Chronic kidney disease (CKD) increases blood pressure variability (BPV) and affects stroke outcomes. However, the effect of BPV on early neurological deterioration (END) may be different according to the renal function.We enrolled ischemic stroke patients with a National Institutes of Health Stroke Scale of ≤5. END was defined as worsening of ≥1 point in motor power or ≥2 points in total score. BPV was calculated with BP measured during the first 5 days and presented as standard deviation (SD) and coefficient of variation (CoV). Renal function was classified using the Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD. Variables were compared between those with (KDIGO classification: moderate- to very-high-risk) and without renal impairment (KDIGO classification: low-risk) and factors associated with END were investigated.P<0.001) and CoV  were associated with END.Among the 290 patients , END was observed in 59 (20.3%) patients. BPV parameters and the risk of END increased as renal function was impaired. Renal function and systolic BP (SBP) mean, SD, CoV, and diastolic BP (DBP) mean, SD were independently associated with END. We found no association between BPV parameters and END in normal renal function patients; however, among impaired renal function patients, SBP SD (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.09–1.32, The association between END and BPV parameters differs according to renal function in minor ischemic stroke; BPV was associated with END in patients with renal impairment, but less in those with normal renal function. Chronic kidney disease (CKD) is a well-known independent risk factor for cerebrovascular diseases, including ischemic stroke –3. MoreoEarly neurological deterioration (END) is defined as neurological worsening during the acute stage, which influences stroke outcomes, especially in initially minor strokes , 9. The Based on previous studies, we hypothesized that patients with ischemic stroke with impaired renal function may show a higher BPV, and that BPV may be associated with END and the effect of BPV on END may differ according to renal function. For verification, we investigated CKD as a risk factor for END and the effects of BPV in minor ischemic stroke patients with and without renal impairment based on the Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD.We retrospectively reviewed the data from the patients with acute minor ischemic stroke who were admitted to the Asan Medical Center between October 2019 and May 2020. Patients were included in our study if they fulfilled the following criteria: (1) age ≥18 years; (2) time from symptom onset to hospital admission of ≤7 days; (3) acute ischemic stroke confirmed with a diffusion-weighted image, and (4) minor stroke defined with a National Institutes of Health Stroke Scale (NIHSS) score of ≤5. We excluded patients with incomplete medical histories and who had end-stage renal disease (ESRD) including those who were on hemodialysis because hemodialysis can cause changes in blood pressure (BP).We determined the stroke subtypes using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) subtype classification system: large-artery atherosclerosis, cardioembolic stroke, small-vessel occlusion, undetermined, and other determined. Informed consent from the patients was not obtained because the study was retrospective. The local ethics committee of Asan Medical Center approved this study (IRB No. 2021–1269).2 with normoalbuminuria, moderate-risk group as 1) eGFR ≥60 ml/min/1.73m2 with microalbuminuria or 2) 45−59 ml/min/1.73m2 of eGFR with normoalbuminuria, High-risk group is defined as 1) 30−44 ml/min/1.73m2 with normoalbuminuria, 2) 45−59 ml/min/1.73m2 with microalbuminruia, or 3) eGFR ≥60 ml/min/1.73m2 with macroalbuminuria. Finally, very-high-risk group is defined as 1) eGFR <30 ml/min/1.73m2 with normoalbuminuria, 2) eGFR <45 ml/min/1.73m2 with microalbuminuria, or 3) eGFR <60 ml/min/1.73m2 with macroalbuminuria. Moreover, the low-risk group is recognized as having normal renal function in KDIGO classification. Therefore, we divided study population into the two groups: normal renal function group (low-risk group) and impaired renal function group .KDIGO guidelines classify CKD into four groups according to eGFR and albuminuria . eGFR waBP was measured using a validated, calibrated, automatic, and noninvasive BP-monitoring device  in the acute stroke unit and general ward according to our local stroke center’s protocol as follows; all BP measurements were performed in a resting, comfortable state with quiet environment; during the patient’s stay in the acute stroke unit, BP was regularly measured every 6 hours; in the general ward, every 8 hours, regardless of day and night; permissive BP is allowed and patients with anti-hypertensive medications stopped taking anti-hypertensive medications in the acute stage of ischemic stroke. In our analysis, we used the BP recorded during the first 5 days of hospitalization. We excluded BP data after END because these could be confounded by additional factors, such as induced hypertension treatment. We calculated the systolic blood pressure (SBP) variability and diastolic blood pressure (DBP) variability, presenting them as standard deviations (SDs) and coefficient of variation  . AdditioSeverity of the stroke was determined using the NIHSS score, which was evaluated by trained nurse  and confirmed by a neurologist. END was defined as an increase of at least 1 point in motor power or a total NIHSS score deterioration of ≥2 points within 3 days after admission . P < 0.001), SBP CoV , DBP mean , and KDIGO classification  were associated with END.Univariate analysis showed that old age , SBP SD , SBP CoV , and DBP mean  were associated with the presence of END. Moreover, the risk of KDIGO classification, especially moderate and very high risk group, was independently associated with the presence of END . However, for the patients with impaired renal function (KDIGO classification: moderate to very high risk), SBP SD, SBP CoV, and DBP mean were higher in those with END than in those without , only SBP mean showed significant difference between those with and without END (P < 0.001), SBP CoV , and DBP mean  were associated with END. Additionally, logistic regression analysis of SBP and DBP ARV were also performed  and DBP SD  approached the borderline of significance  in univariable analysis , findingerformed . Althougificance .The study shows that the presence of END, BP, and BPV parameters can vary depending on KDIGO classification of CKD; as the risk based on KDIGO classification increased, the BPV parameters and END prevalence increased. Among those patients classified as very high risk in our study, a considerable proportion of patients showed END. Furthermore, KDIGO classification and BPV were independent factors affecting END. However, the effect of BPV was different according to renal function. Note that BPV parameters were not significantly associated with END in the normal renal function group, whereas in the impaired renal function group, SBP SD, SBP CoV, and DBP mean were independently associated with END.Previous studies have shown that various CKD parameters, such as eGFR, albuminuria, and cystatin C, were associated with the outcomes of stroke , 6, 20. CKD increases BPV by sympathetic overactivity, reduced arterial compliance, and fluctuation of the renin angiotensin aldosterone system . Daily iThe damage to the microvasculature in the brain and kidneys correlate to each other, as both have shown anatomical similarities; the low resistance and sudden decrease in vessel diameter of the glomerulus and cerebral perforators can lead to a high correlation between impaired renal function and imaging biomarkers of damage to the cerebral microvasculature , 13. PatOur study has some limitations. First, because we performed the study at a single center with a small sample size, it is difficult to generalize the results. Especially, the number of high risk and very high risk group was too small. Therefore, the findings require further verification in a larger, prospective study. However, measurement of BP was performed using the center’s protocol, which was standardized across patients. Second, we measured albuminuria and creatinine only once on the day of admission. These parameters can fluctuate according to the sampling time or stress of the stroke. Follow-up data for albuminuria and creatinine may have strengthened our results. Third, it is well known that obesity has been associated with low-grade false positive albuminuria. Additional test for the obese patients would have improved our study more clearly .Despite these limitations, we have shown that the effects of BPV on END are associated with renal function in acute minor ischemic stroke. BPV and END increased as the renal function decreased according to KDIGO classification. BPV was associated with END in patients with impaired renal function, but less in those with normal renal function. Therefore, we must consider BPV more carefully in patients with impaired renal function.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S1 FigNIHSS, National Institutes of Health Stroke Scale.(TIF)Click here for additional data file. 2 Aug 2022
 PONE-D-22-18870

 Blood Pressure Variability and Early Neurological Deterioration according to Renal Function in Minor Ischemic Stroke Patients

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 Please submit your revised manuscript by September 15, 2022. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.
