was as a supplemental agent to assist with the control of T2DM, and it was often used as an adjunct to other agents. Its weight loss properties provided an additional benefit, but recent trials have further demonstrated cardiovascular and kidney benefits, making this medication a new potential option for earlier utilization in patients with DKD . The initial trials for GLP-1 agonists evaluated cardiovascular effects, with recent studies examining kidney protective effects. 2. The primary outcome in this trial was the cardiovascular outcome. Secondary microvascular events evaluating nephropathy was lower in the liraglutide arm . This trial also showed that the group with eGFR of 30–59 mL/min/m2 had an HR for the primary end-point of 0.67 (95% CI 0.54–0.83), whereas those with eGFR < 30 mL/min/m2 and eGFR ≥ 60 mL/min/m2 did not have a statistically significant difference in the primary end-point, when compared with the placebo [The LEADER trial was an early study investigating GLP-1 outcomes that provided insights into potential kidney benefits. This trial randomized patients with T2DM and high CV risk into receiving liraglutide or placebo. Roughly 75% of these patients had an eGFR > 60 mL/min/m placebo .2 or the need for dialysis, and was lower in the semaglutide group  [The SUSTAIN-6 trial compared semaglutide to placebo in patients with T2DM. The primary outcome in this study was CV death, non-fatal MI, or nonfatal stroke. One of the secondary outcomes—“new or worsening nephropathy”—included macroalbuminuria, persistent doubling of the serum creatinine, a creatinine clearance less than 45 mL/min/m46–0.88) .The first major randomized trial involving GLP-1 agonists that specifically evaluated patients with moderate-to-severe CKD was the AWARD-7 trial. A number of 3–4 CKD patients were randomized 1:1:1 to either receive dulaglutide at 0.75 mg weekly or 1.5 mg weekly, or to receive insulin glargine as basal therapy. Secondary outcomes included change in eGFR  equation by cystatin C and serum creatinine) and UACR. There was a significant decrease in the UACR with the high dose (1.5 mg) dulaglutide arm, when compared with the placebo. The trial also showed that the insulin arm experienced a statistically significant decrease in eGFR at 24 weeks, whereas the two dulaglutide arms kept eGFR similar to where it was at the start of the trial .2. Kidney disease was one of the secondary outcomes investigated in this trial, defined as the development of a UACR > 300 mg/g in those with lower baseline concentrations, sustained 30% or a greater decline in eGFR or chronic need for KRT. Those randomized to the placebo arm had 4.07 kidney incidents per 100 person-years, compared with 3.47 kidney incidents per 100 person-years for those receiving dulaglutide  [The REWIND trial was designed to assess high-risk cardiovascular patients with a broad range of glycemic control, with a weekly subcutaneous dose of dulaglutide versus placebo. The majority of these patients had an eGFR of >60 mL/min/m77–0.93) .A meta-analysis with a total of 56,004 participants from seven trials, including the LEADER , SUSTAIN2. The trial included a composite kidney outcome, which was defined as incident microalbuminuria with a UACR of >300 mg/g, >30% UACR at baseline, a decrease in eGFR > 40% for 30 days or more, KRT > 90 days, or eGFR < 15 mL/min/1.73 m2 for >30 days. The composite kidney outcome in this trial occurred in 13% of those receiving efpeglenatide, versus 18.4% of those receiving placebo  [The AMPLITUDE-O trial compared efpeglenatide to placebo in patients with a history of CV disease or CKD, defined as an eGFR of 25.0–59.9 mL/min/1.73 m57–0.79) .2, initiation of KRT or death from kidney disease and death from CV cause [The FLOW trial is an ongoing DKD outcomes trial with semaglutide, where the primary end-point is a persistent 50% or more reduction in eGFR, an eGFR of less than 15 mL/min/1.73 mCV cause . Given the frequency of gastrointestinal complications related to GLP-1 agonists such as nausea, vomiting and diarrhea, it is important to start these medications at lower doses and titrate slowly. The prescriber should also make sure patients being started on a GLP-1 agonist is aware of these effects as tolerabilities are being determined. Furthermore, it may be necessary to adjust other diabetic agents when a GLP-1 agonist is being initiated to avoid hypoglycemia. GLP-1 agonists should not be used in combination with dipeptidyl peptidase-4 (DDP-4) inhibitors. Mineralocorticoid receptor (MR) mechanisms of action exceed beyond their antagonism on the epithelial sodium channels (ENaC) in the collecting tubules. MR are expressed in numerous tissues including colonic, cardiac and vascular tissues . In addiThe earlier mineralocorticoid receptor antagonists that are still widely used are spironolactone and eplerenone. These steroidal MRAs were shown to protect from oxidative stress in animal models ,55 and, The introduction of non-steroidal MRAs, with the most notable being finerenone, came with great promise for potentially providing cardiac and proteinuric benefits, while having a less profound effect on inducing hyperkalemia. Finerenone has numerous properties differentiating it from the steroidal MRAs, including its tissue distribution and the mode in which it causes MR inactivation, as well as other pharmacodynamic properties .Finerenone is a welcome addition to our armamentarium, promising the same benefits of steroidal MRAs, but with less side effects. Numerous landmark trials have recently been published demonstrating the therapeutic potential of finerenone in DKD . The Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) paved the way for future studies into finerenone. This study was divided into two parts, where part A was performed to evaluate the safety, tolerability and kidney effects of the drug, while part B included patients with moderate CKD. The study showed that finerenone was at least as effective as spironolactone in decreasing biomarkers for hemodynamic stress, while inducing less hyperkalemia and a decrease in renal function . ARTS-DN2), >40% decrease from the baseline eGFR or death from kidney cause. The primary outcome was significantly lower in the finerenone group with an HR of 0.82 (95% CI 0.73–0.93). Hyperkalemia occurred in 11.8% of patients in the finerenone arm, compared with 4.8% of patients in the placebo arm [Building on the ARTS trials, the FIDELIO-DKD trial was a clinical outcomes study of finerenone compared to the placebo in patients with T2DM and CKD already treated with a maximal dose of ACE-I or ARB. The primary outcomes included kidney failure  [The FIGARO-DKD went beyond what was investigated in the earlier FIDELIO-DKD trial, evaluating patients with T2DM with a boarder range of CKD stages. Patients in this study were grouped into eGFR 25-90 mL/min/1.73m2 with UACR of 30–300 mg/g and an eGFR≥ 60 mL/min/1.73m76–1.01) .Hyperkalemia remains a side effect that a prescriber should be aware of when starting finerenone. Other common side effects include hypotension and hyponatremia. Endothelins comprise three structurally similar peptides involved in various vasoconstrictor pathways . The kidEndothelin receptor antagonism has been shown to improve kidney microcirculation , and theGiven this evidence of potential kidney benefit, trials have been conducted to assess the benefits of endothelin antagonists in the treatment of patients with DKD . The ASCEND trial randomized patients to receive either avosentan or placebo, and the primary outcome of the trial was a kidney composite which included the doubling of serum creatinine, ESKD, or death. The trial was