Blood pressure measurement is important for treating patients. It is known that there is a discrepancy between cuff blood pressure vs arterial blood pressure measurement. However few studies have explored the clinical significance of discrepancies between cuff (CPB) vs arterial blood pressure (ABP). Our study investigated whether differences in CBP and ABP led to change in management for patients with hypertensive emergencies and factors associated with this change.This prospective observational study included adult patients admitted between January 2019–May 2021 to a resuscitation unit with hypertensive emergencies. We defined clinical significance of discrepancies as a discrepancy between CBP and ABP that resulted in change of clinical management. We used stepwise multivariable logistic regression to measure associations between clinical factors and outcomes.P-value <0.05) and history of peripheral arterial disease  were factors associated with clinical significance of discrepancies.Of 212 patients we analyzed, 88 (42%) had change in management. Mean difference between CBP and ABP was 17 milligrams of mercury (SD 14). Increasing the existing rate of antihypertensive infusion occurred in 38 (44%) patients. Higher body mass index (odds ratio [OR] 1.04, 95% confidence Interval [CI] 1.0001–1.08, Approximately 40% of hypertensive emergencies had a clinical significance of discrepancy warranting management change when arterial blood pressure was initiated. Further studies are necessary to confirm our observations and to investigate the benefit-risk ratio of ABP monitoring. Blood pressure (BP) monitoring is an essential component of managing hypertensive disease processes, many of which require maintenance of specific BP windows. Intra-arterial blood pressure (ABP) monitoring is widely considered the gold standard of BP measurement in critical care settings; however, its invasive nature also presents some rare but serious risks including bleeding, thrombosis, infection, embolism, and nerve damage.4Previous studies have shown, however, that discrepancies exist between noninvasive CBP and invasive ABP measurement.Guidelines established by several professional societies recommend specific BP goals for various hypertensive disease states. For example, current guidelines for management of acute aortic diseases suggest a SBP goal of <120 millimeters of mercury (mm Hg) in Type A dissection and SBP goal of <140 mm Hg in Type B dissection.A few previous studies provide evidence for the utility of ABP monitoring in hypertensive critically ill patients. Manios et al found that CBP measurements underestimate ABP in patients with ischemic stroke, most markedly in those with critically high SBP.Our prospective study sought to investigate the clinical significance of the difference between ABP monitoring vs CBP monitoring, in real time, among patients with hypertensive critical illnesses. We specifically aimed to determine whether the difference in monitoring between CBP and ABP would result in change in clinical management for patients with hypertensive emergencies and to identify clinical factors predicting change in management between the two measurement modalities. We hypothesized that the difference between monitoring of ABP and CBP values would lead to a change in BP management in at least 30% of our patients with hypertensive emergencies.What do we already know about this issue?Discrepancy between arterial (ABP) vs cuff blood pressure (CBP) monitoring exists. CBP is commonly used although ABP monitoring is considered the gold standard.What was the research question?Does a discrepancy between the two blood pressure monitoring modalities result in change of clinical management?What was the major finding of the study?88 patients (42%) had a change of management in real time resulting in increasing doses of antihypertensive medication.How does this improve population health?In a patient with hypertensive emergency whose blood pressure is at borderline of recommended guidelines, ABP should be considered.This prospective observational study took place in the critical care resuscitation unit (CCRU), an intensive care unit (ICU)-based resuscitation unit that was created at our quaternary-care institution with the goal of expediting transfer of patients with time-sensitive critical illnesses from other hospitals when there are no available beds at one of our traditional ICUs.We included consecutive adult patients with any hypertensive emergency diagnosis  who required ABP monitoring upon admission to the CCRU between January 2019–May 2021. Patients who had CBP and ABP measurements within 60 minutes of each other were eligible. Exclusion criteria included the following: arterial catheter in place prior to arrival; arterial catheter and BP cuff placement on opposite side of body ; unreliable arterial measurements according to the clinicians; use of vasopressors prior to or starting at the time of arterial catheter placement. We additionally excluded patients with non-hypertensive diagnoses . We excluded these patients because their BPs are managed differently. Patients who require vasopressors or have nonhypertensive diagnoses are managed in accordance with their mean arterial pressure, instead of SBP, as recommended by previous management guidelines for hypertensive emergencies.Prior to the study recruitment period, we created a standardized form and educated the CCRU clinicians  on the use of the form for all patients requiring arterial catheter placement. Most of the CCRU nursing staff were blinded to the study hypothesis and were not involved in preparation of the manuscript. The form contained sections for clinicians to record patient demographic information , CBP values, ABP values, arterial catheter site , cuff site (right/left arm or leg), and management decisions as guided by each BP value.Before placing the arterial catheter, the CCRU nurse or the clinician prospectively filled out the form in real time to indicate CBP values immediately and the associated management according to the CBP monitoring values . After arterial catheter placement, the clinicians additionally recorded the ABP monitoring values and the management decision guided b those values . An APP and the principal investigator adjudicated the missing data on the prospective data collection form, using patients’ electronic health records (EHR). We identified approximately 23 patients (11%) who did not have a diagnosis that required ABP monitoring in the CCRU. These included 14 patients with aortic aneurysms and nine other diagnoses.Members of the research team retrospectively collected additional patient data from our institution’s EHR. Extracted demographic information included age, gender, body mass index (BMI), and past medical history. They also collected clinical data during hospitalization, including lab values (serum creatinine and lactate), echocardiography results , medications used at the time of arterial cannulation, and patient outcomes . Additionally, they collected information regarding complications associated with arterial catheter cannulations and total duration of arterial catheter insertion. We defined arterial catheter complications as bleeding, aneurysm, extremity necrosis, local nerve damage, or definitive source of local or systemic infection or embolism.We obtained all retrospective data in compliance with methodologic standards for medical record review.Our primary outcome was the prevalence of clinically significant difference between measurements of ABP and CBP monitoring. We defined this as a difference in clinical management based on the values obtained from ABP vs CBP monitoring, as determined in real time by the clinicians upon placement of the arterial catheters. For example, the American Heart Association Task Force on Practice Guidelines recommends a SBP of ≤120 mm Hg for type A aortic dissection.If a patient with Type A aortic dissection had CBP of 115 mm Hg and ABP of 125 mm Hg, the difference in BP measurements necessitated a change in management between the two modalities. In this case, the CBP value indicated the SBP was at goal and no further action was needed. In contrast, the ABP suggested that increasing the dose of the current antihypertensive infusion was warranted. Alternatively, if the patient had CBP of 135 mm Hg and ABP of 145 mm Hg, the clinician indicated that both values required increasing the dose of current antihypertensive infusion, in accordance with the guidelines to lower SBP to ≤120 mm Hg. Thus, this action indicated that no clinically significant difference existed.Our secondary outcomes included mean difference between CBP monitoring and ABP monitoring and the percentage of patients with difference of ≥20 mm Hg between the two modalities. Given that previous guidelines suggested that patients with a difference of ≥20 mm Hg may be at risk for worse outcomes than those with a difference ≤20 mm Hg,We calculated our sample size according to a prior study from Ruszala.t-test or Mann Whitney U test, while the chi-square test was used for categorical variables.We used descriptive analysis to present patient data. Categorical variables are presented as percentages, and continuous variables are reported as mean (+/− SD) or median (interquartile range), as applicable. We analyzed differences between groups of continuous variables using the Student To graphically represent the distributions of ABP and CBP monitoring differences, we used the Bland-Altman analysis. The Y-axis of the Bland-Altman graphs depicted the values of [ABP-CBP] differences. If ABP values are >CBP values, there would be more dots in the positive region of the Y-axis. The X-axis represented the ranges of patients’ CBP monitoring values. A dispersed distribution along the X-axis would suggest that the differences between [ABP-CBP] occurred at all ranges of CBP monitoring values.P-value > 0.05 indicates a model with a good fit of independent variables. We reported the variance inflation factors (VIF) for assessment of the multicollinearity of independent variables, and factors with VIF ≥5 were considered to have high multicollinearity and thus were removed from the logistic regression. The discriminatory capability of the regressions was assessed via the area under the receiver operating curve (AUROC). Models with AUROC approaching −1 or +1 were considered having perfect discriminatory capability between dichotomous outcomes.We used forward stepwise multivariable binary logistic regressions to identify associations between independent variables and the outcomes . We a priori determined the independent variables included in regression analysis, which are listed in P-value of less than 0.05 was considered statistically significant.We performed all statistical tests using Minitab version 19.0 . A We identified a total of 350 patients with hypertensive diagnoses and arterial catheter cannulation for ABP monitoring between January 2019–May 2021 . Among tOf the included patients, the most frequent hypertensive diagnoses included spontaneous intraparenchymal hemorrhage (22%), type A dissection (20%), type B dissection (16%), and subarachnoid hemorrhage (14%) . BaselinThe mean difference between ABP and CBP in the overall study population was 17 mm Hg (SD 14), with a mean difference of 11 mm Hg (SD 10) in the group without clinically significant BP difference and 26 mm Hg (SD 14) in the group with clinically significant difference . SeventyThe Bland-Altman graph illustrating [ABP-CBP] differences among the included patients demonstrated that the mean difference between the two BP measurements was 10.6 mm Hg . The graWithin our study population, 88 of 212 patients (42%) had a clinically significant difference between CBP and ABP monitoring as demonstrated by a change in management between the two measurement modalities . Of patiOf patients who did not have a change in management between ABP and CBP monitoring, 64% required continuation of the current regimen, 23% required an increased dose of current antihypertensive infusion or an addition of a new medication per both values, and 2% warranted a decreased dose per both CBP and ABP monitoring . In 11% P-value <0.05). Patients who had history of peripheral arterial disease were also associated with having lower likelihood of a clinically significant difference between ABP and CBP monitoring   . The modWhile two retrospective studies have demonstrated clinically relevant differences in CBP and ABP measurements,In this study, CBP monitoring underestimated ABP monitoring (by 17 mm Hg on average), and measurement of the latter warranted increases in antihypertensive medication. This suggests that the use of CBP monitoring alone to guide management of patients with hypertensive emergencies may result in unrecognized and untreated levels of hypertension. Barton et al suggested that patients with spontaneous intracerebral hemorrhage who sustained hypertension during the acute phase in the emergency department (ED) were associated with poor neurological outcome at one-month and 12-month follow-ups.36Although patient outcomes  in univariate analyses were not different between groups with or without clinically relevant differences, clinicians should thus consider the use of ABP monitoring in hypertensive patients for whom adherence to specific BP goals is important. Additionally, when a patient is having BP at the borderline recommended by current guidelines, coupled with prolonged boarding time in the ED, the addition of ABP monitoring would provide helpful information for further medical decision-making, as it has been shown that CBP monitoring is not as reliable.The use of invasive ABP monitoring is not entirely without risk and expense. Risks of ABP monitoring include bleeding, thrombosis, infection, embolism, and nerve damage; however, the incidence of complications is low with major complications occurring in less than 1% of cases.The use of ABP monitoring does incur additional cost of care. At our institution, the one-time, per-patient supply cost for initiation of ABP monitoring is approximately $55 US dollars (USD). With a change in management rate of 42% among our patients upon insertion of an arterial catheter, ABP monitoring was able to detect one change in management for approximately every three patients. The total cost to detect one clinically significant BP difference for every three patients with hypertensive critical illness is, therefore, $165 USD. This observational and exploratory study was not designed to detect differences in patient outcomes such as mortality, ICU or hospital length of stay, and did not demonstrate a direct benefit for ABP monitoring in the study patient population. Further studies should investigate the benefits-risk ratio between potential benefits vs financial cost and complications between ABP and CBP monitoring.Within our patient population, patients with clinically significant difference between CBP and ABP monitoring had higher BMI than those without a clinically significant difference , although the difference was not statistically significant. Previous studies have identified an association between obesity and greater differences between ABP and CBP monitoring, with CBP measurements typically underestimating direct intra-arterial SBP.14both ABP and CBP monitoring values from patients with peripheral artery disease, and their resulting arterial stiffness, would be higher than the recommended goal of SBP by guidelines. Thus, both ABP and CBP monitoring values would recommend an increase of current antihypertensive infusion, which is not considered a change in clinical management by our definition. However, our patient population included only six (3%) patients with peripheral artery disease; further studies with higher percentages of patients with peripheral artery disease are necessary to confirm our observations. The result from our multivariable logistic regression also showed that ABP monitoring on the right side was associated with lower likelihood of greater differences between CBP and ABP. While our study could not explain these findings, it could be a confounding finding or it could be due to the number of patients with acute aortic dissection within our patient population. Patients with acute aortic dissection have been shown to have greater differences between both arms, with BP on the left arm being affected more.Our finding that patients with peripheral artery disease were associated with lower odds of change in clinical management appeared counterintuitive at first. However, a study by Iida et al suggested that patients with arterial stiffness would have higher BP than those who did not.Although identification of specific subsets of patients who would most benefit from ABP monitoring may be helpful in directing the placement of arterial catheters in the acute stages of illness, our study revealed very few predictors of such. The high incidence of clinically relevant ABP-CBP discrepancy and lack of clear distinction as to which patients are more likely to require different BP management after placement of an arterial catheter suggest that clinicians should consider invasive ABP monitoring more often in patients with hypertensive emergencies requiring a continuous antihypertensive infusions, at least during the acute resuscitation phase.Our study has several limitations, the first having to do with the clinical setting and the patient population. Although most of these disease states are encountered in the ED setting, the results in our setting may not be applicable to many EDs. Thus, our study may lack external validity. Additionally, we did not address any downstream consequences, such as clinical outcomes and throughputs that could have been derived from the change of clinical management of these patients, as this topic was beyond the scope of this study. The heterogeneity of our patient population with respect to hypertensive emergency diagnosis limits our ability to draw conclusions about specific subsets of hypertensive disease. Because intra-arterial BP monitoring is considered the gold standard, we did not randomize patients to management guided by ABP vs CBP monitoring to determine associations between each measurement modality and patient outcomes. Finally, our limited sample size may have prevented accurate depiction of the incidence of arterial catheter complications or patient-related outcomes. Despite these limitations, our study does provide further evidence to support the use of invasive arterial catheters for BP monitoring in patients with hypertensive emergencies and requiring continuous antihypertensive infusions.Approximately 4 in 10 patients with hypertensive emergencies had a change in management between monitoring of cuff blood pressure vs arterial blood pressure monitoring, indicating clinical relevance of the discrepancy in BP values obtained by these two measurement modalities. Patients with high BMI were associated with higher likelihood of requiring change of management due to the discrepancies between ABP and CBP monitoring. Additional studies and less heterogenous patient pathologies are recommended to further explore patient outcomes associated with these findings. Further studies are necessary to confirm our observations and to investigate the benefit-risk ratio of arterial blood pressure monitoring.


Background: Endstage kidney failure rates are higher in South Asians than in White Europeans. Low birth weight is associated with adult chronic kidney disease and is more common in South Asians. Foetal kidney size was smaller in South Asians in the Born in Bradford (BiB) birth cohort. As part of BiB follow up, we aimed to investigate if there were ethnic differences in kidney function and blood pressure in early childhood and whether this was different by foetal kidney size.Methods: Serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP) were analysed in blood and urine samples from those who participated in the BiB follow-up at 7–11 years. Ethnicity was categorised by parental self-report as White European and South Asian. Estimated glomerular filtration rate (eGFR) was calculated using Schwartz, and cystatin C Zappitelli and Filler equations. Linear regression was used to examine the association between ethnicity and eGFR, PCR and blood pressure.Results: 1591 children provided blood (n=1403) or urine (n=625) samples. Mean eGFR was 92 ml/min/1.73m2 (standard deviation (SD) 9) using Schwartz (n=1156) and 94 (SD 11) using Zappitelli (n=1257). CKD prevalence was rare  had raised ACR (>2.5 mg/mmol in boys/3.5 mg/mmol in girls). Diastolic blood pressure was higher in South Asian children  but was not significant in adjusted analysis. There was no evidence of association in adjusted models between ethnicity and any eGFR or urinary measure at this age.Conclusions: There was no evidence of significant ethnic differences in kidney function at pre-pubertal age despite differences in kidney volume at birth. Longitudinal follow-up is required to track ethnic patterns in kidney function and blood pressure as children develop through puberty. The reasons are not fully understood but Type 2 diabetes and diagnosed hypertension are more common in South Asian adults and blood pressure (BP) is higher at similar levels of obesity. Whilst two primary care studies in the UK reported decreased stage 3 chronic kidney disease (CKD) prevalence in South Asians, the prevalence was higher in South Asians at more advanced stages. Albuminuria is more common in South Asians. Data on differences in CKD progression to ESKF in South Asians and competing risk of mortality are limited.The incidence of end stage kidney failure (ESKF) is higher and occurs at a younger age in adults of South Asian heritage compared to White EuropeansThe excess incidence of advanced CKD has major implications for disease burden internationally, as the South Asian diaspora increases and ages, and globally with over 1 billion people on the Indian subcontinent. CKD is an independent factor for cardiovascular disease, and understanding causation is key to prevention of CKD and its complications in such populations. and is associated