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 Dear Dr. Kim,

 Your manuscript “ Blood Pressure Variability and Early Neurological Deterioration according to Renal Function in Minor Ischemic Stroke Patients” has been assessed by our reviewers. They have raised a number of points which we believe would improve the manuscript and may allow a revised version to be published in PLOS ONE. Their reports, together with any other comments, are below.If you are able to fully address these points, we would encourage you to submit a revised manuscript to PLOS ONE.Kind regards,Donovan Anthony McGrowderAcademic EditorPLOS ONE

 Reviewers' comments:Reviewer's Responses to Questions  Comments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: PartlyReviewer #2: YesReviewer #3: YesReviewer #4: PartlyReviewer #5: YesReviewer #6: Partly**********  2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: NoReviewer #2: YesReviewer #3: YesReviewer #4: I Don't KnowReviewer #5: YesReviewer #6: No**********  3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.  The Reviewer #1: NoReviewer #2: YesReviewer #3: YesReviewer #4: NoReviewer #5: YesReviewer #6: No**********  4. Is the manuscript presented in an intelligible fashion and written in standard English?  PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: YesReviewer #3: YesReviewer #4: YesReviewer #5: YesReviewer #6: Yes**********  5. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: Jae-Chan Ryu and coworkers evaluated the relationship of inpatient blood pressure variability and CKD risk category with early neurological deterioration in patients with mild stroke. They report intriguing findings, but i have several reservations and suggestions.Major comments:————————The Title and several additional phrases are misleading in that not “Renal Function” is studied but rather CKD risk categories. The authors must choose whether studying relationships with kidney function  or CKD risk categories.In my opinion, BP variability should not by analyzed outside the context of blood pressure. the SD of BP, and to a lesser extent the CoV of BP, are both dependent on the blood pressure mean. Thus, SBP (or DBP) should be included in all models, alongside the BP variability index .When hypothesizing that the association between END and BPV is conditional upon CKD risk category, an appropriate interaction term must be included and tested in the statistical models (e.g. END ~ SD(SBP)*[CKD risk category]). It is not sufficient to claim that the association was only significant in a certain group and not the other.Information about “medications stopped” should be presented and included in the models, as this clinical management decision (please cite an appropriate justification) surely increases BP variability.Minor comments:————————Line 29 “estimated glomerulus filtration ratio (eGFR)” - glomerulus should be glomerular and ratio should be rate.Lines 133-134 please also present ranges and p-value.Line 143 - neurological severity on admission was LOWER in the highest CKD risk group according to the respective table.Figure 1 is intriguing, but some values may be concealed due to the semi-3D nature. please provide all values in a supplementary table.Table 2 - albuminuria should be presented as median and 25th-75th percentile.Reviewer #2: Interesting study evaluating the effects of BPV on END in patients with and without CKD.In patients with minor stroke, study does show age as well as BP along with CKD affect neurological outcomes. Advanced CKD patients usually have atherosclerotic diseases that might be confounding factor.Nevertheless an interesting article to prove CKD is an important risk factor for stroke outcomes.Would consider authors to comment on whether the effect of ckd on END can be independent of BPV.Reviewer #3: The authors revealed that the association between END and BPM parameters differs according to renal function in minor ischemic stroke; BPV was associated with END in patients with renal impairment, but less in those with normal renal function. These findings are interesting, and the manuscript is well written, hence the article would have potential for acceptation. Although several points should be described clearly.I basically agree with your data and conclusion, but there were some discrepancies in patients with high risk levels of CKD patients. These data were seen to be severe outcomes in patients with moderate risk than high risk. Could the authors explain this inverted phenomenon?When the authors confirmed the creatinine levels and determined the CKD stage? The creatinine levels may increase at the timing of admission (due to dehydration or some reason). Could the authors describe the timing for measurement the creatinine levels? Moreover, if the authors determined the CKD stage at admission, could the authors show the change of creatinine levels?Could the authors show the medication for antihypertensive agents and antithrombotic agents at the time of admission? The class effect of antihypertensive drug on prevention for stroke was observed in the recent report .Were there differences for treatment for stroke between patients with CKD and non-CKD?Because I could not realize the data of CKD G3bA3 in Figure 1, could the author show the data of Figure 1 not only 3D graph but also table?Reviewer #4: The manuscript entitled of “Blood pressure variability (BPV) and early neurological deterioration (END) according to renal function in minor ischemic stroke patients” used a single center, retrospective data to analysis the effect of renal impairment on blood pressure and on early neurological deterioration in minor ischemic stroke cases. The authors found that there is a significant association of BPV to EDV in renal impairment group but not in the normal renal function group. However, several issue need to be addressed before further consideration.Comments:1. The author provided “CKD” related references in the Introduction part and cited the KDIGO guideline to classified the study subjects into 4 “risk groups”  in the method part. The low risk group is depicted as “normal renal function” in the method part. In the result part, the author used the term of “impair renal function” to include the moderate, high, and very high risk groups. And all these term were used in the discussion portion.My concern is that these complicating terminology may confuse the readers. For example, a subject with eGFR more than 60 ml/min/m2 without albuminuria is not a CKD case by the KDIGO definition. The subjects of ”low risk” or “normal renal function” in this study maybe are non-CKD cases.For CKD cases, the disease severity are usually classified into CKD stage I to V according to eGFR. However in this study, the author used the risk predicting grouping. To be noticed, the KDIGO guideline do provide evidence-based risk grouping but the classification varies regarding different outcomes. Therefore, I will suggest the method part should include clear definition of the above terminology, criteria for risk grouping, and the data for grouping should consider to be provided as a supplementary table.2. Is the “stroke mechanism” at line 144, 173, of the Result part equals to the parameter of “subtypes of stroke”? I will suggest more deliberation or careful statement regarding the issue.3. It is confusing that the author used both “SBP SD, SBPV SD", “SBP Cov, SBPV CoV” to name a few in tables, and in different sentences of results and discussion. Do they mean the same data? Or they were generated by different calculating algorithm? Please ensure the methodology and use consistent term. In addition, the BP variation is the key issue of this article. We could not tell if the BPV come from all BP records from every subjects of a group, or each individual’s BPV was in consideration in the analysis. Please include the rationale and citing the calculation method in the Method part.Reviewer #5: In this single-center retrospective cohort study, the authors investigated whether the relationship between END after minor stoke and parameters of BPV was different between with and without impaired kidney function. Several BPV parameters were significantly associated with END in the subgroup with moderate to very high-risk CKD prognosis, but not in the subgroup with low risk (non-CKD) according to KDIGO 2012 classification.1. The authors described that they evaluated parameters of BPV using the recorded blood pressure (BP) data during the first 5 days after admission. However, END was determined according to the NIHSS score change during 3 days after admission and BPV parameters in the END group were evaluated ignoring BP data after the diagnosis of END. Therefore, the duration obtaining BP data to evaluate BPV would be different between END and non-END groups. I think the period during which BP data were obtained to evaluate BPV parameters should be standardized to the first 3 days in both END and non-END patients.2. In Table 3, results of multivariate logistic regression analyses in the normal and impaired renal function subgroups were shown. Please show the results of comparison of clinical parameters same as shown in Table 2 in the impaired renal function subgroup. In this subgroup, were there any clinical factors with significant difference except for age, NIHSS, and BPV parameters between patients with and without END? If there are factors which are significantly different between patients with and without END, they should be included in the multivariate logistic regression analysis.3. Table S1 showed the results of multivariate logistic regression analysis and the authors argued that moderate and very high risk groups in the KDIGO classification were independently associated with END. Please discuss the possible reasons why only moderate and very high-risk group, but not high-risk group, were associated with END.4. Figure 1 showed the distribution of percentage of END in each category of KDIGO classification. Very-high risk group looked like to have high prevalence of END, however, because the number of patients seemed to be quite different between categories and there were only 17 patients in the very-high risk group, Figure 1 might be misleading for the readers. Not only percentage but also absolute number of patients in each KDIGO risk category should be shown.5. The described definition of END described in the Methods section seemed to be slightly different from that in the abstract. Which definition was true in your study?6. Table 1 showed patient characteristics in this study. Type of medication for hypertension and use of anti-platelet agents should be also shown.7. In the Results and Discussion section, the terms of “SBPV” and “DBPV” were used but they would be SBP and DBP.Reviewer #6: The article Blood Pressure Variability and Early Neurological Deterioriation according to Renal Function in Minor Ischemic Stroke Patients by Ryu J.