terminated early due to safety concerns related to volume overload and congestive heart failure. Although there was a statistically significant reduction in the UACR in patients in the avosentan arm, there was no statistically significant difference in the kidney composite .2 and a UACR of 300–5000 mg/g on maximal tolerated RAAS blockade for 4 weeks were initially treated with atrasentan during the enrichment period. Patients who tolerated atrasentan without substantial volume retention were then randomized to receive atrasentan or placebo. The primary end-point was a kidney composite which included the doubling of serum creatinine for ≥ 30 days, or ESKD in the intent to treat population. The trial showed that the patients who tolerated the endothelin antagonist had improved kidney outcomes with HR of 0.65 (CI 95% 0.49–0.88). The trial did show higher amounts of fluid retention and anemia in the artesentan arm. Moreover, higher hospitalization for heart failure was seen in the atresentan arm (3.5% vs. 2.6% in the placebo arm), although the difference was not statistically significant [The SONAR trial was designed to evaluate whether endothelin antagonists could have a role in certain populations with DKD. In this trial, patients with T2DM, an eGFR of 25–75 mL/min/1.73 mnificant .Given the early termination of the ASCEND trial and the “enrichment period” performed in the SONAR trial, it is important to monitor for signs of volume overload should a patient be started on an endothelin agonist.In addition to GLP-1 agonists, there is early evidence suggesting DDP-4 inhibitors could provide benefit for patients with DKD. Trials such as SAVOR-TIMI 53  and CARMGiven the role various inflammatory pathways have been shown to play in the progression of DKD, pharmacologic intervention targeting these pathways have been areas of interest for potential treatment approaches. One promising pathway involves JAK1/JAK2 inhibition by baricitinib. This has been shown to decrease albuminuria; however, it remains unclear how it would affect the progression of DKD . Other pThe future of DKD management has the potential to include a more personalized approach, where each patient can have a tailored treatment regimen based on their genetic and biomarker profile . For years, RAAS inhibition with ACE-I and ARBs was the sole therapeutic option we could offer patients with DKD. These agents certainly remain the cornerstone for managing these patients, but we are now fortunate to be able to offer other agents which can complement the benefit of the RAAS blockade. SGLT2 inhibitors are taking the nephrology world by storm with unequivocal protective benefits that extend beyond DKD. GLP-1 agonists are now preferred oral agents for the managements of diabetes in CKD patients, according to the inaugural KDIGO guidelines . FinerenThese expanded therapeutic options have ushered in a new era of DKD management, enabling, cardiovascular, kidney, and survival benefits.


Liu et alStudy (CHIPS), which aimed to compare the reduction in diastolic blood pressure to tight control <85 mmHg and less‐tight control <100 mmHg, no difference according to SGA (defined as birth weight <10th percentile or <3rd percentile) was found.However, according to the current state of knowledge, the possibilities of preventing the negative effects of high blood pressure in pregnancy are limited. In the randomized Control of Hypertension in Pregnancy Regarding Liu's results, it is interesting how blood pressure lowering would affect LBW/SGA risk. Likewise, since the target blood pressure in pregnancy is unknown, it is extremely important to understand the relationship between achieved blood pressure and pregnancy outcomes. Unfortunately, no blood pressure values were reported.According to the position paper on the peripartum management of hypertension by the European Society of Cardiology Council on Hypertension and the European Society of Hypertension, these issues should be addressed to researchers in the field of hypertension in pregnancy as they represent significant gaps in knowledge.The author declares that there is no conflict of interest.Piotr Sobieraj contributed to the conception of the manuscript, drafting the review paper, and final approval of the version to be published.


Background and objectiveChronic kidney disease (CKD) comprises a spectrum of pathophysiologic processes with increased cardiovascular disease (CVD) risk mediated mostly by endothelial dysfunction other than traditional risk factors. The present study is carried out to see the cardiovascular risk in CKD patients with special reference to the determinants of endothelial dysfunction.Materials and methodsWe enrolled 60 CKD patients along with 120 healthy controls in the age group 18-50 years belonging to the same ethnicity and localities. Demographic and clinico-laboratory information including markers of endothelial dysfunction were recorded followed by univariate and multivariate analyses to assess the relationship between CKD and CVD risk.ResultsCases comprised of 60 CKD patients (mean age = 38.47±8.56 years) including 35 (58%) females and 25 (42%) males. Etiology in 43% of cases was idiopathically followed by diabetes and hypertension (42%) and obstructive uropathy (13%). On comparing the means of inflammatory markers between cases and controls, calcium phosphate product, c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil: lymphocyte (N:L) ratio was found to be significantly higher (p < 0.05) in cases as compared to controls but carotid intima-media thickness (CIMT) and low-density cholesterol (LDL) did not show a significant difference (p < 0.05).ConclusionOur study showed uniformly higher levels of inflammatory markers in cases irrespective of age and gender except for LDL and CIMT which uniquely showed a positive correlation with age. CKD patients require appropriate treatment and preventive measures for CVD with a high index of suspicion as endothelial dysfunction cannot be adequately gauged by traditional risk scoring methods. Chronic kidney disease (CKD) comprises a spectrum of pathophysiologic processes associated with abnormal kidney function and progressive decline in glomerular filtration rate (GFR). There is a rising incidence of chronic kidney disease that is likely to pose major problems for both healthcare and the economy in future years.Cardiovascular disease (CVD), the leading cause of death, is mostly precipitated by cardiometabolic risk and chronic kidney disease. Traditional risk factors cannot exclusively explain the high prevalence and incidence of cardiovascular disease in chronic kidney disease, therefore other non-traditional risk factors such as endothelial dysfunction, oxidative stress, and insulin resistance have increasingly been studied. The endothelium is the largest organ in the body strategically located between the wall of blood vessels and the bloodstream. Hypertension, inflammation, diabetes-associated factors such as advanced glycated end products, and uremic toxins are some of the prevalent risk factors of endothelial dysfunction in CKD -2. MoreoDue to immense difficulty in assessing the function of the endothelium directly, surrogate markers such as c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), etc are finding place as means to assess endothelial function indirectly albeit with variable specificity and sensitivity -4. NotabThe North Eastern Region (NER) of India has a high incidence and prevalence of chronic kidney disease. However, there is a relative paucity of studies of the incidence, prevalence, and etiological factors contributing to the burden of kidney disease in this region -10. HencStudy design and sample sizeA hospital-based analytical cross-sectional study was conducted, involving two groups of subjects, namely (i) a case group (consisting of CKD patients), and (ii) a control group  in a tertiary care teaching hospital at Shillong, Meghalaya in the northeastern region of India.The study was powered at 80% with a two-sided α = 0.05. The prevalence of endothelial dysfunction in the CKD was considered as 50% based upon previous data, and it was conservatively expected to detect an odds ratio (OR) of at least four. Based upon these assumptions, it was found that at least 50 cases and 100 controls would be needed for each group if the cases and controls were to be selected at a 1:2 ratio. These sample size calculations were performed using OpenEpi v3.0.1. Taking into consideration a non-response rate of 20%, the sample size was estimated to be 60 cases and 120 controls.Study participants and data collectionOn the basis of the above sample size estimations, 60 patients with CKD (diagnosed as per CKD-EPI criteria) in the age group of 18-50 years, were recruited prospectively for the case group from January 2017 to December 2017 from the medicine out-patient department (OPD). The exclusion criteria were patients with clinical suspicion or investigations showing acute or chronic infections such as urinary tract infection, lower respiratory tract infection, or tuberculosis, patients who have known chronic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, etc., patients below 18 years and above 50 years. For comparison, 120 healthy individuals  from similar socio-economic backgrounds and from the same ethnicity and geographical areas were enrolled in the control group for the study during the same period.Relevant demographic and clinical details were taken and entered as per a pre-tested proforma. Demographic data included name, age, sex, religion, occupation, and marital status. Detailed and relevant history was obtained along with clinical examination comprising of measurement of weight, height, blood pressure, general physical examination, systemic examination, etc. were carried out. GFR was calculated by the CKD-EPI formula. A case was said to have diabetes based on self-report or if diagnosed with diabetes during biochemical analysis. A case was said to have hypertension based on self-report or detection of blood pressure > 140/90 mmHg on two separate occasions. Blood was collected from the patients under sterile precautions and the following laboratory parameters were tested: complete hemogram including ESR, blood urea and serum creatinine, Liver function test, serum electrolytes, lipid profile, c-reactive protein. Blood and urine cultures were sent for all cases to rule out the presence of subclinical infections.Carotid intima medial thickness (IMT) was assessed by Doppler ultrasound of bilateral common carotid arteries. It was measured at three different sites on each side and the average of the three readings was taken. The normal carotid IMT is 0.74 ± 0.14 mm. Some literature also said that carotid IMT < 0.8 mm is associated with normal individuals, and a value ≥1 mm is associated with atherosclerosis. The collected data was entered in Microsoft Excel (Microsoft Corporation 2010).Statistical analysisThe data were analyzed using Statistical Package for the Social Sciences . Continuous data were presented as mean [with standard deviation (SD)] or median (with range) depending upon whether they were normally distributed or not. Subsequently, their comparisons among groups were performed by an unpaired t-test, the Mann-Whitney U test, one-sided analysis of variance (ANOVA), or the Kruskal-Wallis test, as appropriate. On the other hand, the categorical data were expressed as count (with percentage), and their comparisons were performed by Fisher’s exact test or the chi-square (χ2)-test, as appropriate. In all calculations, a two-tailed p-value < 0.05 was regarded as statistically significant.EthicsThe study complied with the tenets of the Helsinki Declaration and it was approved by the Institutional Ethics vide letter No. NEIGR/IEC/2017/20 dated 22/05/2017 and informed written consent was taken from all participants in the study. Voluntary informed written consent was procured from all the participants of the study.Our study included 60 patients with chronic kidney disease and compared it with 120 controls. Cases had a mean age of 38.47±8.56 years of which 35 (58%) were female and 25 (42%) were male. The majority of the cases of CKD included in the study were in stage 5 (76.67%) with only eight cases (13.33%) in Stage 4 and six cases (10%) in stage 3. In the majority of cases (43%) from the study, group etiology could not be found, whereas diabetes and hypertension were found in 42% of cases followed by obstructive uropathy in 13% of cases.Our study showed a significant disease burden especially in the younger population as 53% of the cases were below 40 years of age. The patients in the case group were comparable to subjects in the control group n = 120) with respect to age (p = 0.11) and sex (p = 0.375) composition  between cases and controls. The p-value for both is > 0.05 suggesting that they are not significantly different from each other. BMI, in turn, was found to be higher in the controls group with a significant difference Table .Following this multivariate analysis was carried out to assess the impact of age and gender on the study variables in addition to the presence or absence of chronic kidney disease. On multivariate analysis, it was found that the cases group had statistically significant higher values of ESR, CRP, N:L ratio, and calcium phosphate product as compared to controls with insignificant differences in terms of LDL and CIMT. Combined analysis with age group and sex did not yield similar significant results implying that the study variables depended mostly on the presence or absence of CKD. This implies that irrespective of age group and gender the aforementioned study variables have statistically significant higher values in the cases group as compared to controls Table .Our study had diabetes and hypertension as one of the most common causes of CKDs (41.67%). However, an almost equally large population presented with idiopathic CKD (43.3%), i.e on evaluation, the exact predisposing cause couldn’t be ascertained. This can be attributed to the lack of screening, late diagnosis or referral, and lack of health awareness in the community. Many of the cases had shrunken kidneys with advanced uremia at presentation not amenable for a renal biopsy. Also, the presentation of CKD in relatively younger patients as evidenced by 53% of cases being < 40 years should encourage the health care provider to evaluate in the lines of glomerulonephritis, interstitial nephritis, etc. which are common causes of CKD in the younger population. This is however another challenge in the resource-poor settings in the Northeastern states of India.Markers of inflammation and its determinantsAmong the cases, 75% (45) had a raised CRP level, and the mean CRP among the cases was 28.2+/-22.3 mg/L, which was significantly higher (p < 0.05) than the mean CRP in the control group (7.93+/-7.95 mg/L). The findings were confirmed via t-test as well as multivariate analysis which suggested CRP to be higher in the cases group irrespective of other study variables such as age and gender. Compared to several other studies conducted on the prevalence of CRP in CKD patients, our study showed both a higher prevalence as well as a higher mean CRP level -18.ESR, N:L ratio, calcium phosphate product which was the other surrogate markers of endothelial dysfunction included in our study showed significantly higher values in cases as compared to controls. 