Alterations in renal perfusion play a major role in the pathogenesis of renal diseases. Renal contrast-enhanced ultrasound (CEUS) is increasingly applied to quantify renal cortical perfusion and to assess its change over time, but comprehensive assessment of the technique’s repeatability is lacking. Ten adults attended two renal CEUS scans within 14 days. In each session, five destruction/reperfusion sequences were captured. One-phase association was performed to derive the following parameters: acoustic index (AI), mean transit time (mTT), perfusion index (PI), and wash-in rate (WiR). Intra-individual and inter-operator  repeatability for the perfusion variables were assessed using intra-class correlation (ICC), with the agreement assessed using a Bland–Altman analysis. The 10 adults had a median (IQR) age of 39 years (30–46). Good intra-individual repeatability was found for mTT (ICC: 0.71) and PI (ICC: 0.65). Lower repeatability was found for AI (ICC: 0.50) and WiR (ICC: 0.56). The correlation between the two operators was excellent for all variables: the ICCs were 0.99 for PI, 0.98 for AI, 0.87 for mTT, and 0.83 for WiR. The Bland–Altman analysis showed that the mean biases (± SD) between the two operators were 0.03 ± 0.16 for mTT, 0.005 ± 0.09 for PI, 0.04 ± 0.19 for AI, and −0.02 ± 0.11 for WiR. A growing body of evidence recognises that alterations in renal perfusion play a major role in the pathogenesis of different renal diseases, including the syndromes of acute kidney injury (AKI) ,2 and chThe interest in microvascular quantification stems from the fact that perfusion alterations can occur at the microcirculatory level without changes in large vessel blood flow , and sinContrast-enhanced ultrasound (CEUS) is an alternative bedside technique for quantifying microvascular perfusion . CEUS usSome studies have adopted standardised acquisition and analysis techniques to try to ameliorate variations in contrast perfusion variables ,3,20,23.This was a cross-sectional observational study designed to assess intra-individual and inter-operator variability of quantitative CEUS measures of renal perfusion. The study was approved by Research Ethics Committee (403-1910), and all participants provided written informed consent.®).Ten adults were recruited between February 2021 and April 2021. Inclusion criteria were healthy people above the age of 18 years, with no known kidney disease, diabetes, or hypertension and no known sensitivity to the CA . No specific preparation was required from participants prior to the scan. Demographic and anthropometric details including age, gender, ethnicity, height, and weight were recorded, with blood pressure (BP) and heart rate (HR) also measured at each visit. All CEUS scans were performed by a single sonographer with CA administration performed by a medically qualified member of the research team. The primary outcome was intra-subject repeatability of CEUS-derived cortical perfusion parameters.®  CA was prepared as per manufacturer’s instructions to yield 4.8 mL. This then was further diluted with 15.2 mL of 0.9% sodium chloride solution to yield a total volume of 20 mL. The CA syringe was then inserted into a dedicated infusion pump , which rotates the syringe to keep the contrast dilution agitated, preventing constituted bubbles from separating. The infusion line  was then primed and connected to the participant’s cannula, and the infusion rate was set at 3.3 mL/min.CEUS scans were performed using a Philips iU22 ultrasound machine , with contrast-specific software and a Philips C5-1 curvilinear transducer. Participants were instructed to lie on their left side, so the right flank was easily accessible for right kidney scanning. A 20 G cannula was placed in the participant’s right antecubital vein. SonoVueCA infusion and imaging recording were started simultaneously. A period of two minutes was allowed for the CA to reach steady state, during which CA arrival to the kidney was visually observed. After this 2 min period, participants were instructed to hold their breath for 10 s and the transducer was held still in place. Five cycles of destruction/replenishment loops were captured, allowing participants to regain their breath between breath-holds. The destruction/replenishment loops involved a brief high mechanical index (MI) ultrasound pulse (flash) that caused complete CA destruction in the imaging field of view (FOV), followed by a replenishment phase when contrast re-entered the kidney. Upon completion of each assessment, recorded clips were exported to a hard drive in DICOM  format for off-line analysis.Ultrasound machine settings were optimised at the beginning of each scan. The frame rate was 11 Hz and depth 14 cm. The focus depth was set below the kidney for a more unified beam towards the kidney. Time-gain-compensation (TGC) was set as follows from top to bottom: 53, 71, 71, 73, 73, 73, 73, and 73. The view displayed was set to dual contrast/B-mode, which was essential as contrast imaging supresses signals from background tissue to enhance the signals from inflowing bubbles. B-mode images were used to guide scanning and transducer position. Contrast resolution (C40) and MI (0.04) were the same on both sides, with higher gain on the contrast (96%) compared to tissue (80%) side. For destruction/replenishment loops, the low MI was 0.04 and the high MI was 1.07.The right kidney was scanned in all patients but one, where the view was not satisfactory so the left kidney was scanned instead. A coronal or longitudinal imaging plane of the kidney was initially obtained with the same imaging plane used for all subsequent scanning. This was confirmed by reviewing first visit images and referring to notes on transducer position made at time of the first scan. The selection of the best view was based on the image quality of the visualised renal cortex that was clear of artefact, e.g., acoustic shadow from ribs.