-C. tries to confirm the interrelationship between kidney function and brain damage. The authors retrospectively analyzed data of patients who were admitted hospital with acute minor ischemic stroke.Although the study's hypothesis sounds promising, the approach to the available data has some significant limitations.1. Introduction – should be improved. Indeed, kidney failure and brain damage share similar pathophysiological mechanisms that affect microcirculation (you mention some sentences in the discussion), and it is a result of vascular aging and other vascular risk factors that you mention . Moreover, emerging evidence shows that blood pressure variability is associated with arterial/aortic stiffness (a proxy of vascular age) that alters brain microcirculation and increases permeability in the blood-brain barrier, leading to brain damage.2. Methods and Results:a. The flow chart of the participant inclusion/exclusion would increase readabilityb. Even though you acknowledge as a limitation that you had only one measurement of UACR, it is a considerable drawback of the study. Based on this single measurement, you then divide patients into risk groups. Additionally, you don’t mention the anthropometrical measurements of the patients. The thing is that obese individuals seem to have higher creatinine excretion in the urine and, therefore, false low UACR.c. Blood pressure measurements – was it one measurement every 6 to 8 hours? Usually, standardized blood pressure should be performed, meaning three values in a row should be taken, and the average BP should be calculated.d. You have divided patients into groups according to the KDIGO classification and had only 22 patients and 17 patients in high-risk and very high-risk groups, respectively. These numbers are too low to make conclusions about trends among groups. What is noteworthy is that you had 30 (30.9%) patients in the moderate CKD group with END, while only 8 (or 47.7%) patients with END were in the very high-risk group. I suppose you could try to analyze eGFR as a continuous variable without classifying it and show the connection between END and BPV.e. Prognostic factors of END – the main limitation of this analysis is again too small sample numbers in high and very high-risk groups to conclude.f. Table 3, in logistic regression, the BPV should be adjusted for diabetes even though diabetes was not significant in univariate analysis. Diabetes causes autonomic dysfunction that per se affects blood pressure variability. Hypertension and sex should also be included as covariates in logistic regression.3. Discussion – you claim that “among those patients classified as very high risk, near half showed END.” It sounds like a solid and vital statement. However, you refer only to 8 patients from 17 in the very high-risk group. I suppose that you should tone down this statement.**********https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  19 Aug 2022All responses are included in the Response to Reviewers.AttachmentCKD and END Response to Reviewers [PLOS ONE].docxSubmitted filename: Click here for additional data file. 24 Aug 2022Blood Pressure Variability and Early Neurological Deterioration according to the Chronic Kidney Disease Risk Categories in Minor Ischemic Stroke PatientsPONE-D-22-18870R1Dear Dr. Kim,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Donovan Anthony McGrowder, PhD., MA., MScAcademic EditorPLOS ONEAdditional Editor Comments:Dear Dr. Kim,The manuscript entitled “Blood Pressure Variability and Early Neurological Deterioration according to the Chronic Kidney Disease Risk Categories in Minor Ischemic Stroke Patients” was revised in accordance with the reviewers’ comments and is provisionally accepted pending final checks for formatting and technical requirements.Regards,Dr. Donovan McGrowder (Academic Editor) 29 Aug 2022PONE-D-22-18870R1 Blood Pressure Variability and Early Neurological Deterioration according to the Chronic Kidney Disease Risk Categories in Minor Ischemic Stroke Patients Dear Dr. Kim:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Donovan Anthony McGrowder Academic EditorPLOS ONE


Arterial hypertension is facing some changes in the last years. Its prevalence is increasing in elderly subjects. This growing prevalence is due to longer survival of the population worldwide, among other factors. On the other hand, recent guidelines have insisted in the relevance of out of office blood pressure measurements, to improve diagnostic and management of hypertension. Therefore, elderly subjects with hypertension could benefit from out of office blood pressure measurements, like ambulatory blood pressure measurements; nevertheless, there are very few or no specific recommendations regarding this.In this review, we will gather the most important information about this subject.As hypertension in the elderly has some specific characteristics related to aging of the cardiovascular system, the most important aspect could be that these characteristics make ambulatory blood pressure measurement suitable for its use in elderly. Among those a higher prevalence of white coat hypertension, white coat phenomenon, and a higher nocturnal blood pressure and higher prevalence of nondipper and riser pattern, represent aspects that should be considered for better diagnostic and an improved management.As the prevalence of hypertension will grow in the next years, more studies specifically directed to this subject are needed.The online version contains supplementary material available at 10.1186/s40885-022-00205-6. Arterial hypertension is the principal risk factor for cardiovascular disease (CVD) and affects a portion of the population equivalent to 22.3% globally and 26.5% in middle income countries . HyperteAnother important aspect related to hypertension is that all recent guidelines have highlighted the relevance of out of office blood pressure (BP) measurements in diagnosis, evaluation, and management of hypertension, mainly ambulatory BP measurement (ABPM) and home blood pressure measurement –13. ThisWhite coat hypertension (WCH): That is more common in older than in younger adults.Pulse pressure: As there is a predominant increase in 24-h systolic BP with a mild decrease in 24-h diastolic BP after 60–70 years of age, as a result, an increase in 24-h pulse pressure occurs and, therefore, the prevalence of 24-h isolated systolic hypertension is higher.Nondipping pattern is more common in the elderly.Exaggerated BP variability and morning BP surge is also more common in elderly subjects.Postural and postprandial hypotension is also more common.But what do clinical guidelines, and position papers, recommend on ABPM in elderly subjects? There is no specific guideline for this subject. In fact, the 2021 European Society of Hypertension practice guidelines for office and out of office BP measurement  define tOther guidelines point out that out of office BP, preferably ABPM, in addition to an accurate, standardized OBPM, should be undertaken to exclude white coat effect , 13.These changes are, often, indicative of autonomic failure, therefore it is important to identify them, so that treatment can be tailored to take account of such fluctuations in BP. They are, also, relevant as outcome studies in the elderly have shown that 24-h systolic BP, as 24-h ambulatory pulse pressure are more closely associated with cardiovascular events, cardiovascular mortality, and total mortality than office BP, being these associations closer for stroke than coronary artery disease –20.More specifically, the Spanish ABPM Guidelines recommend ABPM in elderly patients since this population group has specific characteristics that requires an ABPM to confirm, such as a higher prevalence of WCH, an alteration of the circadian profile with a higher proportion of the reduced dipping profile and a higher prevalence of postprandial and orthostatic hypotension (OH). All these alterations are associated with increased cardiovascular risk and mortality. Poor sleep quality in the elderly can affect the interpretation of ABPM results .Hypertension in elderly subjects is a special situation due to different aspects. We know that the prevalence of hypertension rises with age, particularly, in Korea among hypertensive patients, the proportion of hypertensive patients aged 65 years or older was 37.4% in 2018 . A recenBeside the increasing prevalence , there aCross-sectional and longitudinal population studies have shown that systolic BP continuously increases with age, while diastolic BP rises until 50 years of age and then levels off or even slightly decreases . This phIt is also called isolated office hypertension, and it is referred