80% of the cases had an elevated ESR level. The findings correlated to other studies conducted on levels of ESR in CKD patients which have reported a 75% to 100% prevalence of raised ESR in CKD patients -22. NeutOn the other hand, CIMT showed no significant difference in the case and control groups p=0.783). However, on further analysis, CIMT showed a positive correlation with age irrespective of cases or controls. Though CIMT is a marker of cardiovascular risk it didn’t show the same relation as other markers. This can be explained by the lower mean age in our study population as CIMT is strongly dependent on age apart from other factors. LDL levels similarly showed no significant difference among our cases and controls p=0.867). This can again be explained by the fact that dyslipidemia in CKD is uniquely represented by increased triglycerides and lower high-density lipoprotein (HDL) unlike in the general population where LDL levels are independent markers of cardiovascular morbidity [7. This c3. HoweveLimitations of the studyThe study was conducted on a relatively small study population due to constraints of time. The presence of subclinical infections resulting in higher levels of inflammatory markers couldn’t be completely ruled out though every effort was taken to exclude cases with the slightest hint of the presence of any local or systemic infections at the time of the study.Chronic kidney disease is always a challenge to the treating physician. With the ever-increasing burden and younger population being diagnosed with the disease, the morbidity owing to it is increasing. Cardiovascular disease and risk assessment though being an established field are still evolving especially in the context of chronic inflammation and endothelial dysfunction contributing to the same. The search for the ideal biomarker to assess endothelial dysfunction is continuing and still has a long way to go. Until then a high index of suspicion is required in order to treat the cardiovascular complications of CKD as they may not show a correlation with age and traditional risk factors. In fact, in CKD patients, cardiovascular disease is one complication that can never be overdiagnosed. The need for further research is imperative to bring into light the causes of chronic kidney disease plaguing the region which can aid to prevent or delay progression to end-stage kidney disease and treatment of respective causes whenever possible.


Although Brazil has one of the largest populations on haemodialysis (HD) in the world, data regarding patients’ characteristics and the variables associated with risk of death are scanty.This is a retrospective analysis of all adult patients who initiated on maintenance HD at 23 dialysis centres in Brazil between 2012 and 2017. Patients were censored after 60 months of follow-up or at the end of 2019.P<0.0001), starting dialysis in the hospital (P=0.016), having diabetes as the cause of kidney failure (P=0.001), high alkaline phosphatase (P=0.005), CVC as first vascular access (P=0.023), and FO (P<0.0001) were associated with higher death risk, whereas higher body mass index (P=0.015), haemoglobin (P=0.004), transferrin saturation (P=0.002), and serum albumin (P<0.0001) were associated with better survival. The same variables, except initial CVC use (P=0.14), were associated with death risk in an analysis of subdistribution proportional hazards ratio including the competing outcomes.A total of 5,081 patients were included in the analysis. The median age was 59 years, 59.4% were men, 37.5% had diabetes as the cause of kidney failure. Almost 70% had a central venous catheter (CVC) as the initial vascular access, about 60% started dialysis in the hospital, and fluid overload (FO) by bioimpedance assessment was seen in 45% of patients. The 60-month survival rate was 51.4%. In the Cox regression analysis, being older (The present study gives an overview of a large HD population in a developing country and identifies the main predictors of mortality, including some potentially modifiable ones, such as unplanned initiation of dialysis in the hospital and fluid overload.The online version contains supplementary material available at 10.1186/s12882-022-02705-x. The prevalence of kidney failure is increasing worldwide. Haemodialysis (HD) is the most common treatment method for this population. Brazil has one of the largest populations on HD in the world, and the number of patients has increased from nearly 87,000 to 133,000 over the last 10 years [The life expectancy of patients undergoing HD remains dramatically shorter than in the general population, although a trend for improvement in the survival over the years has been recently documented in the USRDS  and the Several factors have been associated with mortality of HD patients, including older age, presence of diabetes and cardiovascular disease, and some potentially modifiable factors such as the presence of a central venous catheter, hypervolemia, and anaemia , 6. MoreThis is a retrospective analysis of all incident HD patients from July 01, 2012 to June 30, 2017 in 23 Fresenius Medical Care dialysis centres in Brazil. The dialysis centres were distributed among 6 out of 27 states of Brazil . All data were extracted from the European Clinical Dialysis Database (EuCliD®), a standardized electronic database used by the participating centres.Patients under 18 years of age and those who underwent peritoneal dialysis or kidney transplantation before starting HD were excluded. Demographic, clinical and laboratory data on the admission to the clinic were used to define the baseline characteristics of the patients. At the onset of the maintenance haemodialysis, the patients had the body composition analysed by bioimpedance spectroscopy (BIS) - BCM®, Fresenius Medical Care. They were classified as fluid overloaded if pre-dialysis excessive extracellular volume was higher than 13% for women and 15% for men [Data were censored at 60 months of follow-up or on December 31, 2019. Data were also censored in cases of transfer to another dialysis centre, kidney transplant, migrating to peritoneal dialysis, recovery of renal function or abandonment of therapy. The primary outcome was all-cause mortality. This study was performed in accordance with the Declaration of Helsinki and was approved by the local ethics committee under the number CAAE 76623317.1.0000.5243. No written informed consent was requested due to the retrospective nature of the study.p-values lower than 0.10 in the univariate assessment were included in the multivariate analysis. Additionally, similar analyses were done with adjustment for competing outcomes  using the subdistribution proportional hazards model described by Fine and Gray [P-values < 0.05 were considered statistically significant. All analyses were performed using SPSS version 18.0 for Windows , except the subdistribution hazard ratio analysis by the Fine-Gray method, which was performed using the freely available software R version 4.0.2.Kolmogorov-Smirnov test was used to test for the distribution of variables. Continuous variables with normal distribution were expressed as mean ± standard deviation or as median and interquartile range otherwise. Categorical variables were presented as frequencies. Comparisons between means were made using the unpaired t test or Mann-Whitney test and comparisons between frequencies were made using the chi-square test. The survival rate was calculated by Kaplan-Meier method and curves were compared by the Log-Rank test. The hazard ratios for death were