® (Version 7.2.0.58362) Gastrointestinal (GI)I Perfusion Package  with this software calibrated to “Philips IU22, C5-1, C40, Map 2 Chr. Map Off”  from the acquisition settings.Analysis was performed using VueBox® measures the average intensity within the drawn ROI, so small ROIs were avoided to minimise local heterogeneities. VueBox then displays time–intensity curves (TIC) and a parametric image (heatmap), as shown in Each of the five recorded loops was analysed individually. First, using the clip editor, unwanted frames (beyond 10 s) were removed. A systematic approach was then adopted for region of interest (ROI) placement. A single ROI was drawn so that it included the largest possible area of renal cortex perpendicular to the ultrasound beam. In addition, the visualised renal cortex had to be free from any artefacts (acoustic shadow/enhancement), renal interlobar or arcuate vessels (verified by absence of bubbles right after the flash frame), inadequate insonification (flood of ultrasound waves), or excessive out-of-plane motion. VueBox® version 9  so the method of generating the TIC could be specified. The non-linear one-phase exponential decay model (Y = (Y0-Plateau) × exp(−K × X)+ Plateau) was used, with Y0 constrained to Y0 = 0. The following perfusion parameters were derived for each loop individually: acoustic index (AI) (or plateau), which is the maximal intensity after reperfusion; mean transit time (mTT), which is the time needed after CA destruction to reach 50% of the maximal intensity; perfusion index, which is the ratio of AI to mTT; and wash-in rate (WiR) or K, which is the maximum slope. Each destruction-replenishment loop was analysed, and then, the median value was calculated for each parameter. A minimum of three loops with data of sufficient quality for analysis was required.The ROI of the first loop was saved and loaded into subsequent loops for consistency. Minor adjustments to the ROI were performed as necessary, bearing in mind the same cortex depth and kidney pole. The generated data were analysed independently using GraphPad PrismImage analysis was performed independently by two operators (S.J.A. and A.P.) to assess inter-observer variability.® . Normality of distribution was tested graphically. Non-normally distributed variables were log-transformed prior to analysis. Data are expressed as median and inter-quartile range (IQR) for non-normally distributed data. A p-value of <0.05 was considered statistically significant. The perfusion variables obtained from the two renal CEUS sessions for each participant were assessed for repeatability using an intra-class correlation (ICC) one-way model. Inter-observer variability was assessed using ICC two-way mixed model with absolute agreement. This was interpreted with reference to the criteria by Cicchetti [Analyses were performed using IBM SPSSicchetti , where aThe mean difference between the first and second scans was also calculated for each parameter. Associations between perfusion variables and subject characteristics were assessed using a two-tailed Pearson’s correlation for normally distributed data of continuous variables and with independent samples t-test for categorical variables. For non-normally distributed data, Spearman’s correlation and Mann–Whitney tests were used for continuous and categorical data, respectively. Sample size was determined based on the number of participants in most of the identified papers in the literature. Additionally, this sample size is adequate to demonstrate important points regarding the differences in repeatability between intensity-based and time-based measures that have relevance to the design of other studies using CEUS to assess renal perfusion.2 (22.3–25.9).We recruited 10 participants , with a median (IQR) age of 39 years (30–46) and body mass index (BMI) of 24.9 kg/mPerfusion variables are shown in p = 0.03). The corresponding value for PI was . Only fair, non-significant correlation values were found for AI  and WiR . As seen in A good degree of repeatability was found for mTT  and perfusion variables. Similarly, there was no difference in perfusion values between genders .In this study, we report intra-subject repeatability data from healthy volunteers for each of the measures of renal cortical perfusion generated from renal CEUS using the destruction/replenishment technique. The time-based measure of mTT had the best repeatability, whilst measures based on image intensity (AI) performed less well. The individual curves for each participant show results consistent with this , with soIn the present study, we employed a systematic approach to tackle potential factors that could contribute to variations in the acquisition of CEUS perfusion measures. Image acquisition was performed with a standardised approach using consistent machine settings. Parameters obtained from a certain ROI depend on the attenuation properties of the tissues overlying it, through which ultrasound waves propagate. These vary not only with the type of the tissue but also across the population and may also be influenced by pathology . TherefoThe analysis was performed with the ROI placed at the same depth and with those of the same size as far as possible. However, this was still subject to a degree of variability between the repeated flash/reperfusion loops. However, we have demonstrated that the analysis technique is repeatable with high inter-operator ICC values, and hence, the analysis process is unlikely to be a major source of variation.2) ROIs have been used in some studies [® calculates the average of intensities in a ROI. The good inter-observer agreement for all CEUS perfusion parameters reflects the minimisation of heterogeneity and reinforced our analysis approach. It is worth pointing out that we did not identify a reference ROI for normalisation as with renal tumour perfusion quantification studies, which means that a comparison of intensity-based variables between individuals becomes challenging. A reference ROI is normally placed within adjacent representative renal tissue at the same depth, an approach that was not possible with this method [Previous studies using renal CEUS for cortical perfusion quantification have used a variety of ROI sizes/numbers. Three small 5 × 5 mm ROIs hav studies ,29, wher studies ,3,23,30. studies , as VueBs method ,33.In accordance with our findings, a study by Harrois et al.  shows diThere are some limitations to this study. First, the sample size was relatively small, and as this study was performed on healthy volunteers, the results may not be generalisable to patient cohorts. Future studies should report intra-subject repeatability for patients with kidney disease . Other potential physiological factors such as hydration status, dietary salt intake, or tobacco use were not evaluated nor controlled and, although unlikely to have been significantly different within individuals between study sessions, have potential to influence results. Finally, inter-operator variability was only assessed for the analysis process, not for image acquisition, another aspect that should be considered as scope for future work.The current study reports the repeatability of CEUS-derived perfusion variables for renal cortical perfusion. Based on data from healthy individuals we conclude that the time-based variable (mTT) had good repeatability and is likely the most reliable measure for future studies in which CEUS is used to assess renal perfusion in patient cohorts and to assess changes in perfusion over time. The large intra-individual variation in intensity-based measures (AI) seen in some participants suggest that this parameter may not be suitable for this purpose.


