To evaluate (i) the prevalence and association of euthyroid sick syndrome (ESS) [decreased FT3 and/or FT4 and normal/decreased TSH] with severity indexes of type 1 diabetes mellitus (T1DM) onset such as diabetic ketoacidosis (DKA) and kidney damage , (ii) relationship between clinical/metabolic parameters at T1DM onset and thyroid hormones, and (iii) ESS as a prognostic indicator of delayed recovery from kidney damage.A total of 161 children with T1DM onset were included. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin (NGAL) and/or tubular reabsorption of phosphate <85% and/or fractional excretion of Na>2%. ATN was defined by RTD+AKI.Of 161 participants, 60 (37.3%) presented ESS. It was more prevalent in case of more severe T1DM presentation both in terms of metabolic derangement (DKA) and kidney function impairment . Only ATN, however, was associated with ESS at adjusted analysis. FT3 inversely correlated with serum triglycerides and creatinine, and urinary calcium/creatinine ratio and NGAL. Participants with euthyroidism showed earlier recovery from AKI than those with ESS. ESS spontaneously disappeared.ESS is associated with T1DM onset severity and spontaneously disappears. ESS delayed the recovery from AKI.This is the first longitudinal study describing in detail the relationship between clinical/metabolic factors at type 1 diabetes mellitus (T1DM) onset and thyroid hormones, with particular attention to the relationship between diabetic ketoacidosis (DKA)-related kidney function impairment and euthyroid sick syndrome (ESS).Participants with more severe T1DM onset presentation both in terms of metabolic derangement and kidney function impairment had an increased prevalence of ESS.Children with ESS had a slower recovery from acute kidney injury compared with those without ESS.ESS spontaneously disappeared in all participants. ATD is characterized by damage to the cells of the renal tubules which determines the loss of solutes in the urines. AKI occurs as a consequence of the ATD by vasoconstriction of the afferent arterioles which determines a fall in the glomerular filtration rate in order to reduce the solutes loss in the urine. This mechanism, however, could lead to persisting renal ischemia that shifts the AKI from functional to intrinsic, so determining acute tubular necrosis (ATN), expression of very severe kidney damage.11 and that the probability of developing ESS increases with the increase of acidosis. Moreover, an inverse relationship between acidosis and concentrations of free thyroid hormones has been found.11 Unlikely, no follow-up data of these patients are available.In retrospective studies, it has been shown that children with DKA can manifest ESS in about 57% of cases6 we aimed to evaluate (i) the prevalence and association of ESS with severity indexes of T1DM onset such as DKA and kidney damage , (ii) the relationship between clinical/metabolic parameters at T1DM onset and thyroid hormones, and (iii) the role of ESS as a prognostic indicator of delayed recovery from kidney damage.We hypothesized that the prevalence of ESS increases with the increase of the severity of the T1DM presentation and that an association between ESS and impaired kidney function at T1DM onset could exist. Taking advantage of perspective data collection of the DiAKIdney (T1DM and AKI) cohort6 The study was approved by Research Ethical Committee of Università degli Studi della Campania “Luigi Vanvitelli”  and all parents provided written informed consent. As previously described, participants with the onset of T1DM with age <18 years and not on any medication apart intravenous 0.9% NaCl infusion were enrolled. Participants assuming any medication for any chronic condition before the T1DM onset or not returning for the scheduled follow-up or with congenital anomalies of the kidney and urinary tract were excluded.6The DiAKIdney cohort was consecutively enrolled between December 2017 and August 2019.All the participants had T1DM autoimmune diabetes with glutamic acid decarboxylase and/or islet antigen two and/or insulin and/or Zinc transporter eight antibodies positive at the time of diagnosis. All the participants needed to be on insulin consistently following diagnosis.6After discharge, all the participants were followed up after 14 days. The participants not having shown recovery from AKI or RTD at this time returned again after 30 days and—in case of persistence of damage—after 60 days.6 ketones, Na, Cl, phosphorus, blood pH, bicarbonates, glycate hemoglobin (Hb1Ac) and a urine sample for urine dipstick, urinary proteins, microalbuminuria, creatinine, sodium, calcium, phosphate, beta-2-microglobulin as well as neutrophil gelatinase-associated lipocalin (NGAL) both at T1DM onset and at follow-up visits were collected.6Data regarding age, weight, height, body mass index (BMI) with its standard deviation score (SDS), blood pressure (BP), heart rate (HR), urinary output for the first 24 h, renal ultrasound, full blood count, baseline blood glucose concentration, serum creatinine (measured by the Jaffe method),In addition to these data, in this manuscript, we used also prospectively collected data about thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) concentrations at T1DM onset. In all the participants also antithyroglobulin and anti-thyroid peroxidase antibodies were dosed. The thyroid hormones were dosed again after 6–12 months.The original DiAKIdney cohort comprehended 185 participants. Among these participants, 1 was excluded because presenting with autoimmune thyroiditis and overt severe hypothyroidism and 23 because data about thyroid hormones at T1DM onset were not available.11 ESS was defined when FT3 and/or FT4 were decreased and TSH concentrations were normal or decreased.11Euthyroidism was defined when FT3, FT4 and TSH were respectively within the following ranges: FT3 2.3–5.5 pg/mL, FT4 9.3–17.1 pg/mL, TSH 0.27–4.2 mcIU/mL.5 According to ISPAD clinical practice consensus guidelines, DKA was classified as mild if venous pH <7.3 or serum bicarbonate <15 mmol/L, moderate if pH <7.2 and serum bicarbonate <10 mmol/L, severe if pH <7.1 and serum bicarbonate <5 mmol/L.12DKA was defined by blood glucose level ≥200 mg/dL, pH ≤7.3 or bicarbonates ≤15 mEq/L, and elevation of serum ketones.13 In brief, stage 1 AKI is defined by serum creatinine 1.5–1.9 times baseline or urine output <0.5 mL/kg/h for 6–12 h, stage 2 AKI by serum creatinine 2.0–2.9 times baseline or urine output <0.5 mL/kg/h for ≥12 h, stage 3 AKI by serum creatinine 3.0 times baseline or urine output <0.3 mL/kg/h for ≥24 h or anuria for ≥12 h. None of the participants presented stage 3 AKI nor required hemodialysis; therefore, we considered the participants with stage 2 AKI as affected by severe AKI for the analyses of this manuscript.AKI was defined according to the Kidney Disease/Improving Global Outcomes (KDIGO) serum creatinine and/or urine output criteria.14 Prerenal-AKI (P-AKI) was defined by KDIGO creatinine and/or urine output criteria associated with FeNa <1%.15We considered as basal the creatinine values obtained at the last follow-up when all the biochemical parameters showed normalization and estimated glomerular filtration rate (eGFR) was within the normal range by age.16 TRP <85%, and FeNa >2%.In general, we considered the participants as having RTD if presenting with one or more abnormal values among urinary levels of beta-2-microglobulin >0.33 mg/L, neutrophil gelatinase-associated lipocalin (NGAL) values >95th percentile by age,17TRP was calculated as follows: TRP(%) = 1 – [(Urinary phosphorus/Serum phosphorus) ×  the presence of AKI, FENa between 1 and 2%, and/or urinary levels of beta-2-microglobulin >0.33 mg/L18 and/or neutrophil gelatinase-associated lipocalin (NGAL) values >95th percentile by age16 and/or TRP <85%.19ATN was defined by (i) the presence of AKI according to KDIGO criteria15FeNa was calculated as follows: FeNa(%) = (Urinary sodium/Urinary creatinine) / (Serum sodium/Serum creatinine).20Recovery from RTD was defined by normalization of the investigated physiological and biochemical parameters. AKI resolution was defined by a complete reversal of AKI.22Levels of cholesterol and triglycerides were considered within the normal range if <200 and <125 mg/dL, respectively.P values <0.05 were considered significant. Differences for continuous variables were analyzed with the independent-sample t-test for normally distributed variables and with the Mann–Whitney test in case of non-normality. Qualitative variables were compared using the χ2 test.Pearson and Spearman correlation tests were applied to evaluate associations of all linear data with FT3, FT4 or TSH. These variables were grouped into clinical, serum and urinary factors in order to give useful information for each of the steps of usual evaluations of patients.For univariate analysis, the Pearson test was used for parametric while the Spearman test for nonparametric variables.After Bonferroni correction, the variables resulting significant at univariate analyses were included in multiple linear regression analyses to identify the