estimated by Cox proportional hazards regression. Initially, univariate analysis was performed for each variable of interest and, subsequently, only those variables that showed and Gray . P-valueA total of 5,081 incident patients on HD in the period were included in this analysis. The baseline characteristics of the patients are in Table By the end of the 60-month period, 33.3% of the patients followed had died, 24.0% remained on HD, 21.6% were transferred to other dialysis units, 10.6% had received a kidney transplant, 5.0% had migrated to peritoneal dialysis, 4.7% recovered from renal failure, and 0.8% had their follow-up lost, as shown in Fig. p < 0.0001), Fig. p < 0.0001), Fig. The survival rates for all patients at 3, 12, 24, 36, 48 and 60 months of follow-up were 93.0, 82.6, 73.5, 65.1, 57.7 and 51.4%, respectively , higher haemoglobin, transferrin saturation (TSAT), serum albumin, blood urea nitrogen (BUN), phosphorus, intact parathyroid hormone (iPTH), diastolic blood pressure and lean mass in BIS assessment were associated with reduction in the death risk. After adjustment, including in the model only variables with ad Table .Table 2Cp = 0.067) were included in the adjusted subdistribution proportional hazards model. Again, the variables associated with death risk were the same found in the Cox regression model, except having catheter as initial vascular access (p = 0.14), Table In the univariate analysis of subdistribution hazard ratio (sHR) by the Fine-Gray model, including kidney transplantation, migration to peritoneal dialysis and kidney function recovery as competing outcomes, the variables associated with death risk were the same found in the unadjusted Cox regression analysis. All those variables plus corrected calcium  patients . HoweverPatients with a higher BMI were shown to have a lower risk of death, confirming a well-known association seen in previous studies. This would happen because in the haemodialysis population, with an unacceptably high mortality rate, the benefits of the obesity-related nutritional reserve would probably outweigh the cardiovascular risks associated with the metabolic disorders, having such phenomenon been called the “obesity paradox” . InteresThe presence of FO in a single assessment on admission was the variable that was found to have the strongest association with the risk of death, even in such a long follow-up period. However, it is questionable whether FO would be directly associated with the cause of death or would be just a marker of other clinical conditions with poor prognosis, such as heart failure, lower residual urinary volume or hypoalbuminemia, contributing to the extracellular volume expansion. Even if such clinical conditions are behind FO, the way the patients are treated forward and how FO is corrected will probably impact the outcomes. Indeed, the long-term exposition to excessive extracellular volume is a much stronger predictor of death risk than the presence of FO at admission on HD, as shown by Zoccali et al . We demoOur study has several limitations. The first is the retrospective nature of the analysis. Second, the lack of BIS assessment on about a quarter of patients. This was because the random lack of registration of BIS evaluation in the electronic database in some clinics, especially in the first years, and also due to a significant number of patients who indeed did not undergo BIS assessment, especially those who were readmitted or died early. Another limitation would be some lack of representativeness of the patients in this study compared to the haemodialysis population in Brazil as a whole. Almost half of the patients in this study were from facilities located in the state of Rio de Janeiro, where only about 10% of the Brazilian population lives, and 42% of them had their treatment funded by the private healthcare system, while the average in Brazil is about 20% [This study gives an overview of a large CKD population incident on maintenance haemodialysis in a developing country and provides information on factors, several of them potentially modifiable, such as unplanned initiation of dialysis in the hospital and fluid overload, which were found to be associated with the risk of death over a 5-year period.Additional file 1.


Orthostatic hypotension (OH) often co-exists with hypertension. As increasing age affects baroreflex sensitivity, it loses its ability to reduce blood pressure when lying down. Therefore, supine hypertension may be an important indicator of baroreflex function. This study examines (i) the association between OH and future falls in community-dwelling older adults and (ii) if these associations persist in those with co-existing OH and baseline hypertension, measured supine and seated. Data from 1500 community-dwelling adults aged ≥65 years from The Irish Longitudinal Study on Ageing (TILDA) were used. Continuous beat-to-beat blood pressure was measured using digital photoplethysmography during an active stand procedure with OH defined as a drop in systolic blood pressure (SBP) ≥20 mmHg and/or ≥10 mm Hg in diastolic blood pressure (DBP) within 3 minutes of standing. OH at 40 seconds (OH40) was used as a marker of impaired early stabilisation and OH sustained over the second minute (sustained OH) was used to indicate a more persistent deficit, similar to traditional OH definitions. Seated and supine hypertension were defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg. Modified Poisson models were used to estimate relative risk of falls  and syncope occurring over four year follow-up. OH40 was independently associated with recurrent , injurious  and unexplained falls . Sustained OH was associated with injurious  and unexplained falls . OH and co-existing hypertension was associated with all falls outcomes but effect sizes were consistently larger with seated versus supine hypertension. OH, particularly when co-existing with hypertension, was independently associated with increased risk of future falls. Stronger effect sizes were observed with seated versus supine hypertension. This supports previous findings and highlights the importance of assessing orthostatic blood pressure behaviour in older adults at risk of falls and with hypertension. Observed associations may reflect underlying comorbidities, reduced cerebral perfusion or presence of white matter hyperintensities. In healthy adults, blood pressure can be maintained within the normal range throughout a range of positions. If the cardiovascular system and neural reflexes are unable to maintain blood pressure on standing from a seated or supine position, the resulting abnormal drop in blood pressure is called orthostatic hypotension (OH). The consensus definition for OH is a sustained drop in blood pressure of ≥20 mmHg in systolic blood pressure (SBP) or ≥10 mm Hg in diastolic blood pressure (DBP) within 3 minutes of standing up [Not surprisingly, OH is common in older adults, but the prevalence varies widely depending on the population and setting examined. Prevalence in community-dwelling older adults has been reported at 6%  while 18Previously, Finucane et al  reportedResearch has also shown significant heterogeneity in fall risk factors even in older adults, therefore it is important to understand how risk factors may interact or co-exist with each other. One of the most common comorbidities associated with OH is hypertension , 14. ThiTherefore, the aims of this study are firstly, to examine the association between OH and future occurrence of recurrent, injurious and unexplained falls and syncope over four year follow-up in community-dwelling adults aged 65 years and older and secondly, to examine