Patient awareness of chronic kidney disease (CKD) is low in part due to suboptimal testing for CKD among those at risk and lack of discussions about kidney disease between patients and clinicians. To bridge these gaps, the National Kidney Foundation developed the Kidney Score Platform, which is a web-based series of tools that includes resources for health care professionals as well as an interactive, dynamic patient-facing component that includes a brief questionnaire about risk factors for kidney disease, individualized assessment of risk for developing CKD, and self-management tools to manage one’s kidney disease.The aim of this study is to perform usability testing of the patient component of the Kidney Score platform among veterans with and at risk for kidney disease and among clinicians working as primary care providers in Veterans Affairs administration.Think-aloud exercises were conducted, during which participants (veterans and clinicians) engaged with the platform while verbalizing their thoughts and making their perceptions, reasonings, and decision points explicit. A usability facilitator observed participants’ behaviors and probed selectively to clarify their comprehension of the tool’s instructions, content, and overall functionality. Thematic analysis on the audio-recording transcripts was performed, focusing on positive attributes, negative comments, and areas that required facilitator involvement.Veterans (N=18) were 78% (14/18) male with a mean age of 58.1 years. Two-thirds (12/18) were of non-White race/ethnicity, 28% (5/18) had laboratory evidence of CKD without a formal diagnosis, and 50% (9/18) carried a diagnosis of hypertension or diabetes. Clinicians (N=19) were 29% (5/17) male, 30% (5/17) of non-White race/ethnicity, and had a mean of 17 (range 4-32) years of experience. Veterans and clinicians easily navigated the online tool and appreciated the personalized results page as well as the inclusion of infographics to deliver key educational messages. Three major themes related to content and communication about risk for CKD emerged from the think-aloud exercises: (1) tension between lay and medical terminology when discussing kidney disease and diagnostic tests, (2) importance of linking general information to concrete self-management actions, and (3) usefulness of the tool as an adjunct to the office visit to prepare for patient-clinician communication. Importantly, these themes were consistent among interviews involving both veterans and clinicians.Veterans and clinicians both thought that the Kidney Score Platform would successfully promote communication and discussion about kidney disease in primary care settings. Tension between using medical terminology that is used regularly by clinicians versus lay terminology to promote CKD awareness was a key challenge, and knowledge of this can inform the development of future CKD educational materials. Chronic kidney disease (CKD) is a chronic disease that requires individual participation in health-related behaviors to decrease the risk of progression and associated cardiovascular disease . PatientReasons for the low prevalence of CKD awareness among individuals with CKD are varied and include patient, provider, and health system factors . Two of To bridge the communication gap about kidney disease among patients and health care professionals and increase testing among individuals at risk for CKD, the National Kidney Foundation (NKF) developed the Kidney Score Platform, leveraging the behavior change wheel, a validated framework used to design interventions to incite individual behavior change . The KidThe patient-facing component of the Kidney Score platform includes a brief questionnaire about risk factors for kidney disease that results in a personalized educational results page providing an individualized assessment of risk for developing CKD or self-management tools to manage one’s kidney disease -3. Devel2, those receiving dialysis treatments, and individuals who were kidney transplant recipients. Veterans who were unable to use a tablet or computer device  were also excluded. Potential veteran participants were mailed a flyer about the study and provided a phone number to opt out of the study. A research coordinator subsequently called veterans who did not opt out of the research to explain study goals and procedures, obtain consent, arrange for hard signatures of necessary forms, and schedule the think-aloud interviews.The Kidney Score Platform was field tested in 2 phases among 20 veterans and 19 clinicians from the VA NY Harbor Healthcare System (VA-NYHHS) and the VA CT Healthcare System at West Haven (VA-CTHS). We used a purposeful sampling approach using the electronic medical record to identify potential veteran participants who were English-speaking, active primary care patients between the ages of 18 and 75 years and who were living with diabetes or hypertension, the 2 most common causes of chronic kidney disease in the United States. Although having kidney disease was not an inclusion or exclusion criterion, we excluded veterans with very advanced kidney disease, including those with an estimated glomerular filtration rate (eGFR) <15 ml/min/1.73mClinician participants included physicians and nurse practitioners who were actively engaged in primary care delivery at either Veterans Administration site. Recruitment of clinicians occurred via email by members of the research team. A research coordinator then followed up with eligible clinicians who responded favorably to schedule the think-aloud interviews.After providing online documentation of informed consent, each participant joined an online platform using a numeric study ID. Two usability facilitators  introduced themselves and provided a brief overview of the goals of the project. Participants were asked again to acknowledge informed consent that participation was voluntary, could cease at any time, and that the session would be audiotaped but their privacy safeguarded. The study was approved by the institutional review boards at VA-NYHHS  and VA-CTHS . The COVID-19 pandemic required protocol modifications with appropriate institutional review board amendments to allow remote participation of veterans and clinicians in online think-aloud sessions in contrast to the original investigation design, which included face-to-face study interactions. The COVID-19 pandemic also extended the research timeline, creating 2 similar phases of work instead of 1.Each session began with a warm-up interview exploring participants’ experience with online resources related to health and kidney health. Veterans were asked about experiences using web-based resources to gain information about their own health; clinicians were asked about use of online resources to communicate about chronic diseases, including but not limited to kidney disease. Thereafter, all participants were provided a weblink to the Kidney Score Platform website and were asked to participate in a think-aloud exercise, during which they were asked to engage with the platform while verbalizing their thoughts and making their perceptions, reasonings, and decision points explicit. Think-aloud exercises are increasingly being used to conduct user testing of digital health interventions . During During phase 1 (March 2020 to April 2020), audio recordings of field tests with 10 veterans and 19 clinicians were reviewed. Thematic analysis was performed, with focus on positive attributes, negative comments, and areas that required facilitator involvement. Clinicians were also asked how they might use this tool in clinical practice. Areas of improvement in the layout or design of the tool were quickly addressed by the research team and the NKF, which developed a second iteration of the Kidney Score Platform. Examples of changes included the following: reducing white space in between educational sections, rearranging location of kidney graphics, and replacing a picture of a heart with the word “love” for clarity. The Kidney Score Platform was reviewed by an additional 10 veterans during phase 2 of field testing (February 2021 to March 2021). Results from both phases were used to finalize the tool.No formal hypothesis