with adult chronic diseases such as hypertension and Type 2 diabetes that are associated with CKD. A systematic review and a subsequent study found an association between LBW and CKD though there were no specific data on South Asians. One hypothesis to explain such CKD risk is that intra-uterine growth retardation (IUGR), especially in the third trimester when foetal kidney development occurs, leads to reduction in nephron number and lower kidney size at birth. As nephron number is fixed at birth, compensatory glomerular hypertrophy, hyperfiltration and hypertension, could lead to further reduction in nephrons, and susceptibility to kidney damage. IUGR has been found to be associated with albuminuria in infancy, with similar estimated Glomerular Filtration Rate (eGFR) at age 2 despite smaller kidney size, suggesting hyperfiltration, and with diastolic blood pressure (dBP) at age 6.Kidney development is one area of focus as low birth weight (LBW) is more common in South Asians. ln a renal subset of BiB (n= 1587), we showed that mean foetal kidney volume at 34 weeks gestation was 16% lower in South Asian babies. In the Generation R cohort in the Netherlands, lower foetal kidney volume was independently associated with reduced eGFR and kidney volume at age 6. In the BiB cohort, dBP was higher in Pakistani children at age 4/5 years.The Born in Bradford (BiB) birth cohort is a prospective longitudinal multi-ethnic birth cohort study that aims to examine the impact of environmental, psychological and genetic factors on health and wellbeing in a deprived population. The full BiB cohort recruited 12453 women involving 13776 pregnancies (13858 births) between 2007 and 2010The BiB cohort is an ideal context in which to explore the origins of ethnic differences in CKD. This study aimed to investigate whether there were ethnic differences in kidney function and damage and BP in childhood (age 7–11 years) and whether this was different by foetal kidney size.Women were recruited to the BiB cohort study while attending for their glucose tolerance test (OGTT), offered to all pregnant women registered at Bradford Royal Infirmary at 24–28 weeks of gestation.BiB Growing Up Study). Detailed parent and child questionnaires, BP, anthropometry and blood samples were collected. Written informed consent was collected for the follow-up and for continued routine data linkage.BiB children aged 7–11 years and their families were followed up using a multi-method approach between 2017 and 2020  at 34 weeks for standard anthropometrics and foetal renal dimension measurement. Data on renal ultrasound was available for 1802 women, details of recruitment and ultrasonography were published previouslyBiB renal ultrasound follow-up. This was expanded to the broader cohort due to lower than expected uptake and children who had blood sampling as part of their BiB Growing-Up follow-up were included. From January 2019, all participants who agreed to blood sampling were also asked to provide a urine sample. We called this theBiB extended renal follow-up. Study recruitment ended in March 2020.Recruitment for the renal US sub-study follow-up commenced in January 2018 and was initially limited to children whose mothers had participated in the baseline renal sub-study and had a foetal ultrasound, termed theFor this analysis we only included those with a White European or South Asian ethnicity, who were born at term and who provided blood or urine measures.. Non-fasting blood samples were taken. First morning urine samples were taken at home and transported to the Bradford Royal Infirmary laboratory. Data collection was undertaken by trained staff in schools, clinics or at the participant’s home using standard operating procedures.Participants’ height and weight were measured without shoes and in light clothing. BP measurements were taken at the brachial artery preferably on the left arm, twice with skinfold measurements in between the first and second measurement, using an Omron electronic monitor 705-CPII. The appropriate cuff size was used. Children were seated for two minutes prior to the BP measurement. One BP measurement was recorded per child consistent with other studies undertaken within a school settingBlood samples were analysed for creatinine, urea and cystatin C. Creatinine and urea were analysed on Beckman AU650. The creatinine calibrator is traceable to the Isotope Dilution Mass Spectrometry (IDMS) reference method used by the National Institute of Standards and Technology Standard Reference Material 967. The coefficient of variation (CV) for serum creatinine was 5.7%. Cystatin C was measured using particle enhanced immunoturbidimetric assay on Roche/Hitachi cobas c systems. The assay is standardised against the ERM-DA471/IFCC certified reference material for cystatin C. CVs were 1.6–2.6% in the range assayed.Urine samples were analysed for protein, albumin, creatinine and retinol binding protein (RBP). The urine protein method was based on Pyrogallol red, urine albumin using a turbidometric assay and urine creatinine was an enzymatic assay, all measured on Beckman AU680. The limit of detection for urine albumin was 3mg/L. CVs were 2.6% for creatinine, 8% for albumin and 7.5% for protein. RBP was measured using the immunonephelometry method on a Siemens Atellica630 Neph Nephelometer. The reference range is <15mg/L, the limit of detection is 3mg/L and CV was 5.3%.Outcomes included eGFR, urinary albumin to creatinine ratio (ACR), urinary protein to creatinine ratio (PCR), RBP and systolic blood pressure (sBP) and dBP. Each outcome was considered separately and all (except RBP) were assessed as continuous variables. eGFR was calculated using four published equations as follows:cr)Schwartz creatinine only = 41.3*(height (m)/ S2)/Scr(mg/dl)]0.456 x [1.8/cystatin C (mg/L)]0.418 x [30/blood urea nitrogen (mg/dl)]0.079 x [1.076male] x [height (m)/1.4]0.1792012 CKiD Schwartz combined serum creatinine and cystatin C = 39.8 x [(height (mZappittelli cystatin C only = 75.94/[cystatin C^1.17]Filler cystatin C only log(eGFR) = 1.962 + (1.123*log(1/cystatin C))Child height required to calculate eGFR using both Schwartz equations was measured at the same visit as the blood sample in 52.0%, the height measurement was standardised to time of sample using centile charts if not measured at the same visit.Urine albumin was only detectable in 296/595, 49.7% of the sample.. Mothers of other ethnicities (n=68) were excluded due to small numbers. Ethnicity was categorised as White British and South Asian (predominantly of Pakistani origin).Ethnicity was self-reported by mothers at baseline interview, with participants given response options based on the UK Office of National Statistics guidanceMaternal: body mass index (BMI), age, parity, smoking, alcohol consumption, measures of socio-economic position , marital status  and gestational diabetes (during pregnancy).Child: Birth weight, gender and gestational age at birth; age and measured weight and height at follow-up. Measured weight and height were used to calculate BMI and body surface area (BSA). BMI was converted to age- and sex- adjusted z-scores according to the UK 1990 growth reference charts. BSA was calculated using the Du Bois formula (BSA = weight (kg)0.425 x height (cm)0.725 x 0.007184). BP was not identified as a covariate to adjust for from the directed acyclic graph (DAG) but as the direction of this relationship is not known, we included BP as a covariate Basic descriptive statistics are presented for the overall sample and stratified by ethnicity. Univariable comparisons were carried out using t-test (continuous variables) and chi square test . Pearson correlation was used to assess the relationships between the outcome measures . Linear regression was used to examine the association between ethnicity and the outcome measures, except for the ACR detectable binary outcome where logistic regression was used with the ACR result outcome conditional on a positive ACR detectable outcome.Covariates were added sequentially to form multivariable models:Model 1: maternal age, maternal education, housing tenure, employment status, marital status and child age at kidney function measurement (socio-demographic);Model 2: additionally adjusted for maternal BMI, parity, smoking and alcohol consumption in pregnancy, and gestational diabetes ;Model 3: further adjusted for birthweight, BSA (kidney outcomes) or BMI (BP outcomes), gender, sBP and dBP (kidney outcomes) (fully adjusted).We adjusted for foetal renal volume in the sub-sample that had renal ultrasound scans in pregnancy. A statistical significance level of 0.01 with 95% confidence interval (CI) was used.Data on covariates such as marital status, employment status and housing tenure collected through baseline questionnaires were missing in women who did not complete the questionnaire (n=1057 of 12453 women from the BiB baseline sample). Some of these women completed an additional questionnaire at follow-up which reduced the missing data on ethnicity and educational attainment but not on other covariates. It was not possible to impute missing data as data were missing on all variables collected using the baseline questionnaire.We undertook sensitivity analysis to explore the impact of differences in timing of height measurement and blood sampling for the Schwartz eGFR formulae by comparing estimates using standardised height, height as measured without accounting for timing between sampling and measurement, and sample restricted to those with height measurement and blood sample at the same. We also undertook sensitivity analysis replacing BSA with BMI in eGFR, ACR and PCR models.Ethical approval was granted by the Bradford Research Ethics Committee  for Growing Up).In total, 1591 children were available for this analysis, 1403 provided a blood sample and 625 a urine sample . OverallIn total, 986 provided samples (largely blood) in the BiB extended follow-up group, and for response were compared to those who participated in the follow-up but did not provide blood samples. The response rate in both groups was higher in South Asians and in boys, but there was no difference in birthweight or renal volume between responders and non-responders . 2 (SD 5.7). 