these associations in those with co-existing OH and baseline hypertension, measured in both supine and seated positions.The Irish Longitudinal Study on Ageing (TILDA) is a prospective cohort study examining the social, economic and health circumstances of community-dwelling adults aged 50 years and older in Ireland. Details of study design and data collection have been described elsewhere . BrieflyBaseline (Wave 1) data from 8,174 participants aged ≥50 years were collected from October 2009 to July 2011; follow-up data were obtained at Wave 2 (February 2012 to March 2013) and Wave 3 (January 2014 to December 2015). Data collection involved three components, (i) a computer-assisted personal interview (CAPI) that included detailed questions on socio-demographics, wealth, health, lifestyle, social support and participation, use of health and social care and attitudes to ageing, conducted by trained social interviewers in the participant’s home, (ii) a self-completion questionnaire (SCQ) completed by participants and returned to the study centre, and (iii) a comprehensive health assessment carried out by research nurses in a dedicated health assessment centre or a modified version carried out in the participant’s home. All three components were included at baseline assessment with follow-up data obtained from the CAPI at Waves 2 and 3.Inclusion criteria for this analysis was age ≥65 years; Mini-Mental State Examination (MMSE) score ≥18 and no self-reported doctor diagnosis of Parkinson’s disease or cognitive impairment at all wave; availability of valid orthostatic stand data at the baseline health assessment; and available data on falls outcomes obtained from a self or proxy interview at either Wave 2 and/or 3.A number of dichotomous falls variables were derived from data obtained at follow-up (Wave 2 and/or Wave 3). Recurrent falls were defined as two or more falls occurring in the past year or since the last interview. Injurious falls were those in which a participant reported that they had injured themselves seriously enough to require medical attention. Unexplained falls were those in which a participant could not identify the reason for the fall. Syncope was defined as a faint or blackout occuring in the past year or since the last interview.Average seated blood pressure was measured using an Omron blood pressure monitor (two readings 1 minute apart). Hypertension was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg . Non-invSocio-demographic variables such as age, sex, education  and living status  were obtained. Participants self-reported the following doctor-diagnosed cardiovascular conditions  and non-cardiovascular conditions . Participants were also asked if they had ever had a hip or wrist fracture. Participants reported all medications taken regularly and the following medications were identified using Anatomical Therapeutic Chemical (ATC) Classification codes: alpha blockers , beta blockers (ATC code: C07), calcium channel blockers (ATC code: C08), diuretics (ATC code: C03), angiotensin-converting enzyme (ACE) inhibitors (ATC code: C09) and antidepressants (ATC codes: NO6A). Participants reported a history of falls in the past year . Depressive symptoms were assessed using the 20-item Centre for Epidemiological Studies Depression (CES-D) scale .®, Fabrication Enterprises, Inc., White Plains, NY). Gait speed was measured with a computerised walkway (active area 4.88 m) with embedded pressure sensors . Participants walked for 2.5 m before and 2 m after the mat to allow for acceleration and deceleration. The mean of two trials was calculated. Global cognition was assessed using the MMSE [During the health assessment, height and weight were measured using a 240 wall-mounted measuring rod and electronic floor scales respectively , allowing body mass index (BMI) to be calculated. Mean grip strength was obtained from two trials on each hand using a hydraulic hand dynamometer  or syncope occurring over approximately four years follow-up. For each outcome, Model 1 included a limited number of socio-demographic covariates , the number of follow-up waves available (1 or 2) and follow-up time. Model 2 included the variables included in Model 1 plus angina, heart attack, diabetes, stroke or transient ischaemic attack (TIA), heart murmur, irregular heart rhythm, cataracts, glaucoma, age-related macular degeneration, cancer, arthritis, MOCA, CES-D, postural dizziness, baseline SBP and heart rate, gait speed, grip strength, BMI, alpha blockers, beta blockers, calcium channel blockers, diuretics, ACE inhibitors and antidepressants. The analysis was then repeated after stratifying by presence or absence of (i) supine hypertension and (ii) seated hypertension. The main analysis did not adjust for falls history as, while this is a strong risk factor for future falls, it was considered non-causative and possibly related to pre-existing OH or other included risk factors prior to baseline. A sensitivity analysis additionally adjusting for history of falls at baseline and history of hip or wrist fracture is included as a supplement. In addition, correlations were obtained to examine the relationship between SBP and DBP in both seated and supine positions and also between supine blood pressure and blood pressure deficits at 40 seconds and 120 seconds after standing. The number of participants with hypertension was calculated and compared when using supine and seated blood pressure. Statistical analysis was conducted using Stata v14.1 .After exclusion criteria were applied, there were 1500 eligible participants for this analysis . Correlations were even lower for seated blood pressure and deficits in SBP and DBP at 40 seconds and 120 seconds .When the regression analysis was repeated to examine the effect of the presence or absence of hypertension, there were observed associations of at least borderline statistical significance between OH40 and co-existing seated and supine hypertension for all falls outcomes . There wSensitivity analyses showed that adjusting for history of falls and fractures mildly reduced the strength of the OH and falls relationships . EffectsIn this analysis, we found that OH at baseline (OH40 and sustained OH) was independently associated with an increased risk of future recurrent, injurious and unexplained falls in community-dwelling adults aged 65 years and older. OH40 co-existing with hypertension, measured both seated and supine, was associated with increased risk of all outcomes, however stronger effect sizes were observed with seated versus supine hypertension. There were also associations observed between OH40 with co-existing normotension and injurious and unexplained falls. As we controlled for antihypertensives, it is possible that these normotensives have controlled hypertension but may still have other pre-existing risk factors for hypertension such as higher age, smoking and kidney disease, all of which have also been associated with OH in a recent SPRINT trial . This maIn a systematic review and meta-analysis, Mol et al  concludeOH may be directly linked to falls due to reduced cerebral perfusion and a subsequent reduction in oxygenation in the brain within seconds of standing up from a lying or seated position . OH has The clinical syndrome of supine hypertension and OH is well recognised and often challenging to treat clinically . In thisThe clearer stratification of OH effects with seated BP in this analysis may also be due to more accurate resting measurements from oscillometric compared to finometer blood pressure, the 140/90 mmHg cut-point being more suitable for seated blood pressure or from the greater contribution of the