testing was performed due to the qualitative study methods of usability testing. Participants’ demographic characteristics are described using counts and percentages. Notes from direct  observations by the usability facilitators and audio recordings of the field tests were reviewed. Thematic analysis was performed , with a focus on themes derived from the data regarding positive attributes, negative comments, and areas that required facilitator involvement.Veterans were 78% (14/18) male with a mean age of 58.1 years (range 27-71 years); see All veterans and clinicians successfully navigated to the Kidney Score Platform website after being provided a link to the home page. Thereafter, they easily followed the self-assessment questionnaire portion of the Kidney Score Platform, aided by standard button labels and a simple progress indicator  that provided a clear signal about survey length, which was also considered reasonable. The visual design of the personalized results page was appealing to all participants, who also appreciated the inclusion of infographics. Clinicians and veterans both recommended to reduce the overall text copy and include links to additional educational resources on the personalized educational results page.Three major themes related to content and communication about risk for CKD emerged from the think-aloud exercises: (1) tension between lay and medical terminology when discussing kidney disease and diagnostic tests, (2) importance of linking general information to concrete self-management actions, and (3) usefulness of the tool as an adjunct to the office visit to prepare for patient-clinician communication. Importantly, these themes were consistent among interviews involving both veterans and clinicians.Clinicians affirmed that phrasing of questions such as “Have you been told” or “Do you take medications for [disease name]” were likely to yield accurate responses during self-assessment rather compared to asking patients whether they have a particular disease. Providers were concerned that patients may not associate (or identify) with heart disease or high blood pressure even though they were actively taking medications to manage these conditions, especially if these chronic conditions were being well managed. However, a question asking about “Have you been told” directly relates to prior conversations about chronic diseases, regardless of management strategy or success.Aligned with clinician feedback, veterans generally understood the phrasing “Have you been told you have [health condition]” and related questions appeared to garner accurate responses from patients regarding their health risks. Veterans correctly answered yes to being told they had high blood pressure or heart failure even if they were taking medications to manage the underlying condition. However, some individuals struggled to assess whether being at risk for diabetes meant they had prediabetes, in part because they had not heard of the term “prediabetes” before.So my doctor never really told me I have prediabetes. He told me my A1C.Veteran 2Nearly all clinicians were concerned about veterans not recognizing the medical terms “heart failure” or “chronic kidney disease.” Clinicians stated that during their communications with patients, they were more likely to describe the underlying disease rather than rely on disease names, for example, noting to patients that “your kidneys are not functioning properly” rather than using the term “chronic kidney disease.” To be consistent with the lay terminology used during clinic conversations, one primary care clinician suggested the following:I wonder if a question like, have you been told that you have chronic kidney disease, whether it should also say something like, have you been told that you have any problems with your kidneys or if your kidneys don't work completely normally or something that might not be a phrase in medical jargon.Clinician FTwo questions embedded in the self-assessment tool asked about eGFR and urine albumin-creatinine ratio (uACR). Clinicians doubted that any of their patients would know their eGFR or uACR.I’m almost sure no one would know their GFR … I think only a very special person would know [their uACR] even more so than GFR.Clinician BMost clinicians noted that they rarely used these terms in clinical practice when discussing kidney disease with their patients. Instead, they relied on plain language descriptions (“urine test” for uACR) and simplified conceptual explanations (“kidneys functioning at 60%” to describe eGFR). Although several providers acknowledged that this was an imprecise translation, they thought that it was important to make the information more accessible to patients to promote CKD awareness.The question that I get most often when I talk about CKD is, “What percent of my kidneys are still functioning?” Because GFR is a hard number to remember … I’ll tell people, “Listen, I think we lost 50% of your kidney function.”Clinician GClinicians had a similar approach when discussing the presence of albuminuria.When I talk to patients about having protein in their urine, I don't reference the number all that often. Though more so than with eGFR, I'll pull up the trend … But even then, I'll rarely refer to it by name.Clinician FAs clinicians predicted, hardly any veterans were familiar with eGFR or uACR.This is like a foreign language to me. I've never heard those words before.Veteran 3For most patients, the terms themselves were new; all patients answered “I don’t know” to the questions asking about levels of eGFR and uACR . Even amI may not know what my numbers are, but I do know what the tests are, and I do know that I've had them done before.Veteran 10Patients used lay terminology to describe eGFR and uACR, consistent with what was described by clinicians. Most veterans said that their primary care clinician would talk more about the significance of the laboratory results as opposed to using specific terms or values.My doctor just said, “You don’t have protein in your urine.” I don't know the number or whether it was elevated.Veteran 8I know that they have done urine tests in the past, and I know protein and sugar was in my urine.Veteran 13Although clinicians appreciated the personalized nature of the individualized results page about risk factors for CKD , they feI don't see much here for how to manage the risk factors… There's not much here about next steps.Clinician FIf I were a patient, I'd like links to more info about kidney-friendly eating and exercising options. I would want to have information about medications to avoid, medications that can be helpful.Clinician CSimilarly, while most patients understood from the results page that they were at risk for kidney disease, some did not read carefully enough to fully realize the perceived-risk concept between diabetes, heart disease, and kidney disease and that management of the diabetes and heart disease would help mitigate risk of kidney disease. Of those patients who read the results more carefully, some felt empowered by the information, while others reacted with alarm to the risk of CKD. In particular, veterans emphasized the importance of providing actionable education to help motivate individuals to change their personal risks for kidney disease without paralyzing them with the idea that kidney failure requiring dialysis or transplant was inevitable.It's kind of gloom and doom; if I hit these thresholds, things may not be working properly, or may be approaching failure. So the message I get is: if you see these numbers, you're in deep trouble.Veteran 3Although most veterans planned on speaking with their clinicians about the questionnaire results, some were seeking more actionable steps that they could take on their own. They yearned for more concrete recommendations that they could adopt.It suggests exercise, but it’s not telling me the type of exercise to do.Veteran 1What I would be mostly interested in is what is happening, why is it happening, and what can I do to slow it down? Anything I see that's clickable that touches on those points, I would be interested in clicking on.Veteran 11When asked whether they would use the tool in clinical practice, most