to those patients that present a persistent BP elevation in the office with a normal BP outside of the office. This phenomenon is more prevalent in older subjects, and advancing age is the strong determinant of WCH . In the In older hypertensive patients, one of the age-associated BP abnormalities could be the loss of nocturnal BP dip, therefore, the proportion of nondippers tends to increase compared with that of in younger subjects ; in someHowever, we should not forget that quality of sleep-in elderly patients can be affected by concomitant conditions, such as prostatic hypertrophy, sleep apnoea, and sleep fragmentation, and in such cases, nocturnal BP loses some of its prognostic significance .This type of BP dysregulation could be very frequent in elderly. In community dwelling, Asian subjects, the prevalence of OH was found to be an 11.0% . HoweverVallelonga et al. have found that some selected ABPM parameters (number of hypotensive episodes and the presence of awakening hypotension), may be used to screen patients for OH .Beside these phenotypic characteristics of hypertension in elderly subjects, this population presents some other relevant problems. One of them is that the available evidence on the efficacy and safety of BP lowering treatment in these patients is scarce .Another important question to be considered is the possibility of an association between hypertension and frailty syndrome in older patients. This possibility is far from clear for various reasons as, for example, the different definitions and tools used to measure of frailty in the available studies, that are, by the way, very few and with low number of subjects included.As for the influence of frailty on the 24-h BP pattern, it has been explored in a short study with population above 80 years. In this study, frail patients had higher nocturnal systolic BP, and were independently associated with higher risk of nondipping and reduced nighttime systolic BP fall .In another retrospective study, Zhu et al.  includedCognitive decline is increasing its prevalence and it is known that a well-designed management of hypertension, starting on middle age may reduce the onset of dementia in the elderly .Kim et al.  in a recAnother Chinese study was aimed at identifying the relevance of ABPM in cognitive disfunction assessed through MMSE and magnetic resonance imaging . They foP < 0.05 or P < 0.01). The multivariate results showed that 24-h SBPV was associated with IMT, LVMI, and MA  and hypertension mediated target organ damage in elderly patients with hypertension. They found the incidences of coronary heart disease and atherosclerotic plaque as well asintima media Thickness (IMT), left ventricular mass Index (LVMI), and microalbuminuria (MA) were higher in the high BPV group than those in the low BPV group , in the Japan ABPM prospective study, 6359 patients  with at least one cardiovascular risk factor, without cardiovascular disease underwent ABPM at baseline, and were followed annually for possible atherosclerotic cardiovascular disease and HF. The authors found that nighttime BP levels and a riser pattern were independently associated with the total cardiovascular event rate, for HF .Three studies were aimed to evaluate whether ABPM can identify elderly subjects with HF with a worse prognosis. The University of Nara HF study was aimed to assess if they were any association between outcome of elderly patients with different types of HF and BP measured by ABPM. Nocturnal hypertension and nondipper pattern were not associated with either all-cause or cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF), HF with mid-range EF (HFmrEF), or HF with preserved EF (HFpEF), except for sleep-time systolic BP in HFrEF. However, the riser pattern was a significant and independent predictor of all-cause and cardiovascular deaths in patients with HFpEF .Komori et al.  tested iNCT04065620) is an ongoing observational cohort study that has been designed to assess the association ABPM with cardiovascular outcomes in HFpEF, taking also into considerations confounders such as comorbidities, frailty, and functional capacity , and conventional clinic BP can be differed, according to the reference daytime BPs measured by ABPM, masked uncontrolled hypertension or white coat uncontrolled hypertension could be found . In the Hypertension management in elderly hypertensive subjects should include a comprehensive evaluation, to detect also comprehensively their cardiovascular risk. Such an evaluation will help us to know whether a BP lowering strategy, could result in a net benefit, for older patients, and do not increase the safety risks, which are associated to these strategies. Those include OH, WCH, falls, and polypharmacy. This evaluation could also include other parameters related to ABPM, as BP variability, nocturnal hypertension or dipper pattern, which have been associated to higher CV risk. Therefore, ABPM could be a useful tool that could answer many of these questions, and to improve hypertension management in older patients. More specific studies investigating the relevance of ABPM in elderly subjects are needed.Additional file 1.


Lithium has been the mainstay therapy for bipolar disorder (BD) for decades, but there is little consensus regarding its possible effects on kidney function and the rate of change in estimated glomerular flow rate (eGFR) over time.To describe patients with BD regarding their renal function and their sociodemographic and clinical characteristics potentially related to eGFR.This is a cross-sectional study with an initial sample of 95 patients with BD. Multiple linear regression analysis was applied to investigate the association of lithium serum levels and their duration of treatment with eGFR, independent of confounding factors. We excluded patients without data regarding any of the variables from the final model.In the multivariable analysis, the model was composed of eight variables . The mean duration of treatment was 10 years . Serum lithium level was associated with low levels of eGFR ; among the other variables, only age remained associated with it (β = -0.72 (-1.10 - -0.33), p = <0.01).We replicated the correlation between serum lithium levels and eGFR. Our results contradict the claim that duration of treatment with lithium correlates with lower levels of eGFR, while suggesting serum lithium level could be a possible early marker of lithium nephrotoxicity.No significant relationships.


Coronary artery disease (CAD) detection in asymptomatic patients still remains controversial. The aim of our study was to evaluate the usefulness of ophthalmologic findings as predictors of the presence of CAD when added to cardiovascular classic risk factors (CRF) in patients with acute coronary cardiopathy suspicion.After clinical stabilization, 96 patients with acute coronary cardiopathy suspicion were selected and divided in two groups: 69 patients with coronary lesions and 27 patients without coronary lesions. Their 192 eyes were subjected to a complete routine ophthalmologic examination. Samples of tear fluid were also collected to be used in the detection of cytokines and inflammatory mediators. Logistic regression models, receiver operating characteristic curves and their area under the curve (AUC) were analysed.Suggestive predictors were choroidal thickness (CT)  and tear granulocyte colony-stimulating factor (G-CSF) . We obtained an AUC of 0.9646 (95% CI 0.928–0.999) when CT and tear G-CSF were added as independent variables to the logistic regression model with cardiovascular CRF: sex, age, diabetes, high blood pressure, hypercholesterolemia, smoking habit and obesity. This AUC was significantly higher (p = 0.003) than the prediction derived from the same logistic regression model without CT and tear G-CSF .CT and tear G-CSF improved the predictive model for CAD when added to cardiovascular CRF in our sample of symptomatic patients. Subsequent studies are needed for validation of these findings in asymptomatic patients. To date, there have been no in-depth studies into the relationship between ophthalmological findings and coronary artery disease (CAD), which may seem paradoxical considering the anatomical and physiopathological characteristics shared by both systems , 2. CardSince the Framingham Heart Study identified the classic risk factors (CRF) for developing CVD , numerouIts particular structure and the ease of access to the eye make this organ a candidate for obtaining potentially useful parameters in this sense, bearing in mind its involvement in a multitude of systemic processes whose first sign may even show itself as an ophthalmological symptom . MoreoveThe objective of this work was, therefore, to analyse the utility of the ophthalmological findings and biomarkers in tears as predictors for the detection of CAD. This would improve on existing models, enabling such predictors to become a useful tool in habitual clinical practice since they represent an unexpensive and less invasive way to categorize and efficiently manage these patients, not only from the perspective of patient health but also of healthcare resource management.Patients of this observational, case–control, single centre study were assessed in the Cardiology and Ophthalmology Departments of the Virgen de la Victoria University Hospital of Malaga between the months of January-March 2019. Inclusion criteria for the study were suspicion of having a coronary heart disease based on presentation of oppressive chest pain at rest or on with an increase in activity or stress, with or without the presence of dyspnoea at the time of the consultation. Exclusion criteria were the existence of advanced kidney failure (defined as a glomerular filtration rate lower than 30 ml/min), suffering from any disease that reduced life expectancy to less than one year, having presented another cardiovascular event before this study, suffering from any type of retinal disease , the presence of amblyopia in either eye or having undergone retinal photocoagulation treatment in the past.To confirm the existence of CAD, the selected patients underwent coronary angiogram and/or a computerised tomography scan of the coronary arteries. Depending on the angiogram results, we defined CAD as such with findings of a minimum involvement of 70% in any major epicardial artery  or more than 50% in the left main coronary artery. Based on the computerised tomography of coronary arteries, we defined CAD as such where there was involvement of at least 50% of any coronary artery. After these results, patients we distributed into two study subject groups: patients without coronary lesions and patients with coronary lesions. After their clinical stabilisation, patients underwent a full ophthalmological examination within the first ten days after the onset of the clinical symptoms that were the reason for the cardiovascular study.