higher seated diastolic measurements to the hypertension category. While 140/90 mm Hg was used in this study, there is no formal definition for supine hypertension. Krzesinski et al  reportedLevels of antihypertensive use were similar in participants with and without hypertension, in line with an earlier analysis showing 50% treatment efficacy in the TILDA population  and corrThe American Geriatrics Society/British Geriatrics Society guidelines  for fallThe current results also support evaluating OH in older adults with hypertension, especially if their BP is poorly controlled. There is sometimes reluctance clinically to aggressively treat hypertension in older adults for fear of increasing the risk of OH, falls and syncope, however recent evidence suggests that intensive treatment of hypertension is beneficial, with studies reporting a decreased prevalence of OH  and incrStrengths of this study include the large, nationally representative sample of community-dwelling older adults, the ability to detect OH using beat-to-beat blood pressure monitoring which has been suggested to have the largest clinical relevance  and the Fall diaries with regular follow-up was not feasible in this study, therefore one limitation is the use of self-reported falls in the past year/since the last interview. Yearly recall of falls has been found to have a sensitivity of 91–95% and a specificity of 80–89% and while it is subject to recall bias, recurrent falls  and injurious falls should be less susceptible to this . In addiIn conclusion, OH, particularly when co-existing with hypertension, was independently associated with an increased risk of future falls, but not syncope, in community-dwelling adults aged 65 years and older. Stronger effect sizes were observed when hypertension was measured seated although effects were also observed with supine hypertension. There were also associations observed between OH40 and unexplained falls and between sustained OH and injurious falls in normotensives. The current analysis provides further support to highlight the importance of including a structured cardiovascular assessment within a multifactorial fall prevention assessment to reduce the risk of adverse outcomes associated with falls such as injury, fracture, reduced independence, premature nursing home admission and death .S1 Table(DOCX)Click here for additional data file.S2 TableHTN-, not classified as having hypertension; HTN+, classified as having hypertension; OH40, orthostatic hypotension at 40 seconds. Adjusted for age, sex, education, living alone or with others, follow-up time, number of follow-up waves available, angina, heart attack, diabetes, stroke or TIA, heart murmur, irregular heart rhythm, cataracts, glaucoma, age-related macular degeneration, cancer, arthritis, MOCA, CES-D, postural dizziness, baseline systolic blood pressure and heart rate, gait speed, grip strength, BMI, alpha blockers, beta blockers, calcium channel blockers, diuretics, ACE inhibitors, antidepressants, history of falls in last year, history of adult hip or wrist fracture. *p<0.05, **p<0.01, ***p<0.001.(DOCX)Click here for additional data file.


Pharmacological blood pressure (BP) intervention for high blood pressure is controversial for a wide spectrum of hypertensive crisis in the emergency department (ED). We evaluated whether medical control of BP altered the short- and long-term outcomes among patients with hypertensive crisis who were discharged from the ED under universal health care. This retrospective cohort comprised 22 906 adults discharged from the ED of a tertiary hospital with initial systolic BP ≥ 180 mmHg or diastolic BP ≥ 120 mmHg between 2010 and 2016. The main exposure was the use of antihypertensive medication during the ED stay. Clinical endpoints were revisits to the ED or inpatient admission , cardiovascular mortality , and incident stroke . The associations between pharmacological intervention for BP and outcomes were evaluated using multivariable Cox proportional-hazards models. Of the patient data analyzed, 72.2% were not treated pharmacologically and 68.4% underwent evaluation of end-organ damage. Pharmacological intervention for BP was significantly associated with a 11% and 11% reduced risk of hospital revisits within 30 or 60 days of discharge from ED, respectively, particularly among patients with polypharmacy. No association between pharmacological intervention for BP and incident stroke and cardiovascular mortality was observed. A revision of diagnostic criteria for hypertensive crisis is essential. Although pharmacological intervention for BP may not alter the long-term risk of cardiovascular mortality, it significantly reduces short-term health care utilization. Hypertensive crisis (HTN-C), defined as systolic blood pressure (SBP) ≥ 180 mmHg or diastolic blood pressure (DBP) ≥ 120 mmHg, may lead to progressive end-organ damage and even devastating clinical consequences such as stroke, myocardial infarction, and renal failure . In TaiwFor patients with hypertensive crisis, urgent reduction in BP is typically not required, except among patients with HTN-E ,6. The pThis retrospective cohort study used the Clinical Research Data Repository (CRDR), which consolidates 14-year electronic medical records (EMRs) from China Medical University Hospital (CMUH). An average monthly volume of more than 12,000 patients has presented to the ED at CMUH since 2010  and it is estimated that 1-2% of patients with hypertension may develop HTN-C [5]. Therefore, the management of hypertensive crisis and its associated complications are crucial in Taiwan.2. The manuscript has not discussed the proportion of hypertensive urgency and hypertensive emergencies in results separately.Response: Thank you. We could not obtained the real proportion of hypertensive urgency and hypertensive emergencies in this retrospective data, because not all patients were checked the end-organ damage. Moreover, due to the selection procedure used may lead to misclassification the hypertensive urgency and hypertensive emergencies, the aim of this study was explored the association between antihypertensive agents used and short- and long-term clinical outcomes among hypertensive crises rather than hypertensive urgency and hypertensive emergencies which reflecting the real-world setting. 3. Examination of end organ damage in addition to the mentioned diagnosis, acute pulmonary edema, and dissecting aneurysm should also be considered.Response: Thank you. We have added these two criteria in the revision text.Revised content:Pages 5-6, lines 112-115: Examinations for suspected end-organ damage were defined as requesting a serum creatinine exam, troponin I exam, intravenous diuretic therapy, brain CT, or aortic dissection during the index ED visits, regardless of the exam results.4. Table 02 at page no. 12 results should be expressed in percentages.Few sentences from the following relevant articles can be added in Introduction or Discussion part for the improvement of the paper. Though these papers are giving information on management of hypertension in hemodialysis patients but still it can be related with control of BP in general population:https://link.springer.com/article/10.1186/s40545-019-0169-yhttps://link.springer.com/article/10.1007/s11845-018-1813-2https://link.springer.com/article/10.1007/s40267-020-00763-5Response: Thank you for this suggestion that improve the quality of this paper. We have added the information on management of hypertension, particularly for patients with special health status. We humbly request to keep the original results of Table 2 due to the hazard ratios could be simply converted