10% of mothers smoked during pregnancy and 11% reported consuming alcohol. Compared to White European mothers, South Asian mothers were more likely to: be older; be married; to own their own home, be of lower educational attainment and higher parity, and less likely to work, smoke or drink alcohol during pregnancy. A higher percentage had gestational diabetes. Renal volume, birthweight and renal volume adjusting for birthweight were significantly lower in South Asian babies.Of the 1591 participants, 69.1% were South Asian and 40.1% had further and higher maternal education . Mean ma2 (SD 9) using Schwartz combined and 94 ml/min/1.73m2 (SD 11) using Zappitelli  with ACR ≥2.5 mg/mmol in boys/3.5 mg/mmol in girls). RBP results were within the normal range for the whole sample. Mean eGFR was slightly higher in South Asian children when using creatinine formulae, but no difference was seen in Cystatin C or Cystatin C based eGFR. Mean ACR and PCR were similar in both ethnic groups. sBP was similar in both ethnic groups but mean dBP was slightly higher in South Asians  than in White Europeans  and the difference was significant (p<0.001). sBP had a small negative correlation with cystatin C eGFR (-0.12) but all other correlation estimates of BP and eGFR/ACR/PCR were <0.1.Mean eGFR was 92 ml/min/1.73mpitelli . CKD preExtended data, Supplementary Table 1).Whilst South Asian children had higher eGFR than White European children using creatinine-based formulae and a higher dBP, these findings were only significant in the unadjusted models and the socio-demographic model for dBP . There wExtended data, Supplementary Table 3).Adjusting for renal volume in the BiB renal ultrasound follow-up subsample did not affect the estimates . There w.South Asian adults are at high risk of premature severe CKD. Prevention of adult CKD may be informed by better understanding of the early origins and lifecourse determinants. Using BiB data, we have previously shown that South Asian infants have smaller kidneys compared with white European infants. It is therefore possible that changes may manifest later in development, hence the need for further follow-up.In this study whilst unadjusted models found higher dBP and higher creatinine-based eGFR in South Asian children, there were no significant ethnic differences in adjusted models on renal function or BP at 7–11 years. These results suggest that any impact of reduced foetal renal volume was not biologically significant on kidney function by this age or alternatively that there was compensation for the presumed reduced nephron number at birth by hyperfiltration. Surinamese Hindustani children had lower kidney volume. The authors concluded that whilst these differences were not clinically significant , they may track and alter adult CKD risk.Published data on ethnic differences in childhood kidney function are very limited. Ethnic differences in kidney volume and function in various ethnic groups (which did not include those from the Indian subcontinent) were found in the Generation R cohort in the Netherlands. Compared to Dutch children, Moroccan and Turkish children aged 6 had a higher eGFR whereas Dutch Antillean and Surinamese-Creole children had a lower eGFR. Ethnic differences in BP were found in the Generation R cohort with Cape Verdean and Turkish children having higher sBP and dBP compared to Dutch children. In a review, higher dBP in Pakistani children was found in the 1999 Health Survey for England (5–15 years) though not in three other studies where ethnicity was combined as South Asian; but was also found in a cross-sectional study in England at 9–10 years and in a longitudinal school-based cohort in London at 14–16 years (though not at 11–13 years).The BP findings extends BiB findings of higher dBP in South Asian Pakistani children aged 4–5 years, which was not related to socioeconomic factors. eGFR calculated using the Filler formula was the highest which has been observed previously. Cystatin C formulae may be more sensitive than creatinine formulae for evaluating kidney function which has been suggested previously given it is freely filtered by glomeruli, fully catabolised by renal tubules and not excreted by non-renal routes. As in adults there is no correction for ethnicity in eGFR formulae.Our study strengths include a large predominantly bi-ethnic population from the same city, availability of baseline foetal and maternal data on covariates, a subsample with detailed ultrasonography with high reliability in pregnancy for renal measures and first morning urine sample taken to measure albuminuria and proteinuria. We measured both creatinine and cystatin C so could compare the findings using the different formulae, all have been validated in paediatric populations. eGFR calculated using the Schwartz creatinine only formula was higher than that using the Zappitelli cystatin C, similar to other studiesThere were limitations to the study. Uptake to follow-up was lower than expected in the renal ultrasound sub-study, and we had to supplement with recruitment opportunistically from those providing a blood sample. This limited our power to study renal volume effects and led to the inclusion of a sample with higher levels of missing baseline data as a proportion of mothers had not filled out the baseline questionnaire. We did not attempt to impute missing values as we had limited data on such individuals. The lower than expected uptake highlights the challenge of undertaking follow-up in a population with ethnic diversity with high levels of socio-economic disadvantage, especially with invasive testing. There was a difference in timing between anthropometric measurements and blood sampling in some children which might have affected the creatinine based eGFR measurement though we used growth centile charts to take this into account, and sensitivity analysis showed no difference. However, we had a slightly higher proportion of South Asian children (54%) than White children (40%) with a difference in timing between the blood sample and height measurement. The growth centile charts are for the UK general population and may overestimate eGFR in South Asian children. Our assessment of kidney function and BP were based on a single measure as in other studies and any variation is likely to reduce the strength of any associations. We had no valid measures of kidney volume in childhood as this was not practically feasible.. The prevalence of albuminuria in children aged 5–18 years from the Australian Health Survey 2011–2013 was 12.8% and higher in girls (15.5%) than in boys (10.2%). A population-based cross-sectional study in Australia (2015–16) reported a higher prevalence of albuminuria  in children aged 11–12 years. The cut-off used to define albuminuria in both Australian studies was different (ACR >3.4 mg/mmol ACR). All three studies used a random urine sample whereas we used the first morning urine sample. The lower prevalence in our study is unexplained.We found lower levels of microalbuminuria (2.5%) than in the Generation R cohort (7.1%) in children followed up at median age of 5.9 years  using the same cut-offs to define microalbuminuriaIn conclusion, there was no evidence of significant ethnic differences in kidney function at pre-pubertal age despite the lower kidney volume at birth in South Asian babies in those with foetal renal ultrasound scans. However South Asian children may be at higher long-term CKD risk through reduced foetal kidney volume with compensatory hyperfiltration, higher BP, and greater propensity to adverse metabolic patterns. Promoting kidney development through childhood and adolescence, for example by aiming for normal weight trajectory and obesity avoidance would be relevant for all children but especially those with higher adult CKD risk such as South Asians. Further longitudinal follow-up is required in the BiB cohort through adolescence when any propensity to metabolic risk becomes more apparent, measuring kidney function and ideally size, to see how kidney function and BP measures track, and to determine if there are emerging differences by ethnicity. This would inform population strategies and risk stratification to prevent adult CKD. The manuscript is basically unchanged. My previous comments regarding the calculation of eGFR in South Asian children and the use of BP index have not been addressed. The authors have not described the limitations of the study on these points either. For example I previously pointed out the presence of the paper on eGFR formulae in South Asian adults, yet the authors have kept the following description; “As in adults there is no correction for ethnicity in eGFR formulae.” They have described the method of BP measurement, but what is the rationale for the following? “One BP measurement was recorded per child consistent with other studies undertaken within a school setting.”Is the work clearly and accurately presented and does it cite the current literature?NoIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?NoAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?NoReviewer Expertise:Developmental origins of health and disease, pediatric nephrology, development, blood pressureI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. The authors responded well to the comments of the reviewers, I have no further comments.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pediatrics, Kidney disease, epidemiologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The authors report on a longitudinal data of mixed ethnicity (South Asians Vs White British) birth cohort in England, concentrating on kidney volume  at 34 weeks gestation (absolute and corrected for birth weight)  and kidney function as assessed during school age, including serum creatinine, cystatin C and urine albumin. The authors report that even though birth weight corrected kidney volume was lower in children of South Asian ancestry. kidney function was not significantly differentץ The overall rate of detection of permanent kidney damage in this study was low   with ACR ≥2.5 mg/mmol in boys/3.5 mg/mmol in girls).Selection bias: only < 2000 out of 13000 pregnancies have been originally followed since pregnancy. The accuracy of a fetal US  to assess true kidney volume.  Specific critiques:   The study reflects a huge effort, and its results are worth a indexing. My concern remains on the methodology, regarding mostly: Are there different normal growth charts for White British and South Asians?Could there be more South Asians than White British with missing heights?Did the authors consider using the new height independent child eGFR equations developed by Pottel et al. ?  Minor critiques:  Page 5 :"Child height required to calculate eGFR... was measured at the same visit as the blood sample in 52.0%, the height measurement was standardised to time of sample using centile charts if not measured at the same visit."  Please comment on the possible bias of this analytical decision, specially. related to:  Page 3 : "Women who were attending for the OGTT at 26–28 weeks of gestation... etc". Please clarify this abbreviation when first used: is it "oral glucose tolerance test"?Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?I cannot comment. A qualified statistician is required.Are all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Clinical pediatric nephrology, epidemiology of childhood CKD, genetic renal diseasesI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. >6000 of the original cohort were followed up at 7-11 years. The renal study was undertaken in a sub-sample and the sample size of 1591 are the participants that provided a blood or urine sample for renal analysis. We assessed difference in sample characteristics at follow-up using selected descriptive variables at baseline (presented in Table 1). There was no obvious major response bias but limited our statistical power as uptake to the follow-up component was lower than expected. The low uptake highlights the challenge of undertaking follow-up in a population with high levels of socio-economic disadvantage and ethnic diversity, especially with invasive testing. We have stated this as a limitation.The fetal ultrasounds were performed by experienced sonographers and intra-observer reliability was high. We are unaware what study the reviewer is referring to regarding the accuracy of the fetal ultrasound and would appreciate if the reviewer could direct us to this. Specific critiques:  No, the growth chart used is for the UK general population and used in clinical practice. However, this could overestimate eGFR and we have added this as a limitation.All children had a recorded height measurement. There was a slightly higher proportion of South Asian children (54%) than White children (40%) with a difference in timing between the blood sample and height measurement which may have introduced bias due to the greater use of growth charts in south Asian.Thank you for the suggestion of height independent eGFR equations. This equation requires a population median serum creatinine which we do not have. We have taken a similar approach and used equations used in other literature that we have cited. Minor critiques:  Thank you, we have clarified the abbreviation at first use in the first paragraph under the methods section. The study aimed to investigate ethnic differences in kidney function and blood pressure (BP) in early childhood, specifically comparing South Asian and White European children. In 1591 children aged 7-11 years, estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio, and BP were assessed. The results showed no significant ethnic differences in kidney function at pre-pubertal age, despite previous findings of smaller fetal kidney size in South Asian children. Diastolic BP was slightly higher in South Asian children.. eGFRcys, on the other hand, underestimates measured GFR . In view of these facts, the use of Schwarz or Zappitelli formulae in South Asian children cannot be justified. The modified formulae to estimate eGFR in South Asian children is needed.In adult South Asians, eGFRCr was reported to overestimate measured GFR, and the modified equation has been created  Page 13, right first line; “As in adults there is no correction for ethnicity in eGFR formulae.“ This statement is erroneous. It is currently not available in children but is needed. The higher creatinine-based eGFR in South Asian children than White European children is in fact contrary to what is expected. The authors speculate this to be due to compensation. Overshooting by compensation (higher eGFR than White European children), however, is unlikely.Regarding BP measurement, the authors do not state which measurement value (before or after the skinfold measurement or the average of the two) was used. The arm width is expected to be variable with the age of the study subjects (7-11 years). Was the right cuff size selected? Also, as the authors stated, the BP was measured on one occasion only. The difference of diastolic pressure between South Asian and White European children is subtle and could result from small variations during BP measurements.One more important point is that in children BP is assessed according to reference values by gender, age, and height. Therefore BP index (BP divided by 95th percentile BP for each patient) not raw values should be used for comparison. The aim of the study is important and the methods are appropriate except for the following two points.Is the work clearly and accurately presented and does it cite the current literature?NoIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?NoAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?NoReviewer Expertise:Developmental origins of health and disease, pediatric nephrology, development, blood pressureI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. https://pubmed.ncbi.nlm.nih.gov/29492066) compared updated Schwartz, original Schwartz and height independent formula to look at eGFR in Pakistani children. Although the sample was malnourished children, the authors found no differences between the different formulae. We recognize there are challenges with different methods of measuring eGFR but we based our approach on those that are well recognised in the literature.  1. Thank you for the suggested references but both are in adults. No formulae are available for children that takes account of ethnicity. While we agree that the different formulae may under- or over-estimate eGFR and that a correction may need to be applied in South Asians, no reliable correction is available for children. This paper ,  who have used actual blood pressure values. 3. Thank you, we are not categorising the individuals as hypertensive where you do need reference values. We followed others ( This report is a birth cohort study from the UK (BiB) assessing ethnic differences in kidney outcomes during childhood. The authors investigated whether South Asian children in the UK who are known to have lower birthweight and kidney volume a birth than White Europeans are at higher risk of early kidney disease at age 7-11. Out of >13,000 children enrolled in the BiB birth cohort, about 1,600 were included in this analysis, of whom a subgroup of 600 had a renal ultrasound follow-up at 8-11 years. In multivariable analyses, there was no differences in various kidney outcomes  between the South Asian and White European populations. In the subsample with renal ultrasound follow-up, the significant ethnic difference seen in kidney volume at pre-pubertal age did no translate into differences in kidney function or blood pressure. The authors concluded that despite no apparent kidney impairment at 7-11 years, South Asians children may be at higher long-term CKD risk due to reduced nephron mass so longitudinal follow-up remains necessary. The paper is very well written, the BiB birth cohort well conducted and the methodology is sound. The flow chart and the DAG are appropriate and the conclusion is supported by the data shown.The study population include 1591 children that is 11% of the BiB birth cohort. How did the authors assess for and handle potential sample selection bias?The authors sometimes used the term mediation. For instance, the objective in the introduction is whether differences in kidney function and BP in childhood are mediated by fœtal kidney size. A mediation analysis method would have been appropriate in this study, but a tradtional multivariable linear regression was performed, which is fine. I would recommend to avoid the term mediation or to consider a true mediation analysis.The directed acyclic graph is rather convincing and well done but remains complex, and the rationale of adding covariates sequentially in 3 distinct models is not completely clear to me. Perhaps a more parsimonious and straightforward model focusing on the main determinants would fulfil the message just as well.The authors mentionned a mean eGFR using Schwartz combined of 92 ml/min/1.73 m² and only 1 child with an eGFR < 60. How many patients would have an eGFR of 60-89 ml/min/1.73 m², and how many have a BP > 95th centile?Could you show in supplementary data the kidney function and BP in the subgroup of patients with actual small volume kidney (for example kidney volume or length < - 2 SDS) irrespective of ethnicity?Could the authors comment on the public health message to take up in this study in addition to tracking kidney function and BP in the BiB cohort? I have a few minor comments:Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pediatrics, Kidney disease, epidemiologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. We assessed difference in sample characteristics at follow-up using selected descriptive variables at baseline (presented in Table 1). There was no obvious major response bias but limited our statistical power as uptake to the follow-up component was lower than expected. The low uptake highlights the challenge of undertaking follow-up in a population with high levels of socio-economic disadvantage and ethnic diversity, especially with invasive testing. We have stated this as a limitation.Thank you, we have removed the term mediation from the paper.Thank you. We added covariates sequentially in terms of the types of determinants  with model 3 being the fully adjusted model including all the covariates from the DAG.476 children with eGFR of 60-89 ml/min/1.73. We haven’t presented the BP >95th centile as not sure what the benefit would be.Thank you for this suggestion. We have looked into this and unfortunately the numbers are too small for us to be able to present this.Our findings did not identify any ethnic specific action per se but we have added the following sentence to the conclusion paragraph: promoting kidney development through childhood and adolescence, for example by aiming for normal weight trajectory and obesity avoidance  would be relevant for all children but especially those with higher adult CKD risk such as south Asians.


Background: The exercise pressor reflex, i.e., metabo- and mechano-reflex, partially regulates the control of ventilation and cardiovascular function during exercise. Abnormal exercise pressor reflex response has been associated with exaggerated ventilatory drive, sympathovagal imbalance and exercise limitation in chronic heart failure patients. Whether metaboreflex is over-activated and participate to poor aerobic capacity in patients with hereditary transthyretin cardiac amyloidosis (CA-TTR) is unknown.Methods: Twenty-two CA-TTR patients  with the V122I  transthyretin underwent a thorough evaluation including heart rate variability metrics, electrochemical skin conductance (ESC), physical function cardiopulmonary exercise testing, and muscle metaboreflex assessment. Eleven control subjects were chosen for muscle metaboreflex assessment.Results: Age-matched controls (n = 11) and CA-TTR patients (n = 22) had similar metaboreflex sensitivity for heart rate, stroke volume, cardiac index and mean systemic arterial pressure. Compared with age-matched controls, metaboreflex sensitivity for systemic vascular resistance (−18.64% ± 6.91% vs 3.14% ± 23.35%) and minute-ventilation responses (−9.65% ± 14.83% vs 11.84% ± 23.1%) was markedly increased in CA-TTR patients. Values of ESC displayed positive correlations with stroke volume  and cardiac index  components of metaboreflex sensitivity, an inverse correlation with systemic vascular resistance  and a trend with mean arterial  components of metaboreflex sensitivity. Peak aerobic capacity (peak VO2%) displayed an inverse correlation with the ventilation component of metaboreflex sensitivity .Conclusion: Consistent with the “muscle hypothesis” in heart failure, it is proposed that deterioration of skeletal muscle function in hereditary CA-TTR patients may activate muscle metaboreflex, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and overall sympathetic activation. Hereditary transthyretin mediated