® strips , central corneal thickness (TCCT and PCCT), axial length (AL) and several variables obtained by means of optical coherence tomography (OCT) and OCT-angiography. In addition, as laboratory variables, we studied the presence of cytokines and other inflammatory mediators in samples of tears.The same ophthalmologist conducted the ophthalmological examinations at the same time of day (15–18 pm). Before carrying out examinations, we collected data about the CRF for the onset of cardiovascular disease for each patient, such as sex, age, presence of diabetes, high blood pressure, hypercholesterolemia, smoking habit or obesity. The ophthalmological examination consisted of evaluating different clinical parameters, such as best-corrected visual acuity (BCVA) with numerical eye charts, intraocular pressure (IOP) using a Perkins Mk3 tonometer , Schirmer's test (ST) using Schirmer-Plus® IIz  topographer and, after administration of tetracaine and oxybuprocaine anaesthetic eye drops, manually with the OcuScan® RxP  ultrasound pachymeter, with calculation of the arithmetic mean of 10 consecutive measurements taken from each eye with the patient seated. AL was automatically obtained with partial coherence interferometry using the IOLMaster® 500  optical biometer. Cirrus™  high-definition (HD)-OCT was used for OCT, with the equipment providing automatically obtained values for central macular thickness (CMT), macular cube volume (MCV), mean macular thickness (MMT), retinal nerve fibre layer thickness (RNFLT), ganglion cell layer thickness (GCLT) and ganglion cell layer minimum thickness (GCLMT). Choroidal thickness (CT) was calculated manually using the device’s ruler from the images it produced, and was defined as the distance between the external hyper-reflective band of the retinal pigment epithelium and the internal hyper-reflective band of the sclera. This was expressed as the arithmetic mean of 10 measurements: 5 on the horizontal axis and 5 on the vertical axis, with a separation of 500 micra between them to either side of subfoveal area. For inclusion in this study, the minimum acceptable image quality was 6 out of 10. The OCT-angiography was performed with DRI OCT Triton™ plus  and the device software automatically provided the values for central vascular density in the different layers of the retina . In the case of prior corneal surgery or a clinically significant eye cataract, we excluded the values obtained for these eyes for BCVA, IOP, TCCT, PCCT and the OCT and OCT-angiography.Central corneal thickness was automatically measured with the Orbscan® 20 at 0.3%, bovine albumin serum at 0.5% and protease inhibitor, for overnight incubation 4º C before collection of supernatant. Measurement of the total amount of protein in each sample used the NanoDrop™ One  spectrophotometer with absorbance measured at 280 nm. Detection of cytokines and inflammatory mediators followed the instructions of the Bio-Plex Pro ™ kit Human Cytokine 27-Plex Assay . The 27 cytokines and inflammatory mediators analysed were interleukin (IL)-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic fibroblast growth factor (FGF), eotaxin (EO), granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, chemokine (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, platelet-derived growth factor (PDGF)-bb, MIP-1β, chemoquine ligand 5 (RANTES), tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF).Conducting ST served also to collect tear samples from each patient. The paper strip was placed to rest in the lower base of each eye, without previous application of topical anaesthetic, and left for 5 min. The study excluded samples from any eyes where moisture on the strip measured less than 6 mm after this period. Valid samples were immediately frozen at -80º C after collection, and remained at that temperature until analysis. For protein elution each paper sample was cut into small pieces that were introduced into 100 μl of PBS with Tween® 17 . Characteristics of participants were described as a mean and standard deviation for continuous variables and percentage for categorical variables. Group comparisons were carried out using a Student’s t-test or Chi-squared test as appropriate.Data were analysed with StataFor each variable associated with the presence of coronary lesions in the bivariate analysis, a logistic regression model was estimated that included the CRF: sex, age, diabetes, high blood pressure, hypercholesterolemia, smoking habit and obesity. We assessed the statistical significance of each variable using the likelihood-ratio test based on the models with and without the variable (only with CRF). For variables that were statistically significant, we estimated the area under curve (AUC) associated with the logistic regression model. To estimate the predictive capacity of these variables, we compared the areas under curve using the Chi-squared test, taking the AUC of the logistic regression model that only included CRF. Finally, a logistic regression prediction model was constructed that included the CRF and all variables whose logistic regression models showed an AUC higher than the only-CRF model.A total of 96 patients were recruited and distributed into the two study subject groups. There were 27 patients without coronary lesions and 69 patients with coronary lesions. The total 192 eyes examined were individually analysed. Table Table The logistic regression study found a direct relationship between CT and RANTES and the presence of coronary lesions, and an inverse relationship between IL-8, G-CSF, MCP-1 and the presence of such lesions. Conversely, the ophthalmological variables that, on an individual basis, significantly improved results of AUC when added to the CRF were CT and G-CSF. Table In the multivariate analysis that included CT and G-CSF along with the other CRF, the AUC obtained was 0.964, which constituted a statistically significant difference in comparison with the AUC value that only considered AUC Fig. , Table 4The results of our study demonstrate that, among the patients studied, the values for CT and G-CSF in tears improve the AUC of the prediction model for CAD when added to CRF for this disease. These variables have a direct and inverse relationship respectively with the presence of coronary lesions. To the best of our knowledge, this is the first study into the use of two ophthalmological variables, one clinical and the other laboratory-based, to facilitate the detection of CAD. Its added advantage is that obtaining the data is relatively quick, simple and non-invasive in the usual clinical practice.The choroid consists of a dense network of blood vessels, located between the retina and the sclera, whose function is to supply oxygen and nutrients to the external layers of the retina and pigment epithelium, the subfoveal avascular zone and the optic nerve. In recent years, a growing body of evidence has shown that changes in choroidal microvasculature might be indicative of other systemic diseases that affect blood vessels , 12. ThuG-CSF is a hematopoietic growth factor produced by monocytes, macrophages, fibroblasts, endothelial cells, vascular smooth muscle cells or bone marrow stromal cells that have the capacity to regulate proliferation, differentiation, survival and growth of neutrophil progenitor cells, contributing to the conversion of granulocyte colony-forming units to polymorphonuclear leukocytes, with their subsequent release from bone marrow into the bloodstream . In addiThe prevention of CVD requires the identification of people who are at high risk, in order to propose suitable pharmacological, dietary or lifestyle interventions. Recent decades have seen the development of a multitude of prediction models for the general population, to name but a few: the Framingham , SCORE , QRISK  or, in oThe main strength of our study resides in the degree of precision in measuring the ophthalmological variables employed. Among its limitations, the foremost are the use of a homogeneous group of patients who come from a single hospital, the relatively small sample size and the fact that it only studied symptomatic individuals. For all of these reasons, future prospective studies with a higher number of patients are necessary to verify these promising results and evaluate the validity of their application in asymptomatic individuals.CT and tear G-CSF improved the predictive model for CAD when added to cardiovascular CRF in our sample of symptomatic patients. Although subsequent studies are needed for validation of these findings in asymptomatic patients, this is the first study into the use of two ophthalmological variables to facilitate the detection of CAD.