to percentages. Please further contact us if you have any concern regarding our response. Thank you! Revised content:Page 16, lines 280-281: Patients with special health status  may influence the effectiveness of antihypertensive drugs in the management of hypertension [22-24].Reviewer #2: Thank you for providing opportunity to review the draft. This is a good study and addressed important issue in ED. However, this study has few shortcomings which should be addressed before considering the draft for further processing.Response: We gratefully thank the reviewer for his/her thoughtful comments and suggestions. Please see below for our response to all comments and questions.1. Since substantial proportion of data is missing in the analysis, authors need to explain its impact on analysis in study limitations.Response: Thank you for this comment. We have added this limitation in the Discussion. Missing data may result the unpredictable bias in statistical findings. To address this problem, we performed multiple imputation by using an iterative Markov chain Monte Carlo procedure with 20 imputations and 100 iterations to replace the missing values with imputed values. The results remained robust (Table R1).Revised content:Page 17, lines 303-305: Fourth, the missing data may result in unpredictable bias in our findings. However, we performed an iterative Markov chain Monte Carlo procedure with 20 imputations and 100 iterations to replace the missing values with imputed values and the results remained robust (S10 Table).Table R1. Hazard ratios (HRs) with 95% confidence interval for ED revisit or inpatient admission, incident stroke, and cardiovascular mortality according to the exposure of pharmacological BP control in the ED setting. BP, blood pressure; ED, emergency department.Pharmacologically blood pressure reduction Model 3a Model 3Multiple imputations Adjusted HR(95% CI) Adjusted HR(95% CI)ED revisit or inpatient service7-day 　 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.94 (0.84 - 1.06) 0.96 (0.86 - 1.08)30-day 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.89 (0.82 - 0.97) 0.92 (0.84 - 1.00)60-day 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.89 (0.82 - 0.96) 0.92 (0.85 - 0.99)Cardiovascular mortality1-year 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.97 (0.67 - 1.41) 1.04 (0.74 - 1.47)3-year 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.95 (0.75 - 1.19) 0.93 (0.75 - 1.16)5-year 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.89 (0.74 - 1.08) 0.93 (0.78 - 1.11)Incident stroke1-year 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.84 (0.59 - 1.19) 0.92 (0.66 - 1.28)3-year 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.84 (0.66 - 1.08) 0.93 (0.74 - 1.16)5-year 　No 1.00 (Ref) 1.00 (Ref)　Yes 0.81 (0.65 - 1.01) 0.86 (0.7 - 1.04)aModel 3: Adjusted for age at ED admission, gender, diabetes, hypertension, cardiovascular disease, chronic kidney disease, random slope of systolic blood pressure, maximum systolic blood pressure, baseline estimated glomerular ﬁltration rate, anti-platelet agents, polypharmacy. 2. Authors should explain the graph and predictive model analysis in details.Response: Thank you. We have added more details of the graph and predictive model analysis in the revised manuscript as follows:Revised content:Pages 6-7, lines 140-144: We also provided the visualization information of subgroup analysis to show the association between pharmacological intervention for BP among patients with HTN-C stratified by subgroup and the effect modification. We performed sensitivity analyses including patients with (1) medication histories prescribed by other hospitals and (2) persistent high blood pressure above HTN-C criteria after the 4-hour ED stay.Page 11, lines 193-198: The HRs between pharmacological intervention for BP and 30-day and 60-day hospital revisits ranged from 0.81-0.83 for patients with polypharmacy and 0.93-0.95 for patients with no polypharmacy . The HRs between pharmacological intervention for BP and 30-day and 60-day hospital revisits ranged from 0.92-0.93 for patients who underwent any investigation for end-organ damage and 0.77-0.81 for patients who were not investigated for end-organ damage .Page 11, lines 203-205: However, there remains no association between incident stroke and pharmacological BP control while considering patients with medication histories prescribed by other hospitals (S6 and S7 Tables).3. Results may be confounded by lifestyle, compliance, dietary habits, use of alternative medicines and patient`s adherence to recommendations. How authors will nullify the impact of these confounders from the analysis?Response: Thank you for this important comment. Due to the present study is a retrospective-based data, we could not obtain unmeasured confounder. Therefore, we applied E-value to address this problem [1]. The E-value is an alternative method to sensitivity analyses for unmeasured confounding factors in observational studies. If the strength of unmeasured confounding is weaker than indicated by the E-value, then the study result could not be overturned to one of the unmeasured confounder. The E-values ranged from 1.21-1.77 for the present study endpoints (Table R2). We added this information in the Discussion section as follows:Revised content:Page 17, lines 299-303: To nullify the impact of unmeasured potential confounders, we conducted E-value analysis [27] and the E-values ranged from 1.21-1.77 for the present study endpoints (S9 Table). It should be noted that if the strength of the potential unmeasured confounder is greater than the E-value, our findings could be affected by an unmeasured confounder.Table R2. E-value for point estimate and confidence interval for ED revisit or inpatient admission, incident stroke, and cardiovascular mortality according to the exposure of pharmacological BP control in the ED setting. BP, blood pressure; ED, emergency department.Pharmacologically blood pressure reduction E-value for point estimate E-value for confidence intervalED revisit or inpatient service 7-day 1.32 130-day 1.39 1.1760-day 1.39 1.2Cardiovascular mortality 1-year 1.21 13-year 1.29 15-year 1.5 1Incident stroke 1-year 1.67 13-year 1.67 15-year 1.77 1Reference1. Haneuse S, VanderWeele TJ, Arterburn D. Using the E-Value to Assess the Potential Effect of Unmeasured Confounding in Observational Studies. Jama. 2019;321(6):602-3. Epub 2019/01/25. doi: 10.1001/jama.2018.21554. PubMed PMID: 30676631.4. I will suggest to improve the writing of manuscript. Though manuscript lack serious syntax errors but has less essence of scientific writing.Response: We thank the reviewer for the thoughtful comment on the writing of the manuscript. We have thoroughly revised and edited the sentence structures throughout the manuscript to improve flow and coherence. We have removed all language that is deemed colloquial to strengthen the manuscript.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 26 Apr 2021Pharmacological blood pressure control and outcomes in patients with hypertensive crisis discharged from the emergency departmentPONE-D-21-00759R1Dear Dr. Kuo,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Amjad Khan, Ph.D.Academic EditorPLOS ONEAdditional Editor Comments :All the queries and suggestions raised by the reviewers have been addressed and incorporated by the authors.Reviewers' comments: 9 Aug 2021PONE-D-21-00759R1 Pharmacological blood pressure control and outcomes in patients with hypertensive crisis discharged from the emergency department Dear Dr. Kuo:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. 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