clinicians viewed the tool’s primary value was for educating patients prior to their next appointment. With limited time during office visits, clinicians did not think that they could review the tool in its entirety with patients; however, they viewed the tool as one that patients could use in preparation for an office visit that could be dedicated to a discussion about kidney disease and cardiovascular risk. Clinicians felt that patients would benefit from having time to go through the self-assessment and results on their own time, particularly if there were more actionable next steps identified for them.If they can sort of generate the results and then bring them in, I think that would be helpful to have a discussion about where they are with their CKD and how we can help sort of reduce their risk of progression.Clinician AFrom my perspective, I wouldn’t use our visit time to go through this. Though maybe patients might find value in going through ahead of time.Clinician HOverall, most veterans felt the tool was useful since it made them aware of kidney disease. All participants said that they planned to email their CKD risk results to themselves to prepare for a discussion about kidney health with their clinician at their next visit.Actually, I like the site better than I thought I would. … those questions were very precise and specific questions. As long as everybody's being honest when they're answering, I think the information that they're going to receive is going to be very useful.Veteran 10There's some good information here. It sounds like it at least presents [information] to you a way to have this discussion with your doctor, and then see if they can test your blood or test your urine, and do the necessary tests to see where you are.Veteran 5Although no patients knew their kidney-health lab values, most were intrigued enough that they planned to bring it up with their primary care clinician at their next visit.It made me more interested in getting a test to see where I’m at.Veteran 4For many, being asked about their kidney health values and not knowing the answer motivated them to speak to their clinician about CKD.Well, let me put this way: I'm now well aware now of the significance of the kidneys and about what the issues are here. And I would definitely consider... When I go to the doctor, I would say to him, “Now, listen. You did the blood tests. But how are my kidneys doing? What are the numbers?”Veteran 6Part of me is kind of mad there, because this a blind spot that me and my doctor, who I feel pretty comfortable with; we have not talked about CKD. I don't know if he didn't want to scare me, or maybe because he's concentrated on the prediabetes. I feel like I'm going to harass him about CKD now.Veteran 7This is something new, so immediately I was like, just another thing to be concerned about. But then I felt kind of empowered, and like I really do want to get ahead of this thing. I feel like I do want to have a conversation with my primary care physician. CKD makes me feel better than end stage renal failure, so that makes me feel empowered because I'm at risk for chronic kidney disease, which is not end stage renal failure.Veteran 7The Kidney Score Platform is an online educational tool that was developed to promote communication and discussion about kidney disease among patients and their primary care clinicians. Usability findings demonstrate that this goal was met, with the majority of patients finding the digital tool to be helpful and easy to navigate. Content areas that would benefit from refinement were also clearly identified.The think-aloud exercises identified 2 key themes pertinent to the development of all educational materials related to kidney disease. First, there is a tension between using medical terminology that is used regularly by clinicians as well as reinforced in laboratory reports and electronic records versus lay terminology to educate patients and promote CKD awareness. This has been an area of debate in the nephrology field for quite some time . PrevaleThe use of low grade-level vocabulary is an important component of adult education and written education materials . However“albumin-creatinine ratio (uACR) or a type of protein in the urine”—to share the medical terminology that is used by clinical laboratories and national awareness campaigns while promoting discussions between patients and their clinicians about the usefulness and importance of these diagnostic tests to identify risks of CKD. Testing these changes in a real-world environment will demonstrate whether this strategy outweighs the risks of alienating individuals with medical terminology, particularly those who may be in denial about their chronic health conditions that increase the risk of developing CKD.Prior investigations that assess CKD awareness using lay terms such as “kidney problem” have shown incremental improvement but overall residual low awareness . In an e2 as a percentage of kidney function, as suggested by this investigation, may help patients understand the relationship between medical and lay terms. Using the test percent performance concept for percent of kidney function with 60 or higher being normal may also make conceptual sense to patients, as 60% is approximately the customary level for scholarly examination failure in the United States. In addition, some patients may better conceptualize eGFR and uACR with the images that were explored in this investigation, with heat map colors (from low risk) of green, yellow, orange, and (high risk) red. Study findings are hypothesis generating for future investigations regarding methods to connect medical and lay terminology as well as integration of images to illustrate the relationships.Connecting medical and lay terms may also require examples or approaches to enhance understanding. Conceptually, describing medical terminology like eGFR in ml/min/1.73mThe second key theme identified the importance of linking education about kidney disease with action-oriented recommendations that can decrease the risk of kidney disease or CKD progression. Clinicians and public health officials may consider awareness of kidney disease an important outcome on its own. However, patients may consider awareness of chronic conditions only as a means to an end—a transitory step that may not lead to improved health unless the education is coupled with actionable risk-reduction tools and motivational interviewing . EmpowerBoth content and sequence are important elements of CKD educational media design. Workflow for time-constrained primary care clinicians is a major barrier to clear and effective bidirectional communication about kidney health, kidney disease risk, and the interplay with an array of cardiometabolic risk conditions. We designed the study to occur before the veteran-practitioner encounters to address this barrier that in turn contributed to the clinicians recommending that the Kidney Score Platform education be delivered before the visits. Additionally, the platform could also be used after a clinician visit, allowing a modified education tailored to the interventions emphasized in the encounter or the after-visit summary for reinforcement.The results of this study should be taken in context of its limitations. Although our sample size was larger than the recommended range of 5 to 7 participants for usability testing , our samInformation derived from this usability study enabled the NKF to strengthen the Kidney Score Platform tool to promote its usefulness as an empowering adjunct to care and provided some key themes that will be applicable to the development of future educational materials.