amyloidosis, i.e., ATTRv, is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively damages multiple organs leading to disability and death . The mosBeside direct myocardial dysfunction, autonomic imbalance and abnormal reflex regulation of the cardio-pulmonary system, i.e., muscle ergoreflex activity, contribute to muscle fatigue and breathlessness leading to exercise limitation. The ergoreflex, that combines metabo- and mechano-reflexes, is a cardiorespiratory reflex activated by exercise coupling ventilation and cardiovascular function to exercise intensity . While tWhether metaboreflex is over-activated and may participate to poor aerobic capacity in CA-TTR patients is unknown. In the present study, we aimed to determine whether metaboreflex is over activated in CA-TTR patients, as well as to assess its relationships with autonomic imbalance and impaired aerobic capacity.http://www.wma.net/en/30publications/10policies/b3/). Informed written consent was given prior to the inclusion of patients in the study. The study was approved by the CHU Martinique hospital’s institutional review board (IRB #01022019). Subjects having coronary artery disease or/and chronic obstructive pulmonary disease were excluded. Subjects were also excluded if they were taking tobacco products or more than 10 alcoholic beverages per week. Only patients with NYHA functional class II or higher status were enrolled. Assessment of cardiac function, cardiopulmonary exercise testing and metaboreflex sensitivity were performed during a maximum time interval of 4 weeks. Eleven healthy controls were matched to patients with respect to age and sex, and underwent metaboreflex assessment and cardiopulmonary exercise testing. Informed written consent was given prior to the inclusion of healthy control subjects in the study.Participants were recruited at the Department of Cardiology of the University Hospital of Martinique from September 2019 to May 2021. Consecutive patients with the diagnosis of hereditary V122I  transthyretin cardiac amyloidosis (CA-TTR) were prospectively enrolled. All patients declared African ancestries. Information regarding the study protocol and main objectives were provided to all patients. Risks and description of the different procedures were explained to the patients. All patients were managed in accordance with the amended Declaration of Helsinki . Cardiac echography  was performed according to standard technique following the American Society of Echocardiography guidelines. Abnormalities on echography suggesting CA-TTR included left ventricular hypertrophy and abnormal myocardial texture characterized as a speckled appearance. Abnormal myocardial texture was defined by granular sparkling of the myocardial walls on echocardiography. Increased wall thickness score (IWT score), which incorporates relative wall thickness (RWT), E/e′, tricuspid annular plane systolic excursion (TAPSE), longitudinal strain and systolic apex-to-base (SAB) ratio was calculated , carpal tunnel syndrome, spinal stenosis were sought for all patients. The presence of dysautonomia  was recorded.® . Patients, in standing position, were asked to place their hands and feet on the devices’ electrodes for 3 min. An electrical stimulus (<4 V) was automatically generated. The electrochemical skin conductance (ESC), measured in micro-Siemens (μS), was recorded. Sudoscan® test results are provided as hands (hESC) and feet (fESC) conductance (mean of left and right side). Sudomotor function was considered normal with values of hESC above 60 μS and/or fESC above 70 μS  with a sampling rate recording of 200 Hz. Heart rate variability was evaluated in patients with sinusal rhythm. The system was programmed to automatically capture all ectopic beats or rhythmic disturbances. Algorithm-based methods filtered for and excluded all non-sinus beats. Validity of exclusion was confirmed by the operator. The root mean square of successive differences between normal heartbeats (RMSSD) was obtained over a 5 min recording period by first calculating each successive time difference between heartbeats in msec. Each of the values was then squared and the result was averaged before the square root of the total is obtained. The standard deviation of adjacent NN intervals (SDNN), the number of adjacent NN intervals that differ from each other by more than 50 ms (NN50) and its percentage (pNN50) were obtained during a 5 min epoch. .Physical function was assessed by the Short Physical Performance Battery (SPPB), developed by the National Institute on Aging (NIA) . The SPPE), oxygen uptake (VO2) and pulmonary CO2 output (VCO2) were measured through breath-to-breath gas analysis . Peak VO2 was defined as the highest value of VO2 attained upon an incremental exercise test designed to bring the subject to the limit of tolerance. Peak VO2 was computed as the highest 30-s average of oxygen consumption and was normalized by the predicted VO2 to derive a percent predicted value according to Wasserman equation (1 multiplied by 35. Peak oxygen pulse (O2 pulse) was calculated and was expressed in mL per beat and as percentage of predicted value by dividing the predicted peak VO2 by predicted peak HR (E relative to VCO2 (VE/VCO2 slope) was calculated off-line as a linear regression function using 10-s averaged values and excluding the non-linear part of the relationship after the respiratory compensation point  (Subjects underwent a cardiopulmonary exercise test (CPET) on an upright electromagnetically braked cycle ergometer. The test exercise protocol involved an initial 3-min rest period, followed by unloaded cycling for 2 min with a progressive 5 to 10W-increment every minute until exhaustion at a pedaling frequency of 60-65 revolutions/minute (rpm), so as to reach a maximum power output within 8–12 min. The Borg scale was used for the assessment of perceived exertion and dyspnea. Minute ventilation (Vequation . Ventila peak HR . Ventila of CO2) . Exercis of CO2) .Participants were instructed to fast for 2 h, to avoid physical exercises in the 48 h, and caffeine or alcohol in the 12 h prior to experimental sessions. Subjects were positioned in a seated position for 30 min with a handgrip dynamometer held in the dominant hand with the limb supported before performing handgrip strength test. Handgrip protocol used in our study  has been®, Manatec Biomedical, Paris, France). Physioflow® device has been previously validated for the non-invasive evaluation of cardiac output at rest and during exercise . Selections of filters including high, low and band-pass/stop options were setup to provide optimal data acquisition of each recorded signal.All experiments were carried out in a temperature-controlled, air-conditioned room (temperature set at 24°C and relative humidity 60%). Hemodynamic parameters were measured throughout all phases of the study. Blood pressure (BP) was monitored noninvasively from an automatic blood pressure cuff , which allows to measure BP within less than a minute thank to a rapid deflate rate setup (>8 mm Hg/s) . Cardiacexercise . For strexercise . VE, VO2Ventilatory and hemodynamic components of the metaboreflex, i.e., metaboreflex sensitivity was quantified as the percentage of ventilatory minute and hemodynamic parameter  responses to exercise maintained by circulatory occlusion during the third minute compared with the third minute of basal recovery. As previously reported , metaborut (CER) .th], while categorical variables were listed as frequencies and percentages. Hemodynamic and breath-by-breath ventilatory collected data were averaged for the last 30 s of the corresponding condition. Independent samples t-test were performed for comparisons between groups of continuous variables if normally distributed, while skewed data were tested with the Kruskal–Wallis test. Differences between groups of absolute values of variables during rest periods preceding handgrip runs were studied by means of the two-way analysis of variance (ANOVA) for repeated measures with group (CA-TTR or control patients) and condition (rest before CER or before PEMI test) as main factors followed by Tukey’s post hoc test when appropriate. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 18.0 for Windows . The level of statistical significance was set at p-value <0.05.We conducted a pilot and exploratory study along with the purpose of testing the hypothesis of interest. Sample size calculation was based on heart failure differences and exercise pressor reflex studies . Assuminn = 11) and twenty two CA-TTR patients (n = 22) with the transthyretin V122I  mutation were enrolled. Main characteristics of control subjects and CA-TTR patients are displayed Eleven control subjects  at the third minute post exercise, without concomitant changes in heart rate , stroke volume , cardiac index , mean systemic arterial pressure , and systemic vascular resistance   .2%) displayed inverse correlations with the ventilation component of metaboreflex sensitivity, while no correlations were found with hemodynamic components of metaboreflex sensitivity  mutation. While this mutation is most commonly associated with cardiomyopathy , growing® is a non-invasive technology that assesses function of C-small sympathetic nerve fibers of the sweat gland via determination of chloride conductance across the skin  and short-term heart rate variability metrics  was associated with changes in hemodynamic components of metaboreflex sensitivity, suggesting a functional shift from a flow-mediated  to a vasoconstriction-mediated hemodynamic mechanism to achieve the target mean systemic arterial pressure during metaboreflex. Overall, these hemodynamic features of metaboreflex sensitivity in patients with CA-TTR resemble abnormalities displayed by patients with chronic heart failure . Correlathe skin . Low elethe skin . Furtherthe skin . Our stuthe skin . Overall2%) were associated with increased ventilation component of metaboreflex sensitivity, while no correlations were found with hemodynamic components of metaboreflex sensitivity. Association between deterioration muscle function and increased ventilation response to metaboreflex activation observed in CA-TTR patients is consistent with the “muscle hypothesis” where a primary muscle disorder increases muscle ergoreceptor sensitivity leading to exercise intolerance and sympathetic activation. Excessive ventilatory responses elicited by metaboreflex activation inversely correlated with physical function and peak VO2, suggesting that metaboreflex over-activation may contribute to exercise intolerance by causing hyperventilation and early onset of dyspnea in CA-TTR patients, as previously shown in chronic heart failure , limiting interpretation of post-exercise muscle ischemia hemodynamic response.In conclusion, patients with CA-TTR display enhanced metaboreflex sensitivity, which is associated with sympathetic overdrive and exercise intolerance. We interpret our findings by postulating that a primary muscle disorder increases metaboreflex sensitivity, causing a chronic sympathovagal imbalance that can impair exercise aerobic capacity.