clinical, serum and urinary factors independently correlating with FT3, FT4 or TSH.Finally, the clinical, serum and urinary variables persisting significant after Bonferroni correction at each  multiple regression analysis were included in a unique final model. In the multiple linear regression analyses the nonparametric variables were log-transformed.The variables included in the univariate analyses, in the multivariate analyses and then in the final model are specified in Tables 6 We added in the multivariate logistic regression analyses the parameters that associated with ESS at univariate logistic regression analysis after Bonferroni correction was applied.Logistic regression models were used with the aim of exploring associations with ESS of the dichotomic variables. These variables were a priori chosen on the basis of the factors previously associated with the severity of T1DM onset.The variables included firstly in the univariate and then in the multivariate logistic regression analysis are shown in Table The time to AKI and RTD recovery in participants with euthyroidism and ESS was studied by survival analysis according to the Kaplan–Meier method. The day of admission was considered as the starting point, while the end point was the date of AKI or RTD resolution. Kaplan–Meier curves were compared by log-rank test.The Stat-Graph XVII software for Windows was used for all statistical analyses with the exception of logistic regression models made with SPSS 25 software for Windows and Kaplan–Meier analysis made with GraphPad Prism 8 for Windows.One hundred and sixty-one children with T1DM onset were enrolled. The mean age was 9.1 years (4.0 SDS). Out of 161 participants, DKA, AKI, and RTD were found in 85 (52.7%), 73 (45.3%), and 120 (74.5%) participants, respectively.More in detail, regarding the kidney involvement of the enrolled population, we found ATN in 55 (34.2%), P-AKI in 18 (11.2%), ATD in 48 (29.8%) and absence of kidney involvement in 40 (24.8%) participants.p < 0.001). ESS was more prevalent among participants with AKI, RTD and ATN compared respectively with participants without AKI, RTD and ATN . More in detail in 49 out of 85 participants (57.6%) with DKA and in 11 out of 76 (14.5%) without DKA at T1DM onset .Participants with ESS at T1DM onset showed older age; lower BMI-SDS, lymphocytes, phosphorus, bicarbonates, eGFR, and TRP levels; higher weight loss, HR, HbA1c, hemoglobin, cholesterol, triglycerides, chloride, ketones, creatinine, highest creatinine/basal creatinine (HC/BC) ratio, UPr/Cr, microalbuminuria, NGAL, beta-2-microglobulin, FeNa, and UCa/Cr levels; lower prevalence of family history of T1DM; and higher prevalence of HR >2 SDS, DKA, AKI, ATN, RTD and proteinuria compared with participants with euthyroidism  compared with participants with euthyroidism   Fig.  while on02) Fig.  and ATN 02) Fig. .Fig. 1KaOur longitudinal study describes in detail the relationship between clinical/metabolic factors at T1DM onset and thyroid hormones, with particular attention to the relationship between DKA-related kidney function impairment and ESS. Moreover, also the effect of ESS at T1DM onset on the recovery from kidney damage has been evaluated. Literature about this topic is scarce.6 It is also known that ESS is associated with DKA severity.10 The remaining question was ESS is related to DKA severity or to AKI. Interestingly, we found that more than severe DKA, the ESS is associated with the maximal expression of kidney damage represented by the ATN which configures the shift of kidney damage from functional to intrinsic.23As expected, the participants with more severe T1DM onset presentation both in terms of metabolic derangement (DKA) and kidney function impairment  had an increased prevalence of ESS. It is known that AKI is associated with DKA severity.24 This change has been suggested as a sort of beneficial adaptation during undernutrition in acute illness, decreasing the metabolic rate and reducing energy expenditure.25Participants with ESS had lower BMI and higher weight loss. This outlines how undernutrition is one of the factors involved in the derangement of thyroid hormone also in DKA. In fact, it is known that fasting induces complex changes in thyroid hormones homeostasis including low serum T3 without increased TSH.26In patients with DKA, higher levels of WBC and neutrophils compared with non-DKA T1DM patients have been described while no clear difference in lymphocytes count was evident.27 We can speculate that lymphopenia at T1DM onset could be a marker of the most severe forms of DKA which in turn could be strongly associated with ESS.Interestingly, among our children with T1DM onset, participants with ESS had lower numbers of lymphocytes. This is in keeping with the recent observation by Grondman et al. of a correlation between abnormal thyroid function and lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19.On the other hand, at follow-up, no differences in lymphocytes count were found comparing patients with and without ESS at T1DM onset. This strengthens the hypothesis that lymphopenia is a marker of T1DM onset severity with its disappearance when the acute phase is resolved.In our work other determinants of FT3 levels were those related to the severity of DKA and to the severity of dehydration causing in turn RTD, AKI and in the most severe cases ATN such as triglycerides and creatinine levels among serum factors, and NGAL and UCa/Cr levels among urinary ones. Similarly, we found a direct association between FT4 and bicarbonates.28 Also cholesterol levels could be higher in DKA patients as a consequence of dehydration but not as often or as much as plasma triglycerides.29 Differently from the T1DM onset, at the follow-up visit we observed similar levels of triglycerides and a similar prevalence of abnormal triglycerides levels comparing participants with and without ESS  at low creatinine concentrations but is still observed with another enzymatic assay testing.36The main limitation of our study is represented by the utilization of serum creatinine as an indicator of AKI in patients with DKA, despite acetoacetates, hyperglycemia, and glycosylated hemoglobin could falsely elevate measured creatinine.5 serum creatinine measurement methods. Finally, serum creatinine is the only marker of renal function adopted in daily clinical practice, also in patients with DKA.For this reason, the AKI prevalence could be overestimated. The prevalence found in our study, however, is in line with a previous study adopting enzymatic37 In our study, however, we used also other urinary biomarkers to define the presence of AKI  and only two participants had isolated increase in urinary NGAL levels, so we think that the overestimation of the prevalence of renal tubular damage due to the presence of DKA-related inflammation is limited.Another limitation is represented by the fact that DKA is associated with a systemic inflammatory condition that could lead to an increase in urinary NGAL levels regardless of the presence of AKI or renal tubular damage.In conclusion, this is the first perspective observational study investigating the relationship between ESS and clinical and metabolic factors at T1DM onset. FT3 levels are inversely correlated with serum creatinine, serum triglycerides, urinary NGAL and UCa/Cr levels while FT4 levels are directly correlated with bicarbonates levels. The more severe the T1DM presentation, the higher the prevalence of ESS. In fact, patients with DKA, RTD, AKI, ATN have higher ESS prevalence compared with patients without these conditions. In multivariate logistic regression, the conditions most strongly associated with ESS are DKA and ATN. Patients with ESS show a lower recovery from AKI compared to those without AKI. ESS spontaneously disappears in all patients.Supplementary figures


Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder involving progressive pancreatic dysfunction. A substantial proportion of patients with T2DM cannot achieve euglycemia despite pharmacologic therapy. Preceding clinical studies have shown that hypertension contributes to glucose dysregulation, and investigators in this study hypothesized that antihypertensive treatment may improve glycemic control in patients with T2DM.This prospective cohort study investigates the effect of adding the antihypertensive drug Amlodipine to standard diabetes therapy on serum glycosylated hemoglobin A1c (HbA1c) and lipid profile in patients with newly diagnosed T2DM. The study enrolled a total of 168 participants with newly diagnosed T2DM.Recipients of additional antihypertensive drug Amlodipine demonstrated significantly lower serum HbA1c , systolic blood pressure , and diastolic blood pressure  compared to recipients of standard diabetes therapy after 24 weeks.Antihypertensive treatment with Amlodipine in addition to standard diabetes therapy improves glycemic control in patients with T2DM and may be an appropriate option in people with diabetes and concomitant hypertension to help maintain euglycemia. Diabetes is a metabolic disorder that substantially influences national health infrastructures . ImpaireA large prospective study has shown that inadequately treated hyperglycemia increases the mortality rate in people with diabetes . MoreoveCurrently there are several classes of antidiabetic drugs available for the treatment of T2DM , with moEpidemiologic evidence suggests that hypertension frequently precedes the development of T2DM . DiabeteEvidence suggests that antihypertensive drugs including calcium channel blockers may improve glycemic control in animal models of T2DM . MoreoveConsidering the link between hypertension and glucose metabolism, the investigators hypothesized that stringent blood pressure management with the antihypertensive medication Amlodipine may improve glycemic control in patients with T2DM. The primary endpoint of this study is the change in plasma glucose parameters after 24 weeks of pharmacologic intervention. Secondary outcomes include the effect of additional antihypertensive medication on lipid profile, blood pressure and urine albumin excretion.This prospective study surveyed patients visiting the endocrinology clinic for eligibility. Inclusion criteria were as follows: (1) adults over 21 years of age, (2) T2DM diagnosed within one month of study referral according to criteria of the American Diabetes Association, namely serum glycosylated hemoglobin A1c (HbA1c) level ≧ 6.5%, fasting plasma glucose (FPG) ≧ 126 mg/dL, 2-hour postprandial plasma glucose levels after 75-gram oral glucose tolerance test ≧ 200 mg/dL, or random plasma glucose levels ≧ 200 mg/dL with classic symptoms of diabetes (3) recipients of metformin monotherapy, (4) no concomitant use of antihypertensive drug at study recruitment, and (5) compliance with medications and dietary intervention.Exclusion criteria were as follows: (1) recipients of any second-line antidiabetic drug in addition to metformin, (2) recipients of any antihypertensive medication prior to recruitment, (3) patients with hemoglobin disorders, chronic kidney disease, or thyroid dysfunction, (4) pregnancy, and (5) inability to comply with therapeutic intervention.Baseline information including age, body mass index, sex and blood pressure were recorded at diagnosis of T2DM prior to pharmacologic treatment. Blood tests for serum HbA1c, plasma lipid levels, and serum creatinine were performed after an 8-hour fast. All participants received nutrition consultation by diabetes educators in which daily recommended calorie intake, carbohydrate counting technique, and exercise recommendations were provided. Moreover, participants were advised to reduce salt intake to less than 2400 milligrams a day to control hypertension. Diabetes educators contacted participants once a week to check on medication compliance and dietary habits.Thereafter, participants were divided into two therapeutic cohorts according to shared decision making between patients and their attending physicians. The control group received standard diabetes therapy including metformin and dietary intervention without any additional antihypertensive drug. The antihypertensive cohort received 5 milligrams of Amlodipine once daily in tandem with standard diabetes therapy.Both cohorts continued their therapeutic regimens for the next 24 weeks. Then the participants returned for follow-up blood tests after an 8-hour fast. Blood pressure measurements were also performed at the clinic visit.The primary outcome measure of this study was the change in serum HbA1c after completing 24 weeks of pharmacologic treatment. Secondary outcomes include changes in plasma lipid levels, blood pressure, and urinary albumin excretion after treatment.Power analysis indicated that a sample size of 75 participants in each group was necessary to detect a significant difference in glucose parameters with 80% statistical power. The therapeutic cohorts include all participants who received at least one dose of the study prescriptions. Blood tests and baseline data at diagnosis of T2DM were considered as the baseline. Outcome measures in this study were based on laboratory tests at the follow-up clinic appointment after 24 weeks of pharmacologic therapy.2-test for categorical variables. Furthermore, variables were compared to baseline levels using paired sample t-test to evaluate the efficacy of antidiabetic treatment. Multiple regression analysis was performed to identify clinical determinants of serum HbA1c levels. All statistical analysis was performed using IBM Statistical Package for the Social Sciences version 22.0 . A two-tailed P value of less than 0.05 indicated statistical significance.The baseline characteristics and clinical outcomes of the treatment groups were compared using Student’s independent t-test for continuous variables and Pearson’s χThe study screened 200 candidates visiting the endocrinology clinic for eligibility. Thirty patients were excluded due to chronic kidney disease and two candidates were ineligible due to thyroid dysfunction. The enrolment protocol is shown in Baseline features of the participants were collected at diagnosis of T2DM prior to pharmacologic treatment. This study included 168 participants who were divided into two therapeutic cohorts according to their prescription of antihypertensive medications at study enrolment.2 vs. 27.7 kg/m2, P = 0.265), and waist circumference  were similar between both cohorts. Moreover, laboratory tests demonstrated comparable kidney and liver function as well as plasma lipid fractions between these cohorts.As shown in After 24 weeks of therapy, participants receiving additional antihypertensive medications demonstrated lower mean serum HbA1c  and fasting plasma glucose  compared to recipients of standard diabetes treatment. Moreover, participants receiving additional antihypertensive prescription had significantly lower systolic blood pressure  and diastolic blood pressure  compared to recipients of standard diabetes therapy. Otherwise, the two groups harbored similar levels of albuminuria , body weight , BMI , and waist circumference , plasma triglycerides , plasma HDL-C , and plasma LDL-C . These findings are summarized in As demonstrated in P = 0.0164) and diastolic blood pressure  are correlated with serum HbA1c levels during diabetes treatment. In contrast, other clinical parameters had no significant influence on serum HbA1c levels in this study.As shown in Sensitivity analysis demonstrates an association between antihypertensive medication and lower serum HbA1c levels with an area under the curve (AUC) of 0.7 as shown in In this study, stringent blood pressure management with the antihypertensive medication Amlodipine for 24 weeks significantly reduced mean serum HbA1C levels compared with standard diabetes therapy in patients with T2DM. Moreover, concomitant Amlodipine prescription lowered blood pressure with neutral effect on lipid profile and urinary albumin excretion. Sensitivity analysis demonstrates that antihypertensive prescription is associated with lower serum HbA1c levels and that systolic blood pressure correlates with serum HbA1c levels.In vitro evidence implies that Amlodipine improves insulin sensitivity by increasing the cross-sectional area of capillaries that supply glucose-metabolizing tissues  inhibitors exert favorable effects on glucose metabolism . ClinicaThis study has several advantages. Firstly, participants in the study received solely the antidiabetic drug metformin, which avoids the confounding effect of second-line antidiabetic drugs on glycemic control. Secondly, participants in both therapeutic groups were stringently selected with comparable baseline features at study enrolment. Thirdly, patients received comprehensive nutrition consultation by certified diabetes educators to ensure compliance with prescriptions and lifestyle modification.Nonetheless, several limitations arise from the study protocol. Firstly, a protocol of shared decision making was applied in terms of antihypertensive drug prescription, and this non-randomized design can lead to potential selection bias . This inAntihypertensive treatment with Amlodipine in addition to standard diabetes therapy improves glycemic control in patients with T2DM. Therefore, antihypertensive therapy may be an appropriate option in people with diabetes and concomitant hypertension to help maintain euglycemia. Further studies are indicated to determine whether other classes of antihypertensive drugs also enhance glycemic control in T2DM.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Institutional Review Board of Changhua Christian Hospital (Ethics committee identifier: P201411-15). The patients/participants provided their written informed consent to participate in this study.J-CL: drafting the manuscript, revising the manuscript. P-CC: conceptualization, data analysis, revising the manuscript. C-NH: conceptualization, revising the manuscript. L-FJ: revising the manuscript. Y-SW : drafting the manuscript, revising the manuscript. C-LL: conceptualization, project design, revising the manuscript. All authors contributed to the article and approved the submitted version.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.