Two subsets of eosinophils have been described: resident eosinophils with homeostatic functions (rEOS) in healthy subjects and in patients with nonallergic eosinophilic asthma, and inflammatory eosinophils (iEOS) in blood and lung samples from patients with allergic asthma. We explored if it would be possible to identify different subsets of eosinophils using flow cytometry and the gating strategy applied to induced sputum. We conducted an observational cross-sectional single-center study of 62 patients with persistent allergic asthma. Inflammatory cells from induced sputum samples were counted by light microscopy and flow cytometry, and cytokine levels in the supernatant were determined. Two subsets of eosinophils were defined that we call E1 (CD66b-high and CD15-high) and E2 (CD66b-low and CD15-low). Of the 62 patients, 24 were eosinophilic, 18 mixed, 10 paucigranulocytic, and 10 neutrophilic. E1 predominated over E2 in the eosinophilic and mixed patients , while E1 and E2 were similar for neutrophilic and paucigranulocytic patients. E1 correlated with IL-5, fractional exhaled nitric oxide, and blood eosinophils. While eosinophil subsets have been identified for asthma in blood, we have shown that they can also be identified in induced sputum. Asthma clinical practice guidelines ,2 recommFlow cytometry, using specific markers for membrane proteins, can also be used to automatically count cells in induced sputum. Although this application has been described ,6, it haEvidence on the existence of different eosinophil subsets may have clinical implications for phenotype definition, patient prognosis, and treatment. Identifying eosinophil subsets in patients with severe, uncontrolled asthma is likely to enable judicious selection of biological treatments; it may even help identify targets for the development of new molecules and treatments specifically focused on pathological eosinophils, which would avoid the deleterious effects of concomitantly eliminating eosinophils with homeostatic functions.The objective of this study was to explore the possibility of distinguishing between eosinophil subsets in the induced sputum of patients with allergic asthma and to determine the distribution of these subsets in different bronchial inflammatory phenotypes.In this single-center cross-sectional observational study, patients monitored for persistent allergic asthma were recruited from Hospital de la Santa Creu i Sant Pau outpatient clinics between September 2016 and January 2019. All patients met diagnostic criteria for persistent asthma according to the current version of the Global Initiative for Asthma (GINA)  was admiSputum induction was performed according to the European Respiratory Society (ERS) standardized methodology . PremediLeukocytes were identified using autofluorescence (FITC), side scatter (SSC), and CD45 expression [Flow cytometry gating defined the eosinophil population that coexpressed CD66b+ and CD15+. Two eosinophil subsets, which we call E1 and E2, were characterized by high expression of CD66b and CD15 and low expression of CD66b and CD15, respectively. Cytokines present in the induced sputum supernatant were analyzed, using LEGENDplex panels , to determine levels of the following: eotaxin; immunoglobulins IgA, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM; interferon alpha and gamma (IFNα and IFNɣ); interleukins IL-1Β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-23, and IL-33; monocyte chemoattractant protein 1 (MCP-1); matrix metalloproteinase 2 and 9 (MMP2 and MMP9); and tumor necrosis factor alpha (TNFα).For normally distributed continuous variables, results were expressed as means and standard deviations (SD), and qualitative variables were expressed as frequencies and percentages. Differences between phenotypes were determined using analysis of variance (ANOVA) for the quantitative variables and Pearson’s chi-squared for the qualitative variables. Posthoc analyses were performed using the Sheffe and Games Howell tests for homogeneity and nonhomogeneity of variances, respectively. Pearson’s correlation coefficient was used to determine dependence between quantitative variables. In all cases, the level of statistical significance was set to 5% (α = 0.05). Statistical analysis was performed using SPSS V. 24.0 for Windows.p = 0.050) and blood eosinophils , and E2 with the ACT score . E1 and E2 correlations with exacerbations did not reach statistical significance.Clinical characteristics for the 62 recruited patients with allergic asthma are summarized in p = 0.040); paucigranulocytic patients, lower ICS requirements (p = 0.033); and eosinophilic and mixed patients, a higher incidence of nasal polyposis (p = 0.042).Bronchial inflammatory phenotype distribution, according to induced sputum cellularity as measured by microscopy, were as follows : eosinopp = 0.302), whereas E1 differed (p = 0.034). E1 predominated over E2 in eosinophilic (20.86% vs. 6.27%) and mixed (14.42% vs. 4.31%) patients, while E1 and E2 distributions were similar for neutrophilic (2.51% vs. 3.85%) and paucigranulocytic (3.25% vs. 2.46%) patients (p = 0.024) and between paucigranulocytic and eosinophilic patients .All four phenotypes had detectable E1 and E2 subsets. E2 was similar across the different phenotypes , inversely with neutrophils by microscopy , and with E1 .No statistically significant differences between phenotypes were evident from supernatant cytokines . There wIn this exploratory study we demonstrate that, using flow cytometry, it is possible to identify two subsets of eosinophils in induced sputum in patients with persistent allergic asthma. Subset E1, characterized by high expression of CD66b and CD15, predominates over subset E2 in allergic asthma with bronchial eosinophilic inflammation. E1 levels are correlated with FeNO, blood eosinophil count, and IL-5 levels in induced sputum supernatant, which would suggest that they play more of an inflammatory than a homeostatic role.As this is the first study that defines subsets of eosinophils in induced sputum, there were no precedents available. For this reason, our gating strategy relied on the expression of CD66b and CD15. The role of CD66b, a membrane protein present in granulocytes that indicates cell activation, in eosinophils has only recently been described. Its activation by monoclonal antibodies or its usual ligand, galectin-3, induces cell adhesion, superoxide molecule production, and eosinophil degranulation . CD15  predominates in patients with allergic asthma and eosinophilic inflammation and is correlated with blood eosinophils, FeNO, and IL-5 in sputum supernatant.


Klotho is an identified longevity gene with beneficial pleiotropic effects on the kidney. Evidence shows that a decline in serum Klotho level occurs in early chronic kidney disease (CKD) and continues as CKD progresses. Klotho deficiency is associated with poor clinical outcomes and CKD mineral bone disorders (CKD-MBD). Klotho has been postulated as a candidate biomarker in the evaluation of CKD. However, the evidence for the clinical significance of the relationship between Klotho and kidney function, CKD stage, adverse kidney and/or non-kidney outcomes, and CKD-MBD remains inconsistent and in some areas, contradictory. Therefore, there is uncertainty as to whether Klotho is a potential biomarker in CKD; a general consensus regarding the clinical significance of Klotho in CKD has not been reached, and there is limited evidence synthesis in this area. To address this, we have systematically assessed the areas of controversy, focusing on the inconsistencies in the evidence base. We used a PICOM strategy to search for relevant studies and the Newcastle–Ottawa Scale scoring to evaluate included publications. We reviewed the inconsistent clinical findings based on the relationship of Klotho with CKD stage, kidney and/or non-kidney adverse outcomes, and CKD-MBD in human studies. Subsequently, we assessed the underlying sources of the controversies and highlighted future directions to resolve these inconsistencies and clarify whether Klotho has a role as a biomarker in clinical practice in CKD. The Klotho gene was first identified as a novel longevity gene in 1997 . It exisKlotho is strongly expressed in the kidney and the level there is related to its functional state . TherefoNevertheless, there has been a significant controversy regarding whether sKlotho serves as a suitable biomarker in CKD because available clinical evidence on the sKlotho value remains debated and is inconsistent . Indeed,As a kidney protective protein, sKlotho deficiency is observed to be associated with reduced kidney function, CKD stages, adverse outcomes, and CKD-MBD, indicating a potential role as a biomarker in CKD. However, available