Hypertension in Mexico has a prevalence of 32% and is the second most widespread cause of consultation in primary care. Only 40% of patients in treatment have a blood pressure (BP) below 140/90 mmHg. This clinical trial aimed to compare the effectiveness of the combination of enalapril and nifedipine versus the empirical treatment for hypertension in patients with uncontrolled BP in a primary care center in Mexico City. Participants were randomized to treatment with enalapril and nifedipine (combination group) or to continue with the empirical treatment. Outcome variables were BP control, therapeutic adherence, and adverse effects at 6 months of follow-up. At the end of the follow-up period, BP control (64% versus 77%) and therapeutic adherence (53% versus 93%) showed an improvement from the baseline values in the group that received the combination treatment. BP control (51% versus 47%) and therapeutic adherence (64% versus 59%) in the group who received the empirical treatment did not show improvement from the baseline to follow-up. Combined treatment was 31% more efficacious than conventional empirical treatment (odds ratio = 3.9), which yielded an incremental clinical utility of 18% with high tolerability extent among patients in primary care in Mexico City. These results contribute to the control of arterial hypertension. Hypertension is a disease that contributes most to all-cause morbidity and mortality worldwide ,2. HyperHypertension can be detected at primary care and low-cost treatments can effectively control it. Although lifestyle modification  is important, it has been very difficult to apply it at the individual and population level, and is often not sufficient by itself to control blood pressure. Therefore, effective pharmacological management is essential for controlling hypertension. However, with the increasing number and diversity of pharmacological agents available that encompasses several key and complementary drug classes, treatment options are now complex and need to be simplified . FurtherWhen combining antihypertensive drugs, the aim should be to maximize the effects with a decrease in adverse reactions. The combination chosen for this study is an angiotensin-converting enzyme inhibitor “enalapril” and a calcium channel blocker “nifedipine” which has an antihypertensive effect and the potential to mitigate side effects of the substances given separately. The combination based on enalapril and nifedipine is justified on several pharmacological, therapeutic, and clinical grounds . This coThe combination of enalapril and nifedipine has not been studied in relation to a treatment scheme, which is highly variable and is based on the experience of the primary care physician . Although the effectiveness of drug combinations for the management of arterial hypertension has been demonstrated in several studies, the specific circumstances at primary care have not been evaluated. Prior to this clinical trial, no direct comparison studies between empirical treatment and this fixed-dose combination at primary care have been conducted that would demonstrate if the combination of enalapril and nifedipine is superior to non-fixed free combinations. The aim of this work was to compare the effectiveness of the combination of enalapril and nifedipine for the treatment of hypertension versus empirical treatment, with respect to blood pressure control, therapeutic adherence, and adverse effects, in patients with uncontrolled blood pressure at primary care.The study design was a randomized clinical trial. It was an experimental study comparing two groups with the aim to evaluate the antihypertensive effectivity of a combined treatment, while describing therapeutic adherence and any possible adverse effects. The combined treatment consisted of enalapril (one tablet of 10 mg every 12 h) and nifedipine (one tablet of 10 mg every 12 h).The participants included in the study were selected from a group of patients with a hypertension diagnosis that attended “Dr. Manuel Escontria” Health Center in Mexico City. All participants agreed to take part in the study by signing an informed consent. Participants were selected in a non-probabilistic manner with consecutive cases and random assignment to the intervention groups. This was a prospective, randomized, open, blinded-endpoint study. Inclusion criteria considered patients, both male and female, over 40 years of age who had a systolic blood pressure between 140 and 180 mmHg and a diastolic blood pressure between 90 and 110 mmHg. All patients had to be recently diagnosed with hypertension or based on a medical opinion, must benefit from a change in treatment.Exclusion criteria considered any patient who had suffered an acute myocardial infarction in prior months, who had arrhythmias, unstable angina, heart failure, diagnosis of a cerebrovascular accident or renal failure. For fertile women, anyone taking contraception or pregnant were excluded, because oral contraceptives can prevent an effective antihypertensive treatment in certain patients . AdditioAny patient who voluntarily decided to leave, abandoned the study, or presented adverse effects that could put their health at risk, was eliminated.This study was approved by the Bioethics Committee of our institution (protocol number 201626). It was carried out in accordance with the provisions contained in the General Health Law of Mexico and the ethical principles contained in the Declaration of Helsinki.The sample size was calculated considering the proportion of patients who are expected to experience a reduction in their blood pressure after application of a combined antihypertensive therapy treatment (40%) and the proportion of patients whose blood pressure figures will be reduced by continuing with an empirical treatment (25%). The sample size was calculated using the 2-proportion comparison formula for experimental studies (Equation (1)).A confidence level of 95% and a power of 80% were considered. The calculated minimum sample size was 145.86, rounded to 146 subjects for both the experimental group and the non-experimental group. Though only 292 patients were required, a total of 328 participated in this study.The sampling process was carried out by a group of 12 primary care physicians and each of them selected a minimum of 30 patients via consecutive sampling. Allocation of the patients to each intervention group was randomized.Participating patients signed an informed consent after one of the physicians explained the purpose of this study. They could be either newly diagnosed as hypertensive or those who, in the opinion of their doctor, could benefit from a change in treatment based on the proposed combined therapy.Patient monitoring lasted 6 months, during which 5 control visits were carried out . In the During each visit, blood pressure, weight and height were recorded; and laboratory tests, including glycemia, glycated hemoglobin, total cholesterol, triglycerides, creatinine, and uric acid were conducted. At the start and the end of the study, systematic analytical controls were registered. The possibility of presenting adverse effects and their degree were recorded whenever they presented. Blood pressure was measured in the morning, before taking the medication, after resting for 5 min, and in the dominant arm. Two measurements were performed 2 min apart in a sitting position, and the average of both was recorded. In each consultation, the results of the Morisky–Green–Levine test for therapeutic adherence and notification of suspected adverse drug reactions were applied and recorded in the patient’s medical record.All blood pressure measurements were conducted using an automatic and validated electronic device (Omron M4). All anthropometric measurements were performed using a scale with a validated digital stadiometer (Seca 213). All laboratory samples were processed in the laboratory of the health center using automated equipment (Cobas c11).The Morisky–Green–Levine test consists of four questions where it is specified, according to the value of the answers obtained, if the patient has had therapeutic adherence to a pharmacological treatment or if the adherence is not adequate. In all cases, the questions must be answered with a “yes” or a “no”. Adherents (ADT) are those who answer NO to the four questions and non-adherents (NADT) are those who answer YES to one or more questions. The test has shown a good correlation between adherence and blood pressure control .In the event of any adverse reaction, the observation was conducted during the clinical interview using the Suspected Adverse Reactions Report format from the National Center for Pharmacovigilance in Mexico.Systolic blood pressure and diastolic blood pressure were measured in mmHg as described above. The main outcome was controlled blood pressure (yes or no), defined as systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg. Adherence to treatment and adverse reactions were the secondary outcomes. The intervention variable was the antihypertensive treatment .2). Clinical variables included comorbidities . Blood chemistry laboratory variables included glucose (mg/dL), glycated hemoglobin (%), uric acid (mg/dL), creatinine (mg/dL), total cholesterol (mg/dL), and triglycerides (mg/dL).Anthropometric variables were age (years), sex , body weight (kg), height (cm), and body mass index (kg/mp < 0.05). Therefore, these variables were reported as median (25th percentile—75th percentile) and were compared between treatments using the Mann–Whitney U test. Within each treatment group, the medians evaluated at 2, 4, and 6 months were compared against the evaluation baseline using the Wilcoxon test. The study variables were compared with respect to uncontrolled hypertension (controlled vs. uncontrolled) using the Mann–Whitney U test  or Chi-square test . To evaluate the efficacy of the combined treatment, we calculated several indices. For each treatment, we assessed the incidence of controlled blood pressure , expressed as percentage. Then, we calculated the clinical utility as the difference between incidence in the combined treatment—incidence in the empirical treatment (expressed as percentage), which corresponds to the absolute risk reduction (ARR), expressed as a proportion. The relative risk (RR) was calculated as incidence of combined treatment/incidence of empirical treatment. The number required to be treated (NRT) was calculated as 100%/clinical utility. Statistical analysis was performed using SPSS Statistics 21.0  and Microsoft Excel 2017.Most continuous variables did not have a normal distribution  treatment to a fixed combination of enalapril and nifedipine and comparing it with the empirical treatment. The results show that after 6 months of treatment, the combination of enalapril and nifedipine improved the control of arterial blood pressure compared with the conventional empirical treatment. The combined therapy also improved the adherence without adverse effects. An important contribution is that this research was performed in the primary care setting, which is one of the largest settings that treats most of the population but has low rates of controlled blood pressure. In regions such as Latin America, low blood pressure control rates are a significant public health issue, considering the high hypertension prevalence, which is about 30 to 45% in the general population and this tend to increase rapidly with age .For a long time, clinicians have been overconfident regarding monotherapy. Guidelines from the European Society for Hypertension (ESH), European Society of Cardiology (ESC) and the Joint National Committee 8 (JNC 8) from the United States of America indicate that most patients will need two or more medications to control arterial blood pressure and shed light on recommendations about possible combinations . MoreoveThe combined therapy is aimed to provide a synergistic effect, more tolerability, higher patient’s therapeutic adherence , simplifThis study also contributes to a change in the way general practitioners prescribe medications, since it is common to find physicians who are reluctant to modify or increase the antihypertensive treatment in patients who present non-controlled blood pressure . TherefoThe lack of adherence to antihypertensive therapy is probably the most important reason for non-controlled arterial blood pressure and it is influenced by multiple interrelated factors . To undeFollow-up laboratory tests were performed on all patients who participated in this study to describe the biochemical changes during the course of the combined therapy. Although the laboratory results were statistically significant for some analytes, these did not result in a change of the clinical state of the patients and the variations were minimal. Further studies are required to test if the combination of enalapril and nifedipine, as a treatment for systemic arterial hypertension, has any beneficial effects in other metabolic variables usually monitored by the blood biochemical tests in primary care.It seems that drug combinations, not restricted to hypertensive drugs but also those with statins and antidiabetics, will be widely used in chronic and degenerative diseases in the near future . CombineA double-blind study was not performed, since no placebo was used and patients with arterial hypertension with different degrees of evolution and clinical complications were included, thereby making it necessary to test the intervention with groups with greater control and stratification to standardize the treatment. Furthermore, although the allocation of patients was randomized, the fact that the selection of patients could be decided based on medical opinion increased the risk of bias in the selection process. We do not know the impact of this intervention on other clinical aspects, such as biochemical parameters, adherence to treatment of diabetes and other comorbidities, survival or risk of hospitalization; these factors should be explored in future research.The combination of enalapril and nifedipine for the treatment of hypertension is more effective in controlling blood pressure than the empirical treatment in patients with uncontrolled blood pressure in primary care. After six months of treatment, the combination showed an increase of 41.2% in the clinical protector effect and an increase of 18.1% in net clinical utility Treatment adherence also improved in the patients undergoing the combined treatment, without any difference in adverse reactions. These findings support the use of simple therapeutic schemes for an easier, more accessible, and effective treatment of hypertension in primary care patients.