Renal hypoperfusion is one of the most common causes of acute kidney injury (AKI), especially in shock and perioperative patients. An optimal blood pressure (BP) target to prevent AKI remains undetermined. We conducted a systematic review and meta-analysis of available randomized clinical trial (RCT) results to address this knowledge gap.From inception to May 13, 2022, we searched Ovid Medline, EMBASE, Cochrane Library, SCOPUS, clinicaltrials.gov, and WHO ICTRP for RCTs comparing higher BP target versus normotension in hemodynamically unstable patients . The outcomes of interest were post-intervention AKI rate and renal replacement therapy (RRT) rate. Two investigators independently screened the citations and reviewed the full texts for eligible studies according to a predefined form.Twelve trials were included, enrolling a total of 5759 participants, with shock, non-cardiac, and cardiac surgery patients accounting for 3282 (57.0%), 1687 (29.3%) and 790 (13.7%) patients, respectively. Compared to lower mean arterial blood pressure (MAP) targets that served as normotension, targeting higher MAP had no significant effect on AKI rates in shock , in cardiac-surgery  and non-cardiac surgery patients  using random-effects meta-analyses. In shock patients with premorbid hypertension, however, targeting MAP above 70 mmHg resulted in significantly lower RRT risks, RR [95%CI] = 1.20 , p < 0.05.Targeting a higher MAP in shock or perioperative patients may not be superior to normotension, except in shock patients with premorbid hypertension. Further studies are needed to assess the effects of a high MAP target to preventing AKI in hypertensive patients across common settings of hemodynamic instability.Trial registration This systematic review has been registered on PROSPERO (CRD42021286203) on November 19, 2021, prior to data extraction and analysis.The online version contains supplementary material available at 10.1186/s13054-022-04236-1. Acute kidney injury (AKI) is a global health burden, with an incidence of roughly 13.3 million cases per year, contributing to approximately 1.7 million deaths . AKI is AKI is a multicausal syndrome with complex pathophysiology, making the development of an effective treatment a challenging research area. To date, no effective pharmacologic therapy has been established to counteract the disorder. Consequently, according to the Kidney Disease Improving Global Outcome (KDIGO) AKI guidelines , managemRenal hypoperfusion is one of the most common causes of AKI, especially in shock- and surgery-related AKI patients. Optimizing hemodynamics therefore is essential for the prevention and treatment of AKI in these settings. Among the strategies, maintaining a physiological MAP is necessary to ensure sufficient kidney perfusion pressure and microcirculatory blood flow . HoweverGiven the higher exposure to fluid and vasopressor use of higher MAP and the heterogeneous settings of AKI patients, it is essential to investigate: (1) whether higher MAP levels, compared to normotension, should be considered to prevent AKI, and (2) in which AKI settings higher MAP are more likely to be beneficial. We thus conducted a comprehensive review with meta-analysis based on randomized controlled trials (RCT) that examined the effect of high versus normotensive MAP on AKI incidence or progression across common settings , and used meta-regression to examine several characteristics that may serve as effect-modifiers.We conducted a systematic review with meta-analysis and meta-regression. The protocol for this systematic review was registered on PROSPERO (CRD42021286203) on November 19, 2021, prior to data extraction and analysis. We reported our study results in accordance with PRISMA guideline.From inception until May 13, 2022, we searched MEDLINE, EMBASE, the Cochrane Library, and SCOPUS for RCTs comparing higher and lower blood pressure (BP) target in shock or perioperative patients. We also searched Clinicaltrials.gov and WHO ICTRP for relevant trial registries. We built the search queries using three concepts: (1) shock, post-cardiac arrest, perioperative patients (2) blood pressure target, and (3) randomized controlled trial. We used both the Medical Subject Headings database and free-text syntax without any language restrictions  screening of titles and abstracts, (2) searching for full texts and results, and (3) reviewing the full texts , intervention , AKI and RRT receipt rate. We contacted the authors via email for further information or unreported results. Some unavailable original data (hypertension percentages) were imputed using the percentage of anti-hypertension medication.We assessed risk of bias (RoB) independently using Cochrane RoB updated version (RoB-2) for which each domain is rated as “low risk”, “high risk”, or “some concerns”. We assessed RoB-2 according to intention-to-treat basis, based on one main outcome of interest reported in the studies: AKI rates and RRT receipt rates, respectively.https://www.gradepro.org) to formulate the Summary of Findings table. Any disagreements regarding RoB or GRADE assessment were resolved by consensus.We assessed the certainty of the body of evidence for each outcome by the Grading Recommendations Assessment, Development and Evaluation (GRADE) approach. We used the Guideline Development Tool , we used the average BP within the intervention period. Since some studies reported AKI using indirect definitions, we did some conversions  software.We conducted meta-analysis on outcomes that were reported in at least two studies. We employed the risk ratio (RR) as the main effect size estimate for dichotomous variables (rates of AKI and RRT receipt) all with 95% confidence interval and p < 0.1 indicates important heterogeneity), and the I2 statistic. We did not conduct meta-analyses where I2 indicated considerable heterogeneity (I2 ≥ 75%).We assessed heterogeneity between trials by visual inspection of the forest plots, the chi-squared test for homogeneity  shock, (2) cardiac surgery and (3) non-cardiac surgery patients. We also conducted subgroup analysis based on the discrepancy level between normotensive and high MAP, and on premorbid hypertension condition where reported results were available. To detect publication bias, we performed funnel plots for primary outcome synthesis and inspected for any asymmetry.p value < 0.05 indicate that the relationship between moderator variables and effect size is stronger than we would expect by chance. Moderators with Z statistics with p < 0.05 were interpreted as their slope is probably not zero, and the treatment effect size would vary according to changes in moderator variables. Positive value of MH log risk ratio is in favour of the renoprotective effect of high MAP.We performed meta-regression using comprehensive meta-analysis version 3 to examine the relationship between predefined potential moderators: (1) percentage of hypertension patients in the cohort, (2) mean age and (3) risk of bias level and the treatment effect size (Mantel–Haenszel log risk ratio). All meta-regression models were adjusted for study group . Q model statistics with We did not conduct trial sequential analysis due to the anticipated heterogeneity of the included populations.We retrieved a total of 8285 citations and removed 2417 duplicates  –10, non-Baseline characteristics of patients varied across studies in terms of age and sex. Most studies recruited elderly participants. Male sex ranged from 40 to 94% across all arms of the included studies. A total of 10 out of 12 studies reported baseline renal functions  as targets for comparison, except for Futier et al.  which usNine out of the 12 studies had an overall low RoB . However, this effect was not significant with 95% CI at − 0.0024 to 0.0098, In this systematic review with meta-analysis, we found that in shock and perioperative patients, targeting higher MAP generally was not superior to normotension in terms of preventing AKI occurrence or progression. In shock patients, our study revealed that MAP above normotension (65–70 mmHg) did not result in reduced post-intervention AKI or RRT receipt rate. A patient-level pooled analysis also demonstrated that higher MAP had no effect on 28-day death or persistent organ dysfunction rate . Since hIn non-cardiac surgery patients, our study found no superiority of higher MAP in AKI prevention, as compared to normotension. One meta-analysis investigated the effects of strict intraoperative BP management strategy (defined as MAP ≥ 70 mmHg/MAP decrease less than 30% from the baseline) on postoperative AKI . The autMAP is the fundamental driver of organ perfusion. Autoregulation is the capacity of healthy essential organs such as the heart, brain, and kidney to maintain a consistent blood flow rate within a range of perfusion pressure . In disrAfter adjusting for patient group, we found no significant effect of hypertension, mean age, or RoB on the link between MAP and AKI in meta-regression models. Nevertheless, subgroup analysis of shock patients with hypertension revealed a renoprotective signal of higher MAP (> 70 mmHg) on reducing the RRT receipt rate. Chronic hypertension is known to shift the renal autoregulation zone to the right, higher MAP is therefore required to maintain adequate perfusion pressure . DewitteThis study has several strengths including a pre-registered protocol, a comprehensive literature search and an updated RoB version. Exclusive inclusion of RCTs comparing different MAP targets on renal outcome helps to isolate the effect of MAP and vasopressor use on AKI prevention and management, whereas extensive selection of different AKI-related settings broadens the scope of the review. Major limitation of this review was the limited number of studies in each patient group, which might link to underpowered statistical findings. This also rendered the multivariable analysis in the meta-regression models. Due to lack of reported results, many subgroup analyses could not be performed. Second, included RCTs had varied AKI definitions, and most did not employ kidney function as a primary objective. Sample sizes therefore may not be powered to detect difference in kidney outcomes. Lastly, some results (hypertension percentage) were not reported in the original publications, and we imputed them using the percentage of anti-hypertension medications, which could be a close approximation.Targeting a higher MAP in shock or perioperative patients may not be superior to normotension in terms of reducing the onset or progression of AKI. Targeting MAP over 70 mmHg in shock patients with premorbid hypertension may reduce the RRT administration rate, suggesting a renoprotective impact. Considering the limitations of the present evidence, additional studies are required to assess the benefits of a high MAP target in preventing AKI in hypertensive patients in common settings of hemodynamic instability.Additional file 1. Supplemental digital content.


Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, and its early pathogenesis is critical. Shear stress caused by glomerular hyperfiltration contributes to the initiation of kidney injury in diabetes. The primary cilium of renal tubular epithelial cells (RTECs) is an important mechanical force sensor of shear stress and regulates energy metabolism homeostasis in RTECs to ensure energy supply for reabsorption functions, but little is known about the alterations in the renal cilium number and length during the progression of DKD. Here, we demonstrate that aberrant ciliogenesis and dramatic increase in the cilium length, the number of ciliated cells, and the length of cilia are positively correlated with the DKD class in the kidney biopsies of DKD patients by super-resolution imaging and appropriate statical analysis methods. This finding was further confirmed in STZ-induced or db/db diabetic mice. These results suggest that the number and length of renal cilia may be clinically relevant indicators and that cilia will be attractive therapeutic targets for DKD. The IntThe kidney is the second most energy-demanding organ (next to the heart) in the human body . The priThe primary cilium is an antenna-like, microtubule-based immotile organelle projecting from the surface of most vertebrate cell types that detects and transmits extracellular signals to regulate diverse cellular processes during development and to maintain tissue homeostasis , 9. A chThe glomeruli of DKD patients are continuously in a hyperfiltration state, and the abnormal lipid metabolism of RTECs is an important pathological basis for the progression of DKD. That is, the lipolysis pathway of RTECs is defective; the decomposition of triglycerides into free fatty acids and the mitochondrial β-oxidation to produce the ATP pathway are blocked, which induces cell apoptosis and dedifferentiation and accelerates the process of renal fibrosis –19. HoweHere, we demonstrated that the renal cilium length and number were positively correlated with the DKD class. Similar results were further confirmed in streptozotocin (STZ)-induced diabetic mice and db/db mice, suggesting that aberrant cilium elongation may accelerate DKD progression. Thus, our study indicates that proper cilia dynamics are crucial in the early progression from diabetes to DKD.22.1n = 3) were obtained from the healthy kidney poles of individuals without diabetes or kidney diseases who underwent tumor nephrectomies. The investigations were conducted in accordance with the principles of the Declaration of Helsinki and were approved by the Research Ethics Committee of Xiamen University after informed consent was obtained from the subjects.Renal biopsies were performed as part of routine clinical diagnostic investigations and were collected as described in All renal biopsy samples that were diagnosed as DKD were classified in accordance with a new pathologic classification provided by the Renal Pathology Society . From mi2.22.2.1Male mice aged 8 weeks were administered with streptozotocin  by intraperitoneal injection after a 6-h fast for five consecutive days (50 mg/kg per day). One week after the last injection, the blood glucose levels were measured. Diabetes was confirmed by a fasting blood glucose level > 300 mg/dl. Age- and sex-matched mice injected with citrate vehicle served as controls. All mice were euthanized at 16 or 24 weeks after STZ or vehicle injection. Body weight and blood glucose levels were monitored biweekly. Urine was collected to measure urinary protein and creatinine levels.Spontaneous type 2 diabetic db/db micedb/db mice (BKS.Leprem2Cd479/Gpt Stock No. T002407) and age-matched nondiabetic db/m male mice were purchased from GemPharmatech Co., Ltd. (Jiangsu China). These mice developed DKD, which is defined by the development of albuminuria at 10 weeks of age. All animal studies were performed according to the protocol approved by the Animal Care Committee at the First Medical Center of Chinese PLA General Hospital.2.3The urine albumin concentration was measured using a mouse albumin ELISA kit . Urine creatinine levels in the same samples were measured using a creatinine colorimetric assay kit  according to the manufacturer’s instructions. The level of urine albumin was normalized to urine creatinine (UACR).2.4The antibodies and reagents used in this study included rabbit anti-ARL13B .2.5For tissue immunofluorescence analysis, kidneys were fixed in 4% paraformaldehyde (PFA) overnight and then embedded in paraffin according to standard procedures. Sections were cut at a thickness of 4 μm. The tissue sections were blocked with 3% BSA and 1% normal goat serum in 0.1% Triton X-100/PBS before being incubated with primary antibodies. The secondary antibody was Alexa Fluor 488–conjugated goat anti-rabbit IgG . DNA was stained with Hoechst 33342 .Images were acquired at room temperature with a 60×/1.42 oil objective 2C, E on2.5.1Kidney samples were fixed overnight in 4% PFA, embedded in paraffin, and sectioned to a thickness of 4 μm. Sections were stained with periodic acid–Schiff (PAS) to analyze the glomerular area and mesangial matrix expansion. Mesangial expansion was defined as a PAS-positive and nuclei-free area in the mesangium. Images were captured using a dotSlide 2.1 virtual microscopy system (Olympus).2.5.2P < 0.05. For all tests, differences were considered statistically significant if P-values were < 0.05 . We performed the statistical analysis using GraphPad Prism. Investigators were blinded during the assessment of all staining assays.The statistically analyzed data are expressed as the mean ± SD. A standard two-tailed unpaired Student’s t-test was used to analyze two groups. To compare the means between three groups, one-way ANOVA followed by Dunnett’s multiple comparison test was used, as noted in the figure legends. Statistical significance was achieved when 33.1To examine the role of cilia in DKD, we first examined cilia formation in the kidney biopsies of patients at different clinical stages  , and the results showed that primary cilia in the RTECs in diabetic mice were much longer at 24 weeks post-STZ injection than those in the 16-week and vehicle groups. Compared with 1.12 μm in the control group, the mean cilium length increased to 2.11 μm at 24 weeks post-STZ injection , a NADc kidney . HDAC6, c kidney , 23. Thec kidney , which dOrhon et al. demonstrated that fluid flow induced autophagy in cultured mammalian kidney epithelial cells through the primary cilium . The autPrimary cilia coordinate a variety of signaling pathways, including the Hedgehog, GPCR, Wnt, and TGF-β signaling pathways, which are important not only in kidney injury, repair, and fibrosis but also during embryonic kidney formation and development . The actCurrent treatment for DKD is limited to strict glycemic control and blood pressure control with ACE inhibitors or ARBs and SGLT2 inhibitors . Our stuIn summary, our work improves the understanding of fundamental cilia biology in kidney disease and is crucial for developing new treatment approaches to alleviate kidney fibrosis and damage.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Medical Ethics Committee of the First Affiliated Hospital of Xiamen University. The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by Ethics Committee of Chinese PLA General Hospital. Written informed consent was obtained from the owners for the participation of their animals in this study.X-MC, QH, and G-YC supervised the project; Y-FB designed and carried out most of the experiments; PL and C-TW carried out the statistics. BF and S-YC provided reagents and suggestions; J-NL analyzed the data; LZ provided clinical samples; Y-FB, QH and X-FS wrote the paper. All authors discussed the results and commented on the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China  and Natural Science Foundation of Fujian Province (Grant No. 2020J011243)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.