clinical studies yielded inconsistent and even contradictory results regarding the correlation of sKlotho with CKD. To some extent, conflicting evidence indicates uncertainty in the application of sKlotho as a biomarker.There is increasing evidence that the source of circulatory sKlotho is derived from the kidney , indicatet al. investigated the sKlotho level in 321 CKD patients of stages 2–4. The sKlotho level did not differ significantly based on the CKD stage, and the baseline eGFR was not changed significantly according to sKlotho tertiles. No apparent association was found between the eGFR and sKlotho levels by Spearman correlation analysis  was not correlated with the eGFR . This finding suggested that lower sKlotho could not predict combined adverse outcomes (p = 0.845) or all-cause mortality risk . This study had the largest sample  and the longest term of follow-up (9.9 years). Another recent observational study with a large sample also failed to show any significant association  is a serious syndrome that is associated with an increased risk for morbidity and mortality . Mostly,scytosis . This inscytosis . RecentlThese conflicting results indicate that there is uncertainty about whether a decrease in sKlotho level correlates with kidney function and clinical outcomes. Based on the evidence to date, a low sKlotho level may not represent a useful biomarker for CKD diagnosis and prognosis.The present evidence base does not currently support using sKlotho as a biomarker in CKD. Several reasons may contribute to the discrepant results and affect the interpretation of the results .First, standardization of sKlotho assays has yet to be achieved . The cirSecond, it remains unclear what happens regarding Klotho production and clearance in the failing kidney. This may be another reason for the inconsistent findings in specific CKD models such as DKD versus non-DKD , pre-diaThird, the sKlotho level is regulated by several pathological processes, including inflammation, oxidative stress, uremic toxins, and the renin-angiotensin system (RAS), as well as commonly administrated agents, such as phosphate binders or active vitamin D in CKD . These pFourth, sKlotho is also produced by extra-renal organs . Extra-rFinally, the quality of the included studies inevitably affects the interpretation of the results. Regarding the correlation of sKlotho with the eGFR, the design of the cited literature is observational or case-control . These sTaken together, there are conflicting results from various sources, such as the uncertainty of sKlotho assays or Klotho production/clearance and differences in disease conditions, treatment modalities, drugs, and study quality. Consequently, these inevitably challenge the translation of sKlotho into clinical practice. Therefore, the current evidence should be interpreted with caution until further studies are reported.Vascular calcification (VC), which results from excess calcium phosphate deposition in blood vessels and/or heart valves, is a hallmark feature of CKD-MBD . It is hKlotho systemic deficiency is associated with severe VC. Experimental studies have shown that increased Klotho expression or Klotho therapy ameliorates VC , indicatBy contrast, some observational and cross-sectional studies reported no association between sKlotho and AVC, CAC, or AAC in CKD patients, indicating the controversy regarding the role of sKlotho in mediating VC. A previous study which enrolled 127 patients with MHD reported that the serum sKlotho level was not related to the AAC or CAC scores neither in a crude model nor adjusted model . AnotherThese discrepant findings represented a more complex role of Klotho in VC. There were several explanations for the conflicting results. First, whether Klotho is located in the vasculature is a matter of debate . AlthougConsequently, due to the above contradictions and insufficient data, the association of sKlotho with VC remains uncertain and needs to be clarified in the future.via FGF23-dependent mechanisms as well as non-FGF23-dependent mechanisms , and calcitonin by balancing their intestinal uptake, renal excretion, and bone mobilization. Klotho-deficient mice exhibited mineral metabolism disorders, including phosphate retention, hypercalcemia; VC, valve calcification; and elevated fibroblastic growth factor-23 (FGF23) levels . These dchanisms . The netchanisms  (Neyra echanisms . In agrechanisms .via FGF23 (+ and K+-ATPase activity (Despite this, there is evidence available that does not support this view. Regarding calcium metabolism, Klotho was reported to increase its reabsorption and reverse renal calcium loss by modulating renal calcium-selective channels independent of FGF23 . This efia FGF23 . With reia FGF23 , and thiia FGF23 . In the ia FGF23 . Generalia FGF23 . Neverthactivity . Klotho activity . Moreoveactivity . Regardiactivity , and itsactivity . Klotho-activity , while sactivity . Surprisactivity . The comactivity .The inconclusive results represent an important controversy in this area. These discrepancies may result from different experimental animals, the CKD stage, diet composition, and varied participant baseline characteristics . AdditiosKlotho is postulated to become a potential marker in CKD; however, one should be aware that there are still contradictory findings in terms of the relationship of sKlotho with kidney function, CKD stage or progression, and CKD-MBD. This indicates that a complete consensus has not been reached in this context due to the existing inconsistent results. To address this issue, the sources of controversies previously described should be resolved specifically before the potential application of sKlotho as a biomarker in CKD.First, one important issue is how to accurately detect sKlotho in serum or body fluid. Several available sKlotho assays failed to precisely determine the actual sKlotho level or the range of the sKlotho reference value . Interes125I-labeled exogenous Klotho is located mainly in the kidney, with much lower levels in other organs, including the spleen, liver, heart, and brain (via transcytosis by renal proximal tubules (et al. recently reported that for CKD patients with an eGFR<60 ml/min, Klotho was also cleared by splanchnic organs (Second, the kinetics of sKlotho is currently still not fully understood . It was nd brain . The hal tubules . Therefo tubules . Not sur tubules . In addic organs . This inc organs , as wellc organs . TherefoFinally, due to the current controversy, high-quality studies, such as interventional trials and prospective or retrospective cohort studies, with standard diagnostic criteria and indicators, are warranted to elaborate and clarify the confusion of Klotho in CKD. In this regard, meta-analysis and systemic review also offer the potential possibility of addressing this issue. Indeed, several meta-analyses have been performed to address this issue in recent years. These published studies supported a close association of sKlotho with kidney function and adverse outcomes in CKD . HoweverCKD is increasingly identified as a global threat to public health, and screening and validating surrogate biomarkers in CKD is critical for its management. Klotho is involved in various biological processes. Its role in clinical nephrology has been particularly examined over recent years. Despite a significant association between sKlotho and kidney function, for CKD outcomes and CKD-MBD, as demonstrated by the experimental and epidemiological studies, there are equally inconsistent findings that suggested that sKlotho may not be a good surrogate biomarker in CKD. This means that much still needs to be resolved regarding the clinical significance of Klotho in CKD. This prompts us to continuously seek the possible sources of controversy and specifically address and resolve this issue in the future. Given the conflicting results, further well-designed research is urgently required to clarify and validate the clinical value of Klotho. In addition, more efforts should be directed to improving sKlotho assay performance. Through this, the possibility of Klotho as a potential biomarker is to be systemically assessed, and a more reliable conclusion can be reached.