IntroductionInvasive blood pressure monitoring is essential in liver transplant surgery due to expected major hemodynamic shifts. The use of central versus peripheral arterial access, however, is institution-dependent, which can affect clinical decisions regarding vasopressor therapy. Although there are studies that demonstrate inconsistencies based on arterial cannulation sites, few studies have compared femoral and radial artery blood pressures in patients undergoing liver transplant surgery. To our knowledge, there are no studies investigating the differences between continuous minute-to-minute femoral and radial artery measurements during all three phases of liver transplant surgery.ObjectiveThe main objective of this study was to evaluate for any differences between central and peripheral blood pressure measurements in liver transplant surgery and to assess for any correlation between vasopressor infusion dose and femoral-arterial pressure differences.MethodsIn this retrospective study, we reviewed and studied the data of 61 patients with American Society of Anesthesiologists (ASA) grade 4 who underwent liver transplant surgery at Loma Linda University Medical Center between January and December of 2019. All patients had both femoral and radial arterial lines placed for liver transplant surgery. Femoral and radial arterial blood pressure values were obtained continuously over 60 minutes in the pre-anhepatic phase, 45 minutes during the anhepatic phase, and 60 minutes into the neo-hepatic phase. Vasopressor infusion doses were also recorded for each patient during these time frames.ResultsThis pilot study found statistically significant differences between the mean femoral and radial systolic blood pressure , diastolic blood pressure , and mean arterial pressure  during all phases of liver transplantation. The meanSBP and MAP differences between femoral and radial arteries were highest  in the late anhepatic and early neo-hepatic phases with SBP differences of 20.8 ± 0.8 mmHg and 22.8 ± 0.8 mmHg, respectively, and MAP differences of 10.0 ± 0.4 mmHg and 9.8 ± 0.4 mmHg, respectively. Higher vasopressor infusion doses were strongly associated with greater differences in femoral-radial SBP and MAP measurements  during the anhepatic phase.ConclusionsPeripheral invasive blood pressure monitoring may result in underestimation of the central blood pressure, as was seen in all phases of liver transplantation. This may lead to excessive vasopressor use with potentially adverse effects. Although the cause for the difference between femoral and radial artery measurements is unclear, increasing vasopressor infusion dosages appears to contribute. Femoral artery blood pressure monitoring allows clinicians to interpret hemodynamic status and administer appropriate vasopressors more accurately. Invasive blood pressure monitoring is warranted in patients with significant comorbidities and in high-risk surgeries where immediate, continuous monitoring is required. Although debate persists on the ideal monitoring site, the most common cannulation site in clinical practice is the radial artery due to ease of access and low risk of complications . FemoralDespite the popularity of the radial artery for invasive blood pressure monitoring, some studies demonstrate inconsistencies between peripheral and central arterial blood pressure values in patients with septic shock, hypothermia, and after cardiopulmonary bypass -5. CompaDue to major hemodynamic shifts and the potential for significant bleeding during liver transplant surgery, continuous invasive arterial blood pressure monitoring is essential. However, the choice of peripheral and/or central arterial access can vary depending on the institution and clinician's preference. Few studies have compared femoral and radial artery blood pressures in patients undergoing liver transplant surgery ,8. To ouA retrospective study was performed after obtaining Institutional Review Board approval from Loma Linda University Medical Center in compliance with Health Insurance Portability and Accountability Act regulations . Patient demographics, femoral and radial arterial blood pressure data, and vasopressor dosages were obtained from the electronic medical record of patients who underwent liver transplant surgery at our institution between January 2019 and December 2019. Patients who experienced cardiopulmonary arrest during the surgery and patients who had missing blood pressure or clamp time data on the electronic medical record were excluded from the study.For all patients, the radial artery was cannulated with a standard 20 gauge 1.75-inch radial artery catheter , and the femoral artery was cannulated with a standard 18 Gauge 6.29-inch femoral arterial catheter (Arrow). Two different transducers, set to the level of the patient’s right atrium and zeroed to atmospheric pressure, were used to measure radial and femoral arterial blood pressures. Intraoperative clinical decisions by the anesthesiologist were based on femoral arterial blood pressure with the goal to maintain mean arterial pressure (MAP) > 65 mmHg.Minute-by-minute blood pressure data (systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP) and vasopressor infusion dosage were obtained for each patient during the pre-anhepatic, anhepatic, and neo-hepatic phases. The pre-anhepatic phase was defined as 60 minutes prior to clamping the inferior vena cava (IVC). The anhepatic phase was defined as the first 45 minutes after clamping of the IVC. Neo-hepatic phase consisted of the first 60 minutes following the removal of the IVC and portal vein clamps.For data analysis, the difference between femoral-radial blood pressures  was measured at each time-point of the pre-defined stages of liver transplantation and averaged for all patients per time-point. This was calculated with a paired t-test using data from the radial arterial blood pressure subtracted from the femoral arterial blood pressure for each blood pressure variable . For each individual vasopressor , the mean infusion dosage was recorded at each time point during the three defined phases of liver transplantation. The correlation between vasopressor infusion dose and the mean difference in blood pressure was subsequently calculated using the Spearman correlation coefficient.Patient demographics2 (range: 18.5 to 42.5 kg/m2), and the mean Model for End-Stage Liver Disease (MELD) score was 30.4 ± 8.1 (range: 15 to 40).A total of 103 patients underwent liver transplantation surgery between January 2019 and December 2019 at Loma Linda University Medical Center. However, 43 patients were excluded from the study due to missing blood pressure data, clamping times, or intraoperative cardiopulmonary arrest. Of the resulting 60 patients included in our study, 37 were male (62%). The mean age of our patients was 54.3 ± 11.3 years (range: 19 to 74 years), the mean body mass index (BMI) was 29.8 ± 5.8 kg/mCentral and peripheral arterial blood pressure comparisonsThe mean difference between femoral-radial SBP, DBP, and MAP measurements of all 60 patients is demonstrated in Table The mean difference between femoral-radial SBP, DBP, and MAP measurements at each specific time point throughout the operation is visualized in Figure The mean femoral arterial SBP, DBP, and MAP were all statistically significantly higher than the radial artery measurements during all three phases of liver transplant surgery  Table . The meaVasopressor infusion dosagesThe average doses of the vasopressor infusions for vasopressin, norepinephrine, and epinephrine were documented for the same time points as the blood pressure values for all 60 patients Figure . No otheCorrelation between vasopressor infusion doses and mean blood pressure differencesTable Pre-anhepatic PhaseDuring the pre-anhepatic phase, the correlation between individual vasopressors and the mean SBP difference was not statistically significant Table . InteresAnhepatic PhaseDuring the anhepatic phase, there was a strong positive correlation between vasopressor infusion dose and the mean SBP difference  Table . The posNeo-Hepatic PhaseFor the neo-hepatic phase, statistically significant positive correlations were found between the norepinephrine and epinephrine doses and the mean SBP difference between femoral-radial artery measurements (R = 0.47 for norepinephrine and 0.85 for epinephrine) Table . NorepinWith the prevalence of significant hemodynamic variability in orthotopic liver transplantation, invasive arterial blood pressure monitoring is essential in providing anesthesiologists with data to support clinical decision-making. Reliable and accurate methods for measuring blood pressure are vital to reducing perioperative morbidity and mortality, especially for critically ill patients undergoing high-risk surgery . While tWith the high volume of liver transplantation surgeries at our institution, our study demonstrates a similar phenomenon in which we appreciate significant blood pressure differences, with femoral artery values consistently measuring higher than the radial artery. This phenomenon is visualized in Figure Few articles compare BP measurement differences specifically in liver transplant patients and the results are conflicting Table .Arnal et al.  observedIn contrast, our study found statistically significant differences between the femoral and radial mean SBP, DBP, and MAP during all phases of liver transplantation surgery (p < 0.0001). A possible explanation for the difference in our findings is that our study examined continuous minute to minute time-points and a larger number of total time points , providing a more comprehensive picture of blood pressure measurements throughout the operation. Similar to the study by Arnal et al. , our widThe mechanisms responsible for the difference in femoral and radial artery blood pressure measurements in liver transplant surgery are not well understood. One theory is that increasing vasopressors constrict smaller caliber vessels more and reduce flow to the radial artery, contributing to the difference seen between radial and femoral artery measurements. Another theory proposes that extreme peripheral vasodilation, as in the early neo-hepatic phase of liver transplantation, can result in decreased distal pressures compared to central pressures, similar to that seen in post-cardiopulmonary bypass physiology . Other pA recent, retrospective analysis of liver transplant surgery revealed patients had an increased risk for 30-day mortality with sustained intraoperative MAPs below 60 . AlthougSmall studies in liver transplant surgery, cardiac surgery, and the intensive care unit argue that utilizing peripheral invasive blood pressure monitoring alone may result in underestimating the central blood pressure -12. Our Some studies suggest that high-dose vasopressors contribute to the discrepancy between central and peripheral blood pressure, creating a cycle that could lead to significant morbidity and mortality . Our stuLimitationsA limitation of our study was that vasopressor boluses were not included in our data, and only vasopressor infusion doses were included in the data analysis. Because all our patients were on vasopressor infusions at the time points measured, we did not compare the effect of vasopressors to no vasopressors on the blood pressure difference. Additionally, our study did not account for other confounding variables, such as the physiologic effects of liver failure or reperfusion on peripheral vs. central artery vascular changes.Though our pilot study shows statistically significant differences between femoral and radial blood pressure measurements, it is difficult to quantify these data into clinical significance. To determine clinical significance, a future study would compare two groups of patients managed separately via femoral or radial blood pressure readings to detect if differences exist in the vasopressors utilized and outcomes of morbidity and mortality.To our knowledge, our pilot study is the first to examine minute-to-minute blood pressure differences in all three phases of liver transplant surgery, with a robust dataset examining femoral and radial arterial measurements. Based on the results, central blood pressure monitoring is recommended in liver transplant surgeries and major surgeries with hemodynamic shifts, massive blood loss, and multiple vasopressor usages. Multiple vasopressors are a contributing factor to the differences between central and peripheral blood pressure measurements. Central arterial blood pressure measurements allow for a more accurate interpretation of hemodynamic status and the appropriate management of vasopressors. Further studies examining additional factors such as blood pH, temperature, patient age, MELD score, and type of operation that may cause the significant differences between central and peripheral arterial blood pressure measurements may yield further insight into how the vasculature reacts in the perioperative period.