Early identification and control of hypertension is critical to reducing cardiovascular disease events and death. U.S. Preventive Services Task Force guidelines recommend health care professionals screen all adults for hypertension, yet 1 in 4 adults with hypertension are unaware of their condition. This gap between guidelines and clinical practices highlights an important opportunity to improve blood pressure (BP) screening and hypertension diagnosis, including measurement outside of clinic settings. To identify targets for future diagnostic interventions, we sought to understand primary care physicians' (PCPs) beliefs and practices regarding use of common forms of BP measurement.N = 27) who had patients enrolled in the BP-CHECK trial. The trial compared the accuracy of 24-h ambulatory BP monitoring (ABPM) to: 1) clinic-based monitoring, 2) home BP monitoring (HBPM), or 3) use of a BP kiosk in clinics or pharmacies. Physicians were interviewed by phone and compensated for their participation. Interviews were recorded, transcribed, and analyzed using a template analysis approach.Study participants were PCPs (Overall, PCPs preferred and trusted clinic BP measurement for diagnosing hypertension, particularly when measured with a manual sphygmomanometer. Concerns with HBPM included the belief that patients did not follow protocols for rest and body positioning at home, that home machines were not accurate, that home BPs could not be entered into the medical record, and that HBPM would make some patients anxious. Issues regarding kiosk measurement included beliefs that the public setting created stress for patients, that patients did not follow resting protocols when using kiosks, and concerns about the maintenance of these machines. ABPM was recognized as highly accurate but was not perceived as accessible. Additionally, some PCPs found it challenging to interpret the multiple readings generated by ABPM and HBPM, especially when these readings differed from clinic BPs.Our findings suggest that both additional physician education and training and investments in equipment and system-level processes are needed to increase the acceptance and utilization of out of office BP measurement for identification and treatment of hypertension. These changes are needed to improve ensure everyone in the U.S receive optimal care for hypertension.NCT03130257. Initial registration date: 4/21/2017.ClinicalTrials.gov The online version contains supplementary material available at 10.1186/s12875-022-01950-1. Hypertension is the most common cause of avoidable death and disability globally . Early iCurrently, the U.S. Preventive Services Task Force (USPSTF) guidelines recommend screening all adults aged 18 years or older for hypertension  , 7. The These guidelines contrast with current practice for many primary care physicians (PCPs) who rely almost exclusively on clinic-based BP measurement using manual or automated sphygmomanometers and no averaging of readings . HoweverThe literature on health care professionals’ knowledge and attitudes regarding BP measurement, especially when used for diagnosis or taken outside of a clinic, is limited. Even fewer studies focus on knowledge and beliefs of health care professionals in the U.S., which has systemic constraints on out-of-clinic BP measurement  such as This qualitative study interviewed physicians whose patients participated in the BP-CHECK study about their beliefs and practices related to using different BP measurement methods and their experience with using HBPM and ABPM for diagnosing hypertension. Our aim was to shed light on barriers and potential facilitators for improving hypertension diagnosis.The goal was to assess primary care physicians’ (PCPs) attitudes and practices after being exposed to a variety of BP measurement options for hypertension diagnosis. (See N = 27) from 12 clinics who had one or more patients enrolled in the BP-CHECK study. Patient participants in the BP-CHECK study were all members of the Kaiser Permanente health care system in Washington state. Patients were randomized to use either home, clinic, or kiosk-based BP monitoring. After completing their assigned measurement protocol, each participant completed ABPM  who followed a semi-structured interview guide. Participants provided verbal consent and were offered $50 as thanks for participation. Interviews were recorded and transcribed for analysis.Transcripts were coded by three qualitative researchers . Using a template analysis approach , the teaOnce coding was complete, data were pulled by code and selected codes were analyzed further. This analysis was summarized in one or more analytic coding memos . These cThe 27 study participants were demographically diverse Table . All butKey themes emerged related to physician beliefs and practices regarding BP screening and measurement for diagnosis. These themes were organized around the measurement methods used in the trial. Overarching themes are discussed at the end of the results section.So, in clinic we always use the manual because I guess from my training that was considered the gold standard. I would say a manual monitor [is more accurate]—at least this is what I'm taught, and this is kind of what I use in my practice—the manual monitor's the most effective. Most PCPs trusted and relied primarily on clinic measurement to make a hypertension diagnosis and tended to rely on BPs taken by an MA or nurse using manual techniques  over automated BP monitor measurements. PCPs explained that reliance on manual BP readings is a product of their training.I have a preference to bring them into my clinic to have a manual blood pressure check by my MA, because I know they have them rest for five minutes before they check the blood pressure, make sure their arms aren't crossed and make sure the arm's rested and held at heart level when they're checking it, because those are sort of the norms we indicate to our MAs when they have a protocol to recheck it, if it's elevated beyond…140/90. If it's elevated beyond that, they usually recheck it in about five minutes and then notify us. Some stated that they prefer clinic readings—either manual or automated—over home and kiosk measurements for diagnosis because they felt more confident that the patient had rested the recommended 5 min before having their BP taken and that all the procedures were correct, including body positioning and support.Well, I think the only thing I hear patients complaining about is having to come in, if they weren't otherwise, needing to make the time, right? So, it's obviously extra work for people to come in through traffic, park and come in and then sit and wait for their blood pressure to be checked, so that would be one obvious barrier. I think having patients come in for a frequent follow up, whether it's a doctor's visit or a blood pressure check visit, is not very patient centered because it's hard for people to come in. In my clinic, I work in a particular…clinic that's extremely non-patient-friendly for access. We have very poor parking…So it's just hard for people to come in. Some patients live far away from clinics so coming to see us even without a copay is really a barrier because it's a 90-minute drive for them. Although many PCPs saw clinic BP measurement as accurate, many also recognized that it was not the most patient-centered option, especially because of the inconvenience of coming into the clinic.I know there have been studies about the automatic cuff being more accurate than the humans. …I'm not sure, I haven’t had access to an automatic cuff since forever… Everything's manually, no automatic cuffs. So, I'd like to do that, I think that would be super helpful, but it's not an option. Others acknowledged that automated machines might be more accurate but stated that they did not have access to these machines. While all clinics had at least one automated BP measurement device, for some clinics the number of devices was not sufficient to make them accessible for consistent use.I'm less comfortable with the kiosk and the home blood pressure reading…if someone's truly been resting or their position and things like that. And then oftentimes if someone brings in home readings, I don't know if their machine is calibrated or something like that, so it makes me a little more uncomfortable. PCPs viewed home monitors as useful tools but did not trust them for diagnosis. They voiced concerns about the accuracy of home monitoring, including the belief that current diagnosis thresholds were based on clinic BPs and therefore may not be accurate for HBPM and that patients may not be resting or seated in the optimal position when taking their BP. The most common concern about HBPM was that home machines were not accurate and needed to be tested against a clinic measurement.I would be much more open to using the home numbers, but for whatever reason they have not been considered a legitimate use of the numbers. So, we'll keep getting reports saying people are out of control and [the EHR will do] automatic outreach and things like that... so it's really just from a practical standpoint, [we] can't use the home numbers because they do not translate into the [health care system’s] goal setting. That's why I use the clinic numbers …. There's a certain kind of tail wagging the dog … I recognize, but somebody emails their home numbers, and they are good, they're still going to show up on a report until they come in and get a blood pressure that looks good. Another challenge of HBPM is that, at the time of the interviews (2018- 2019), the health care system did not consider HBPM an acceptable measure because there was no way to enter readings into the EHR and it did not count for quality measures. These circumstances have since changed due in part to COVID-19 and HBPM measures can