This study aimed to explore the impact of hyperkalemia at admission on hospitalization days (HDs) among advanced chronic kidney disease patients (CKD) with type two diabetes mellitus (T2DM) in China.A total of 270 CKD patients with T2DM were prospectively selected from January 1, 2020 to December 31, 2021. These patients were divided into Group-A  and B . The comparison method between the two groups was taken. Linear correlation analysis was performed using the Spearman correlation method, and multivariate analysis was tested using linear regression.The study found statistically significant result between the two groups (Group-A vs Group-B): HDs (7.4 (5.3-11.2) vs 12.1 (8.2-16.5), p < 0.001), renin-angiotensin-aldosterone system inhibitors (RAASIs) , systolic blood pressure , estimated glomerular filtration (eGFR) (20.35) (18.31-25.26) vs13.4 (12.50-18.50), p < 0.001, N-terminal pro-B type natriuretic peptide (NT-proBNP) , and Hb . Correlation analysis showed that HDs were positively correlated with age, serum potassium, systolic blood pressure, and NT-proBNP, while negatively with eGFR and Hb. After adjusting for relevant confounding variables, the multivariable linear regression analysis showed that hyperkalemia was an independent risk factor for HDs.Hyperkalemia could be an independent risk factor increasing HDs of advanced CKD patients with T2DM. The prevalence of chronic kidney disease (CKD) has increased recently, mostly accompanied by diabetes, hypertension, and coronary heart disease. Although there was significant variation in overall and advanced CKD prevalence, about 434.3 million adults have CKD in Asia.7Hyperkalemia is one of the prevalent reasons for hospitalization among CKD patients. Some observational studies have described the relationship between hyperkalemia and excessive mortality,A total of 270 CKD (stage IV and V) patients with T2DM hospitalized at Baoding No. 1 Central Hospital from January 1, 2020 to December 31, 2021 with complete clinical data from Hebei met the diagnostic criteria of T2DM.11Age ≥ 18 years old;CKD stage was stage IV or V.Serum potassium was initially checked at the hospital. Group A  was taken as serum potassium ≤ 5.5 mmol/L and group B  was taken as serum potassium > 5.5 mmol/L.Diabetes ketoacidosis, hyperosmolar nonketotic coma, severe infection, liver dysfunction, acute coronary syndrome, rheumatic diseases, and other systemic diseases;Pregnant, lactating women or women of childbearing age who intended to conceive;Renal artery stenosis;Previous history of kidney transplantation, hemodialysis, and peritoneal dialysis;Previous decompensation of liver cirrhosis or history of hepatic encephalopathy;Any systematic history of malignant tumor disease in the past five years;Any existing life-threatening condition or expected survival of less than a year;History or evidence of drug or alcohol abuse in the past one year;After admission, transferred to the department, discharge automatically, transferred to dialysis or kidney transplantation;Combined with acute renal injury.This is a prospective study and analysis. The 270 patients who met the above selection criteria were divided into two groups, including 124 males and 146 females, with 150 patients in the non-hyperkalemia group (Group-A) and 120 patients in the hyperkalemia group (Group-B). The specific selection process of patients. is shown in The general clinical data of patients including age, sex, 24 hours urinary output, body mass index (BMI), diabetic duration, days in hospital, systemic blood pressure (SBP), diastolic blood pressure (DBP), primary disease, and main treatment at admission were collected during hospitalization. The main laboratory examinations included N-terminal pro-B type natural peptide (NT-proBNP), platelet (PLT), hemoglobin (Hb), hemoglobin A1c (HbA1c), albumin (ALB), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein (HDL), total cholesterol (TC), triglyceride (TG), C-reactive protein (CRP), 24 hours urinary protein (24-h Upro), and serum uric acid (SUA).2 inspection. The length of stay was taken as the dependent variable and linear correlation and regression analysis were used. Regression analysis fully corrected various confounding factors. The difference was statistically significant (p < 0.05).The data was analyzed using SPSS 22.0 statistical software, and PRISM 8.0 was used as a statistical chart. The normality test was performed first for numerical variables. If both groups met the normality with equal variance between them, the mean ± standard deviation was used for statistical description, and the independent sample t-test was used for the comparison between the two groups. Otherwise, the median (upper quartile ~ lower quartile) was utilized for statistical description, and the nonparametric test of independent samples was used for the comparison between the two groups. For categorical variables, the number of cases (%) was used to describe, and the comparison between the two groups adopted χThe studies involving human participants were reviewed and approved by Ethics Committee of Baoding No. 1 Central Hospital. Reference number: 2020-079. The patients provided their written informed consent to participate in this study.A total of 928 patients were selected, of which 658 patients were excluded and 270 patients were included in this prospective study. Further, 120 patients were categorized in group B , accounting for 44.4% of the total inclusion number. Compared to group A, Group B had lower eGFR and Hb, but higher HDs, renin-angiotensin-aldosterone system inhibitors (RAASIs), systolic blood pressure, and NT-proBNP (p < 0.05)  and II. The total HDs of patients was positively correlated with age, potassium, SBP, and NT-proBNP, and negatively correlated with eGFR and Hb (p < 0.05) . Simple This study is a prospective clinical analysis and single center research. It was found that from January 1, 2020 to December 31, 2021, 270 CKD (stage IV and V) patients with T2DM were hospitalized, of which 44.4% had hyperkalemia. D’Alessandro et al discovered that the prevalence of hyperkalemia was associated with decreased eGFR, up to 36.5% for eGFR < 20 ml/min,14Hyperkalemia is a common electrolyte disorders in the middle and late stages of CKD, which can be caused by various pathophysiological mechanisms.17The correlation analysis between the HDs and its primary variables in our patients displayed that the HDs were negatively correlated with Hb and eGFR, but positively correlated with age, SBP, and serum potassium. The multivariable linear regression analysis showed that eGFR was an independent protective factor, which could reduce HDs, while hyperkalemia was an independent risk factor, which could significantly increase HDs. Although the findings are consistent with the results of Calabrese et al,Hougen et al Therefore, Hyperkalemia in advanced CKD with diabetes is prevalent and burdensome, causing more harm, more complications and higher medical costs, which should be given sufficient attention by medical staff. 20Renal function is significantly damaged when coupled with the aging of patients and the complexity of various drugs and dialysis treatment makes the mechanism of hyperkalemia more complex.24First, this study is a single-centered clinical analysis, with limited samples due to regional restrictions. Secondly, the design of this study failed to clarify the etiology or inducement of hyperkalemia in patients, such as acid-base imbalance, diet, and other factors, and it did not dynamically monitor the change in serum potassium level. Lastly, we did not include all the treatments for those patients, such as therapeutic fluids, some herbal medicine, sodium polystyrene sulfonate and other potassium lowering drugs that may affect serum potassium, making it difficult to completely control the influence of other confounding factors. As a result, the findings of this study must be integrated with the actual clinical situation, and further prospective multicenter research is required to confirm.In this study, CKD (stage IV and V) patients with T2DM were hospitalized, and the risk factors affecting HDs were analyzed systematically. Hyperkalemia was found to be an independent risk factor affecting HDs. This finding highlights the urgent need for efficient serum potassium management measures in hospital in order to avoid the acutely life-threatening effects of hyperkalemia. Furthermore, this study provides a theoretical and clinical basis for preventing and treating hyperkalemia in such patients, which will obviously prevent CKD patients with T2DM from the undesirable outcomes and inpatient economic burdens. Routine monitoring, rational drug use, early detection, and early treatment measures are crucial, which can shorten HDs and reduce the hospitalization expenses of such patients.