While hypothyroidism increases serum creatinine (Cr) levels, it is uncertain whether the elevation is mediated via a decline in the glomerular filtration rate (GFR) or the reflection of enhanced Cr production from the muscles or both. In the present study, we explored an association between urinary Cr excretion rate (CER) and hypothyroidism. A total of 553 patients with chronic kidney disease were enrolled in a cross-sectional study. Multiple linear regression analysis was performed to explore the association between hypothyroidism and urinary CER. The mean urinary CER was 1.01 ± 0.38 g/day and 121 patients (22%) had hypothyroidism. The multiple linear regression analysis revealed explanatory variables with urinary CER, including age, sex, body mass index, 24 h Cr clearance (24hrCcr), and albumin while hypothyroidism was not considered an independent explanatory variable. In addition, scatter plot analysis with regression fit line representing the association between estimated GFR calculated using s-Cr (eGFRcre) and 24hrCcr revealed that eGFRcre and 24hrCcr had strong correlations with each other in hypothyroid patients as well as euthyroid patients. Collectively, hypothyroidism was not considered an independent explanatory variable for urinary CER in the present study and eGFRcre is a useful marker to evaluate kidney function regardless of the presence of hypothyroidism. It is well known that there is a strong interaction between thyroid function and kidney function . An elevHowever, it is still controversial whether thyroid function really regulates the glomerular filtration rate (GFR). While previous reports indicated decreased creatinine clearance in hypothyroidism , other rSince most of the previous reports analyzed the association between hypothyroidism and kidney function by eGFRcre ,18,19, iWe retrospectively reviewed patients with a measurement of 24 h urine collection while hospitalized in the division of kidney, diabetes, and endocrine diseases at Okayama University Hospital. Data from 2006 to 2019 were collected from electronic-based records. Data collection was completed in 2020–2021. Our database of medical records provided 18,068 patients. Among these patients, we collected 629 patients with all the following data of the measurements of s-Cr, 24hrCcr, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), 24 h urinary protein and Cr, total cholesterol, serum albumin, CysC, and glycated hemoglobin (HbA1c). We extracted 566 hypothyroid and euthyroid patients after excluding hyperthyroid and central hypothyroid patients. Other exclusion criteria were as follows: (1) age <18 years, (2) on dialysis, and (3) post-kidney transplantation. Consequently, 553 patients with chronic kidney disease were enrolled for a cross-sectional analysis shown in . The stu2) = 194 × s-Cr (mg/dL)−1.094 × Age−0.287 ) [2) = body weight0.425 × height0.725 × 0.007184 [5. Thyroid function was measured by using an electrochemiluminescence assay . The normal reference range in our institute for TSH was 0.27–4.2 µIU/mL, FT4 was 0.93–1.7 ng/dL, and FT3 was 2.3–4.0 pg/mL. In this study, hypothyroidism was defined as combined overt hypothyroidism (FT4 < 0.93 ng/dL and TSH > 4.2 µIU/L) and subclinical hypothyroidism (0.93 ≤ FT4 ≤ 1.7 ng/dL and TSH > 4.2 µIU/mL) like the previous reports [The following clinicopathologic characteristics were collected at the time of the hospitalization: age, sex, body mass index (BMI), and the use of glucocorticoid, levothyroxine, angiotensin-converting-enzyme inhibitor (ACE-i), and angiotensin II receptor blocker (ARB). HbA1c data are presented as National Glycohemoglobin Standardization Program values according to the recommendations of the Japanese Diabetes Society and International Federation of Clinical Chemistry . eGFRcreemales)) . While temales))  or the Memales)) , it is remales)) ,25. Sincemales)) . Nephrot0.007184 . Particip-values less than 0.05. Data were expressed as n (%) for categorical variables and mean ± standard deviation (SD) for continuous variables. Categorical variables were analyzed with the chi-square test, while continuous variables were compared by using the student’s t-test or Mann–Whitney U test as appropriate. Correlations among urinary CER and continuous variables  were evaluated by Spearman’s correlation analysis. Multiple linear regression analysis was performed to explore the association of variates with urinary CER. For the analysis, candidate variables contained hypothyroidism, sex, age, BMI, and 24hrCcr. Correlations among 24hrCcr and eGFRcre under euthyroidism and hypothyroidism were evaluated by Spearman’s correlation analysis. p for trend was calculated by the Cochran–Armitage trend test or the Jonckheere–Terpstra test.The statistical analyses were performed by JMP version 14.0.0  and Stata/SE version 16.1 . Significance was defined as 2 and 64.6 ± 38.4 mL/min, respectively. The average urinary CER was 1.01 ± 0.38 g/day. Trend analyses revealed that patients showed higher 24hCCr, eGFRcre, albumin, hemoglobin, and FT3 levels , younger age , higher proportion of male gender , higher BMI , and lower proportion of hypothyroidism  with higher urinary CER. To analyze the association between hypothyroidism and urinary CER, we stratified the patients by the presence or absence of hypothyroidism .To explore whether thyroid function affects Cr production, we compared the urinary CER between euthyroidism and hypothyroidism . The uriWhile it is well known that hypothyroidism increases s-Cr levels , detailsWhile the presence of hypothyroidisms was not an independent explanatory variable for urinary CER, age, sex, BMI, and 24hrCcr were associated with urinary CER as previously reported ,41,42. IThere are several limitations in this study. First, the sample size is relatively small in a single university hospital and the participants are mainly hospitalized for education or examination in the division of kidney, diabetes, and endocrine diseases, thus most of the participants had CKD and diabetes mellitus; therefore, selection bias cannot be excluded. In addition, kidney and thyroid function might be affected due to the medical condition for hospitalization. Therefore, it is difficult to generalize our results to patients without CKD and diabetes mellitus. Second, 52 patients with NS were included in the study. Since hypothyroidism is a well-known complication of NS  due to tOur study indicated that hypothyroidism was not considered an independent explanatory variable for urinary CER in the present study and eGFRcre is reliable to evaluate kidney function regardless of the presence of hypothyroidism. Future prospective studies are required for further clarification.