at least temporarily be used for quality measures.But I do think being able to check your blood pressure at home is probably for most people the most convenient thing to do. It's just easy. You don't have to leave the home to go anywhere, which I think is what people prefer, I would prefer that. Especially if you're older, which most of my patients with hypertension are, or a lot of them are. Transportation can be an issue. That's the other thing about the home monitoring. I just feel that works so well for a lot of my patients to just check it at home and have them come in once and make sure the blood pressure cuff is accurate and then we can just titrate meds, do all this virtually. To me that just seems like much better. Although PCPs said they were uncomfortable using HBPM to diagnose hypertension, they often acknowledged that home BP monitors were more patient centered because of the convenience they offer.There is a subset who take a reading and they get anxious and then a minute later they take another reading and it's higher, another minute later they take another reading and it's higher, and they just work themselves up into a complete panic. So [there is a] slice of patients with hypertension and anxiety for whom I'd specifically say I do not recommend that you monitor your blood pressure at home, but that's the minority.” But sometimes the patient is too much like anxious, they are pretty much checking the blood pressure 16 or 17 times per day, and I don't think that is good. …You don't want to get them in a panic…. PCPs also worried that HBPM could make some patients anxious if they were getting high readings. They worried this would lead to a vicious cycle in which a patient would have increased anxiety about high BP readings, which would in turn cause elevated BP readings.Only one PCP mentioned multiple data points as an advantage of HBPM even though guidelines recommend collecting BPs over several days and averaging them.The other one I really don't like is the kiosk ones, just because I find that people say, "I checked the blood pressure at the kiosk and it was high," but they were using it at the store, and they were walking around, and they weren't doing it properly. Or they're obese, and their arm size probably isn't a one-size-fit-all cuff. I think that is my least favorite. PCPs had several concerns about BP kiosks in pharmacies or clinic waiting rooms. First, PCPs were concerned about reliability, maintenance, the setting in which BP kiosks are located, and cuff size limitations.I do refer patients that don't have a cuff to go use those [kiosks]. I think they're another good tool to have. My only concern with them is that often it's hard for people to go sit down for five minutes before they do a blood pressure reading. If you're like at work, you're more in a get-in, get-out attitude. I have no real data to support that, but I tend to believe the readings that we were getting. I just always like to check if they've actually been seated for five minutes before they get their blood pressure checked.” They also felt it would be hard for patients to follow standard procedures to rest before taking their BP when using a kiosk.So, to me, store kiosk blood pressure cuffs are the same as home cuffs in the sense that I don't know how accurate they really are. I'm sure it's variable. But at the same time, I think it helps because if they're measuring high and I'm measuring an office high, I think it helps reinforce the people who aren't convinced that they really have high blood pressure, who think it's only high in the office. So, I do tell people to check outside the office and let me know what reading they're getting, but I'm not 100% confident in them. Several PCPs reported that kiosks tended to give higher BPs readings, which had both benefits and challenges.I would say it [the 24-hour monitor] is just a more robust set of data, so when you're doing ambulatory blood pressure monitoring, that's the gold standard. I guess with the 24-hour monitoring, I do feel more confident telling a patient this really helps confirm your diagnosis being hypertensive and indicates that treatment would be helpful. PCPs reported having a high level of confidence in the overall accuracy and clinical value of ABPM results.Typically, in patients that do not currently carry a diagnosis, but I have an elevated reading, and are uncertain or unconvinced of whether they need medication. So, I'll use it as a tool to confirm diagnosis and establish a need for medication A few had ordered an ABPM to confirm a hypertension diagnosis prior to the BP-CHECK study.I guess with the 24-hour monitoring, I do feel more confident telling a patient this really helps confirm your diagnosis being hypertensive and indicates that treatment would be helpful. So, I guess if they're just in the clinic and they're someone that's had consistent hypertension, I tend to rely more on the manual readings. If it's someone that's had really labile blood pressure, that's when I would usually use the 24-hour blood pressure monitoring. Well, I would like to be able to order a 24-hour home monitoring test whenever there's a lack of clarity behind diagnosis. It happens a lot where I notice that the blood pressure trend in the office has been high, and I suspect that it more likely than not is not simply a white coat hypertension issue and I would like them to start treatment of some kind. However, I have several patients, for whatever reason, that are very resistant to prescription medications and who would prefer to use so-called naturopathic remedies of various types. Or just flat out refuse medications. Or say look, doc, I don't agree. I think the blood pressures that you guys are getting here are inaccurate and I'll take it myself, with my home cuff or self-monitor I would likely say well, let's meet in the middle. Why don't we do a home monitoring test and really see what they are, with a reliable method of monitoring your home blood pressures that I as your doctor feel confident in. Many PCPs reported that ABPM was a good way to resolve situations where patients presented with unclear BPs readings in clinic, inconsistencies between clinic readings and home readings or when patients were resistant to diagnosis and/or treatment.I don't think I've ever ordered a 24-hour ambulatory blood pressure reading, just because the mechanism is not that readily available. That's pretty much it. Mostly in-clinic manual blood pressure readings is what we rely on. I like the 24-hour monitor because I think it's a more realistic reading of what people are experiencing throughout the day, but I think it's a little bit of a hassle to get it set up for patients, the way that it's set up … it has to be a referral to nephrology and follow up with them, not available in primary care directly. However, PCPs and their patients did not have easy access to ABPM. Some PCPs knew the service existed but stated that ABPM was not easy to order and was not very accessible to patients. This limitation was confirmed by delivery system leaders who reported a limited number of machines and staff available to set patients up with the ABPM monitor. Other PCPs were unaware that ABPM was available to them and had never considered it an option.So, the [patients] that get really into it will notice variations. So, then they will point that out. That's usually useful and helpful, especially if there are some that are on the higher side, because then that leads into showing people there is variation, it may be running higher at times when they don't realize it. Two important themes that were not specific to the measurement methods were patient engagement and the influence of the BP-CHECK study on provider attitudes. This section explores patient engagement and the subsequent section expands on the influence of the BP-CHECK Study. Some PCPs valued BP measurement methods that engaged patients in measuring their own BP. They stated that engagement allowed patients to better understand normal variation in BP and helped them feel empowered to manage it.If a patient measures blood pressure, no matter where, in the pharmacy, gas station, fire station, whatever, if a patient has a chance to measure their blood pressure, if they can write it down, I will count that. I guess patient-centered means patients have different needs …. Some patients don't want to invest in a home blood pressure monitor, they are comfortable coming into clinic and having it checked from time to time or going to a kiosk ... Respondents also acknowledged that patient engagement and patient centeredness require flexibility since patients often have different preferences, needs, and circumstances that shape how they want to and can measure their BP.…we more routinely do that second blood pressure reading and we use the automated, we use the machine. And that came out of one of the discussions about the study and the unreliability of certain techniques and certainly the manual technique is less reliable. So, we have been more consistently using the automated cuff and especially for the second blood pressure reading… I find myself more reliably asking for home blood pressure readings outside of the clinic blood pressure readings as additional information. I have ordered a couple of 24-hour ambulatory measurements since then as well.Interviewer: … Is there anything that you can point to that's influenced that particular change?PCP: I think the awareness of the limitation or the unreliability of the single point measurements in clinic… especially with some of our older frail adults – basing treatment on a one-point measurement, they actually increase the risk of harm if that person really doesn't show hypertension outside of clinic. So really feeling certain about the diagnosis, that the study raised awareness of certainty of the diagnosis before initiating treatment. I'm more willing to ask for and use outside readings. I've always been willing to use them, but I've also usually insisted patients still come into properly document for HEDIS [Healthcare Effectiveness Data and Information Set] purposes their results - I've got to admit I'm a little less concerned about that, and more concerned about let's make the right diagnosis and get you treated. Especially as we're trying to push the numbers down lower for good blood pressure control, I'm willing to accept more outside readings. I don't know if this ambulatory study influenced me in that decision - I suspect partly - just a willingness to be more open to use the outside readings, wherever we can get them. So that may be the only real change at this point. Given that respondents interviewed for this part of the BP-CHECK study had received at least one ABPM report on a patient, they were asked if the study had affected their knowledge, beliefs or practice in any way. Most respondents did not directly attribute any changes in practice to the study, but some talked about increased knowledge, beliefs or awareness of ABPM. A few felt the study changed their beliefs and/or practices related to diagnosis, particularly in increased awareness of the availability and advantages of ABPM and the importance of variability in BP.Interviews with PCPs who had experience with ABPM through the BP-CHECK randomized trial revealed that overall, they preferred clinic-based BP measurement for hypertension diagnosis, especially manual BP measurement. PCPs viewed measurement in clinics as accurate because it is performed by a trained professional who can ensure optimal patient rest and body positioning. For HBPM, PCPs worried about patients’ ability to follow best practices regarding rest and body positioning, the accuracy of the monitors they have at home, and whether repeated measurements would cause patient anxiety. These results suggest that PCPs’ confidence in clinic-based BPs and concerns about HBP may be misplaced given that the main findings of the BP-CHECK study found HBPM for diagnostic testing was more accurate than clinic-based BP follow-up measurements. However, in the BP-CHECK study, patients received free validated home BP monitors and were trained to use them .PCPs were also concerned that there was no acceptable way to document HBPM readings in the EHR for HEDIS purposes at the time of the interviews.  Also, subsequent to the COVID-19 pandemic, the Center for Medicare and Medicaid Services approved use of home BP measurements for reporting quality metrics. Pursuant to this change, our health care system is testing several strategies for collecting BPs from home, including a BP telemonitoring program with BP measurements directly transferred to the EHR or patients hand-entering their home BP readings into secure email sent via the patient's shared EHR.For kiosk-based measurements, PCPs were concerned about maintenance of the BP machines, whether testing in a public setting created stress, and patients’ ability to follow recommended resting time and positioning prior to taking measurements. PCPs also noted that kiosk results tended to be high, which aligns with the results of the main study that found kiosks but not clinic or HBPM methods tended to give higher readings than ABPM .While interviewees acknowledged that ABPM is a very accurate method for measuring BP for diagnostic purposes, they correctly perceived that it was not readily available. ABPM devices are expensive and require specialized software and staff who are trained to do ABPM testing and retrieve the data. However, ABPM could be made more easily available, similar to devices that track arrhythmias that can be set up within primary clinics or mailed to patients directly. We know of only one study that is testing strategies for improving access to ABPM and home BP hypertension diagnostic testing and the results are not yet available . A few POur findings are consistent with and expand on prior studies that explored PCP beliefs and preferences about out-of-clinic BP measurement. One key finding from the literature comes from a systematic review of qualitative studies on patients and physicians. The studies were conducted in the U.K. (6 studies), Sweden (1), Malaysia (1), Canada (1) and the U.S. (2) and were about self-measurement of BP for management of hypertension. For hypertension management (not diagnosis), the review found that physicians: 1) recognized that that home monitoring often gave lower measurements than clinic and that created a dilemma about which BP measurements to use, 2) were concerned that HBPM would increase anxiety for patients, and 3) reported that variability in BP introduced by HBPM increased treatment uncertainty. A survey of general practitioners in the U.K. found that only a minority recognized that threshold values for diagnosis using HBPM were lower than those for clinic measurement , 19. ThiOur study also has a unique focus on diagnosis rather than management: Diagnosis has important implications for if and how individuals understand and begin management for their hypertension. Our findings reinforce Fletcher et al.’s themes regarding the concerns that PCPs have with self-monitored BP, including difficulties interpreting variable BP readings and reconciling them against clinic measurements as well as perhaps unfounded worries that HBPM causes patients to become overly anxious about their BP . We alsoOur findings provide additional insight into the reliance and trust that PCPs place in clinic BP measure. PCPs in these interviews articulated a preference for in clinic BP measurement for diagnosis, which was reinforced by a parallel survey our team conducted that found that 64.7% of PCPs and 88.9% of registered nurses and MAs endorsed clinic BP as the most accurate measurement method . This beOur study has many implications for practice. First, our findings highlight the need for education of both PCPs and patients about how to interpret BP values obtained by different methods using established threshold values for abnormal BP that are available for each BP measurement method. Our findings also show the importance for PCPs and patients of understanding the variability in BP and therefore the benefits of multiple readings. Indeed, PCPs appeared to lack understanding about what to do with variable readings and desire to treat BP as a more static vital sign. Our findings also show the need to find ways to demonstrate the accuracy of HBPM and increase PCP confidence in this measurement method. In addition to the need to address PCP knowledge and attitudes toward BP measurement and diagnosis, our results also show the need to address systems barriers for use of HBPM and ABPM, for example by finding secure, user-friendly mechanisms to integrate HBPM results into EHRs, ensuring that these results are acceptable for HEDIS or other quality metrics, and making ABPM more readily available to PCPs. Another policy and systems challenge that health care delivery is facing in the U.S. is that clinics and health plans are not allowed to provide patients with free home BP monitors, because they are considered to be inducements, and would violate anti-kickback laws. They can, however, loan patients home BP monitors, but getting the monitors back and cleaning them for the next patients presents additional barriers. Resources for training patients to use home BP monitors properly also might not be easily available. Overall, both increased education for PCPs regarding how best to screen for and diagnose hypertension in primary care settings and changes to clinical workflow and infrastructure are needed to improve the rate of hypertension diagnosis and treatment in the U.S.Limitations to our study include that it was conducted in a single large, integrated healthcare system with diverse practice patterns, patients, and providers from 12 clinics. Also, the sample size,while considered robust for qualitative methods, may not have captured all possible PCP perspectives. The PCPs who participated in our study were all physicians and their results may not represent the attitudes and practice patterns of non-physicians who provide primary care within our healthcare system. As part of the study, all interviewees ere offered an educational session on BP measurement and diagnosis conducted by the study leader and had more exposure to ABPM than other PCPs not involved in the trial. We expect that PCPs who were most innovative and interested in research would volunteer to participate in the interviews; therefore, we believe this selection bias may skew our results toward PCPs who are more open to considering new methods for measuring BP and diagnosing hypertension. Finally, the results regarding patient centeredness come from the PCPs rather than patients. Our patient data will be reported in a separate manuscript.Ensuring that individuals with hypertension are appropriately identified and treated is critical to preventing cardiovascular events. Current guidelines recommend confirming elevated clinic measurements in individuals without known hypertension through out-of-clinic BP measurements to establish a diagnosis. Our findings reveal a need to improve PCP attitudes and practices regarding BP measurement for hypertension diagnosis, especially in light of recent evidence that HBPM is a more sensitive method for detecting hypertension than clinic-based measurement and now that out-of-clinic techniques are recommended for accurate diagnosis. At the same time, health systems need to invest in equipment and systems to measure and integrate out-of-clinic BP measurements into the EHR, to better facilitate the diagnosis and management of hypertension.Additional file 1. BP check physician interview guide.