Patients with T2D demonstrated increased urinary excretion of RBP-4, GST-π, Col4, BMP-7, and HGF . The excretion of RBP-4, GST-π, Col1, and Col4 was increased in patients with elevated albumin-to-creatinine ratio , while BMP-7 and HGF were increased innormoalbuminuric patients also (p < 0.05). Urinary RBP-4, GST-α1, Col1, Col4, and HGF correlated positively with UACR; meanwhile, no correlations with glomerular filtration rate were found. The results demonstrate that elevated urinary excretions of the markers of tubular injury  and renal fibrosis , as well as HGF, an antifibrotic regulator, are associated with the albuminuric pattern of CKD in subjects with T2D.This study assessed the urinary excretion of markers and mediators of tubular injury and renal fibrosis in patients with type 2 diabetes (T2D) and non-albuminuric and albuminuric patterns of chronic kidney disease (CKD). One hundred and forty patients with long-term T2D and different patterns of CKD and twenty non-diabetic individuals were included. Urinary retinol-binding protein 4 (RBP-4), glutathione-S-transferase α An increased prevalence of diabetes around the world and changes in the management of the disease have transformed the epidemiology and clinical course of chronic kidney disease (CKD) in recent years. A number of studies have documented an increasing proportion of patients with diabetes developing a reduction in renal function without a preceding or concomitant increase in albuminuria ,2,3,4.It was demonstrated that albuminuric and non-albuminuric CKD patterns differ in their pathogenic mechanisms, risk factors, and clinical course ,5,6.AlbuThe study of markers of glomerular and tubular dysfunction and renal fibrosis is considered a promising approach to the diagnosis and prognosis of diabetic kidney diseases ,9,10. WeThis observational, single-center, and cross-sectional study included adult participants with long-term T2D. Men and women with the disease duration of more than 10 years since diagnosis were enrolled. The following set of exclusion criteria was established: end-stage renal disease, verified non-diabetic CKD, current urinary tract infection, ketoacidosis or hyperosmolar state at the time of the survey, malignant neoplasms, inflammatory or autoimmune diseases in the medical history, and high-protein diet.To reduce the risk of misclassification of CKD variants, we also excluded patients receiving antihyperglycemic drugs with established antialbuminuric effects: dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like receptor 1 (GLP-1) receptor agonists and/or sodium-glucose cotransporter 2 (SGLT-2) inhibitors for three months prior to inclusion.2 as a sign of decreased renal function (DRF) and UACR ≥ 3.0 mg/mmol as elevated albuminuria (EA). The values of eGFR ≥ 60 mL/min/1.73 m2 and UACR < 3.0 mg/mmol were referred to as normal renal function (NRF) and normal albuminuria (NA), respectively. Therefore, NRF/NA, DRF/NA, NRF/EA, and DRF/EA groups were identified. The classification principle is shown in Patients were recruited from the institutional database(2012–2018) as described previously ,11.We foWe also included 20 individuals without diabetes, obesity, or cardiovascular diseases as healthy control. The exclusion criteria were the same for control and diabetic subjects.1 (GST-α1), and glutation-S-transferase π (GST-π) as markers of tubular injury [1 and GST-π are considered to be site-specific. GST-α1 is located predominantly in the proximal convoluted tubules. Additionally, low levels of GSTα have been detected in the loop of Henle [We assessed urinary excretion of retinol-binding protein 4 (RBP-4), glutation-S-transferase αr injury ,13,14. Aof Henle . Urinaryof Henle .We measured urinary excretion of transforming growth factor β (TGF-β), a principalfibrotic mediator in the diabetic kidney ,18. In a1C (HbA1C), serum creatinine, UACR, and urinary excretion of total protein, were performed on AU480 Chemical Analyzer . The eGFR was calculated by the CKD-EPI formula (2009).Routine laboratory measurements, including glycated hemoglobin A1, GST-π, TGF-β, Col1, Col4, BMP-7, and HGF were assessed in the morning urine samples by ELISA. The commercially available kits: SEA929Hu for RBP-4; SEA609Hu for GST-α1; SEB090Hu for GST-π; SEU124Hu for TGF-β;HEA571Hu for Col1; HEA180Hu for Col4; SEA799Hu for BMP-7;and EA047Hu for HGF were used in this study. The activation reagent IS044  was applied additionally for the measurement of TGF-β concentration. None of the received results were out of the upper limit of the range defined by the kit manufacturer. The results which were below the lower limit of the range defined by the manufacturer were set as zero. The results were adjusted to the urinary creatinine.The concentrationsof RBP-4, GST-αThe sample size was preliminary calculated with parameters: α = 0.05 and 1 − β = 80% ,26.The m2 test. A difference was considered significant if the p-value was below 0.05.The Statistica 13.0 software package  was used for statistical procedures. The normality was tested by the Shapiro-Wilk test. As most of the quantitative variables were not distributed normally, Kruskal-Wallis H tests were used to assess the differences between the groups. Intergroup differences in discrete parameters were analyzed using the χ1C). The contributor in regression analysis was defined as significant if the standard deviation of the coefficient beta did not exceed the coefficient beta and the p-value was less than 0.05.Spearman rank correlation analysis was used to assess the associations between urinary markers and other parameters. The associations of markers with CKD patterns were checked in logistic regression models. The markers were adjusted on age, sex, body mass index (BMI), diabetes duration, and glycated hemoglobin (HbAp > 0.05). Patients with elevated albuminuria and normal renal function (NRF/EA group) had higher HbA1C as compared with those without CKD .One hundred and forty individuals with T2D were included in the study. Clinical characteristics of patient groups are presented in p = 0.03 and p < 0.001, respectively, 1 excretion.Patients with T2D had higher urinary excretion of RBP-4 and GST-π than control individuals . The increase in RBP-4 excretion in both NRF/EA and DRF/EA groups was significant in comparison with NRF/NA and DRF/NA groups .The changes in the RBP-4 and GST-π excretion were more prominent in albuminuric groups . No correlations were found between tubular markers and eGFR .Urinary RBP-4 and GST-π, but not GST-αp = 0.56and p = 0.11 vs. control, respectively, p > 0.05). Nonetheless, the patients with elevated albuminuria were characterized by higher levels of urinary Col1 as compared with other groups of the participants .Patients with T2D demonstrated no significant changes in TGF-β and Col1 excretion .Patients with T2D as a whole group had elevated Col4 excretion . No correlations with eGFR were found .The excretion of Col1 and Col4, but not TGF-β, correlated positively with UACR . Meantime, the excretion of HGF was increased in all diabetic groups . Additionally, DRF/EA group demonstrated higher urinary excretion of HGF when compared to the DRF/NA group (p = 0.02).Among subjects with diabetes, the elevation of BMP-7 was significant in NFR/NA, NRF/EA, and DRF/EA groups (p < 0.001) but not with eGFR . The excretion of BMP-7 did not correlate with UACR  and demonstrated a weak correlation with eGFR .The excretion of HGF correlated positively with UACR .In logistic regression models, RBP-4, Col1,and HGF were associated with increased albuminuria(UACR ≥ 3.0 mg/mmol) after adjustment for age, sex, BMI, duration of diabetes, and HbA1C . No inde1C. RBP-4 was associated with both albuminuric phenotypes (NRF/EA and DRF/EA) after adjustment for these factors [GSTs are a superfamily of ubiquitous detoxification isoenzymes that conjugate substrates to reduced glutathione . Our stues (T1D) . The stues (T1D) .We found increased urinary excretion of GST-π in patients with T2D; this increase was associated with albuminuria regardless of renal function. Increased urinary excretion of GST-π can be a result of the enzyme release from damaged tubular cells into urine ,14,16. TTGF-β is a key signaling molecule in the development of renal fibrosis ,18,21. IIn our study, we failed to find any differences in urinary TGF-β between control subjects and patients with diabetes, as well as between patients with albuminuric and non-albuminuric CKD. The decreased renal production and urinary excretion of TGF-β were observed previously under an ACE inhibitor administration in rats with subtotal renal ablation . SimilarCol1 is considered to be a component of normal kidney interstitium and glomerular basement membrane. The deposition of Col1 in these renal compartments is increased intubulo interstitial fibrosis. Glomerulosclerosis is associated with de novo expression of Col1in the mesangial matrix . In a laCol4 is a major component of the glomerular and tubular basal membrane and mesangial matrix . An assoCol1 and Col4 are considered as molecules associated with kidney fibrosis . In turnBMP-7, a member of the TGF-β superfamily, demonstrated an anti-fibrotic effect in diabetic nephropathy . It was In experimental models of diabetic nephropathy, a decreased expression of BMP-7 was found in mesangial cells and renal tissues ,57. A hiHGF is a multifunctional cytokine that plays an important role in development, regeneration, and tissue repair ,54. In tVarious hypotheses can be proposed to explain the preferential association of the studied renal markers with the albuminuric phenotype of CKD.Albuminuria is considered to be the result of an increased glomerular filter permeability and disrupted tubular absorption of albumin . SimilarSome molecules can enter the urine from damaged kidney structures. This could be a probable explanation for elevated excretion of GST-π, a marker of a tubular injury ,14,16, COne could speculate that altered bone metabolism may contribute to the elevation of urinary Col1 excretion in albuminuric patients with diabetesand CKD. However, previously, aninverse association of UACR with bone turnover markers, such as procollagen type 1 N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type I collagen (β-CTx),was reported .Finally, activation of the synthesis of the studied molecules in the kidney may increase their urinary concentrations. Elevated production of BMP-7 in renal tissues was demonstrated previously at the early stages of diabetic nephropathy  and undeOur study is not without limitations. Due to the variability in albuminuria and eGFR, some patients could be misclassified when divided into groups. Some intergroup differences may not have been found due to the limited sample size. The cross-sectional design is another obvious limitation. Future prospective studies are needed to elucidate the value of urinary RBP-4, GST-π, Col1, Col4, BMP-7, and HGF as predictors of albuminuric and non-albuminuric CKD in T2D subjects.Patients with T2D have elevated urinary excretion of markers of tubular injury , renal fibrosis , and antifibrotic growth factors . In these patients, urinary RBP-4, GST-π, Col1, Col4, and HGF areassociated with albuminuria independently from renal function. The identification of markers of non-albuminuric CKD in T2D remains a challenge for future research.