Refractory congestion is common in acute and chronic heart failure, and it significantly impacts functional class, renal function, hospital admissions, and survival. In this paper, the pathophysiological mechanisms involved in cardiorenal syndrome and the interplay between heart failure and chronic kidney disease are reviewed. Although the physical exam remains key in identifying congestion, new tools such as biomarkers or lung, vascular, and renal ultrasound are currently being used to detect subclinical forms and can potentially impact its management. Thus, an integrated multimodal diagnostic algorithm is proposed. There are several strategies for treating congestion, although data on their efficacy are scarce and have not been validated. Herein, we review the optimal use and monitorization of different diuretic types, administration route, dose titration using urinary volume and natriuresis, and a sequential diuretic scheme to achieve a multitargeted nephron blockade, common adverse events, and how to manage them. In addition, we discuss alternative strategies such as subcutaneous furosemide, hypertonic saline, and albumin infusions and the available evidence of their role in congestion management. We also discuss the use of extracorporeal therapies, such as ultrafiltration, peritoneal dialysis, or conventional hemodialysis, in patients with normal or impaired renal function. This review results from a multidisciplinary view involving both nephrologists and cardiologists. The clinical course of patients with heart failure (HF) is characterized by frequent exacerbations that require urgent medical attention. It has been demonstrated that congestion, not low cardiac output, is the main reason for these acute episodes, which are associated with increased morbidity and mortality and impose a considerable economic burden on health care systems .Early detection of congestion is paramount since it allows intensification of treatment before signs and symptoms worsen, which, in turn, may prevent the need for urgent medical care . FurtherTraditionally, clinicians have relied on the physical exam to detect congestion; however, clinical signs and symptoms are late manifestations and are neither sensitive nor specific to HF . RecentlGiven the central role of congestion in HF exacerbations, an adequate understanding and knowledge of diverse decongestive strategies is a must for anyone involved in the care of HF patients. Chronic kidney disease (CKD) is present in up to 51–65% of HF patients  and is aThis review covers the main mechanisms that lead to congestion in HF patients, the different diagnostic modalities to detect it, and the available treatment strategies from an integrated cardionephrology approach.cardiorenal vascular system and not as each organ system separately.The association between the kidney and the heart has been reported since the early 19th century when Robert Bright depicted significant cardiac structural changes in patients with advanced kidney disease . Since tcongestive nephropathy. This phenomenon develops when severe volume overload significantly increases the venous system pressure, which is transmitted to the efferent arteriole, reducing the differential glomerular pressures required to generate a sufficient net glomerular ultrafiltration pressure, resulting in oliguria, increased cardiac afterload, and congestion , increasing glomerular hydrostatic pressure, sodium tubular avidity, and water retention while inducing cardiac remodeling and worsening systemic hypertension. These mechanisms are required for survival in the short term; however, they lead to structural heart damage, chronic kidney disease, and volume overload when perpetuated. The latter is of current interest as it has been settled as the primary pathophysiological mechanism of that new entity described as ngestion .renal tamponade, to describe severe cases of congestive nephropathy where the rigid renal capsule, kidney surrounding fat tissue, and the peritoneal cavity exert cumulative pressure on the retroperitoneal space, limiting the space available for renal expansion. Animal models of HF showed that renal decapsulation effectively reduced kidney pressure-related injury. This might be a new vision with potential forthcoming therapeutic implications in HF by alleviating intrarenal congestion.Moreover, The National Heart, Lung, and Blood Institute Working Group has defined the cardiorenal vascular interplay as Cardiorenal syndrome (CRS) and proposed a classification based on the volume retention by the kidneys ; howeverThe classification of CRS is rather complex, mainly because, in many cases, it is almost impossible to identify where the process started . MoreoveCongestion in HF is defined as the combination of signs and symptoms of extracellular fluid accumulation that result in increased cardiac filling pressure . CongestRefractory congestion is defined as the persistence of symptoms that limit daily life  despite optimal treatment, including chronic diuretics ; and desSeveral mechanisms have been classically described as causes of an impaired diuretic response. Among these, we have: 1) a reduced delivery of diuretic to the kidney’s proximal tubule due to reduced cardiac output, which constitutes the cause of the increasingly high diuretic doses required in HF; 2) compensatory sodium reabsorption either after the diuretic effect wears off or at other nephron segments, something that has been described in healthy adults but seems not to occur in patients with AHF ; and 3) In any case, once congestion begins, volume overload will progressively worsen HF signs and symptoms by adding more workload to the heart and increasing renal vein pressures, thus initiating a vicious cycle where diuretic resistance leads to prolonged lengths of stay and increased mortality . TherefoCongestion must be evaluated clinically in patients at risk. Although clinical history and physical exam are the first steps in congestion assessment, other tools can help us identify subclinical congestion, quantify its severity, and provide treatment monitoring and follow-up measures .On anamnesis, we need to identify dyspnea, orthopnea, bendopnea, and paroxysmal nocturnal dyspnea. Also, inquiring about the abdominal or ankle perimeters is critical . Less frPhysical signs of congestion are based on detecting increased filling pressures or extravascular fluid overload. The more specific signs are elevated jugular venous pressure, hepatojugular reflux, third heart sound, and laterally displaced apical impulse . One of However, clinical signs of congestion do not have a high sensitivity and are usually evident in advanced states. In some series of patients with chronic HF, physical signs of congestion were absent in up to 42% of patients with the Pulmonary Capillary Wedge Pressure (PCWP) > 22 mmHg .A clinically helpful biomarker should possess the following characteristics: it should be quickly determined, affordable, and provide additional information not attainable from the clinical interrogatory or physical examination alone. There is no current definitive biomarker that fulfills all these requisites; however, in this section, we will discuss the ones available or under development.intravascular congestion, while not necessarily tissular congestion   . The posrackles) . One of rackles) . They co00 ng/ml . To date00 ng/ml . Given atissular congestion markers, such as pleural effusion, ascites, elevated jugular venous pressure, hepatomegaly, and leg edema (Antigen carbohydrate 125 (CA125), a glycoprotein synthesized by celomic epithelium in pleura, pericardium, or peritoneum, is well-known as a biomarker for some malignancies, such as ovarian cancer. Recently, it has been identified as a reliable biomarker for congestion . Among teg edema . The cuteg edema . Currenteg edema .It is essential to highlight the role of plasma creatinine in clinical practice, as an increase of this parameter could reflect parenchymal damage in the kidney or hemodynamic changes . Thus, if decongestion is being achieved and there is clinical improvement, modest rises in serum creatinine are expected and should not result in treatment suspension or dose reduction, as this phenomenon is not associated with renal damage . On the Hemoconcentration has been seen after diuretic treatment, but studies revealed a weak association, making it a poor marker for decongestive therapy . SolubleChest X-ray has been an essential tool in the diagnosis of congestion. It can show signs of vascular redistribution towards the upper lobes, upper pulmonary veins’ distention, hilar structures’ enlargement, or septal lines in the lower lung (Kerley A and B lines). Moreover, pleural fluid accumulation in right HF leads to the thickening of interlobar fissures or pleural effusion. Another radiologic finding frequently detected in congestion is cardiomegaly. If congestion increases up to alveolar edema, chest X-rays show bilateral opacities with central distribution and no air bronchogram. These radiologic signs can precede clinical symptoms’ onset and may be visible for days after successful decongestion .Although the findings mentioned above in chest X-rays are common, up to 20% of patients with clinical congestion have a normal chest X-ray . Lung ulEchocardiography, used as a bedside tool, can estimate right- and left-sided filling pressures. Assessment of inferior vena cava (IVC) and its collapsibility and width estimates right atrial pressure (RAP) and left ventricular filling pressures . Thus, aWhen the IVC is enlarged, one should assess the hepatic veins. These veins are thin-walled and communicate with the IVC. Although the right and middle veins are the most readily observed, any of the three hepatic veins  can be measured. When applying the pulsed Doppler on the hepatic vein of healthy subjects, the tracing observed should show a small retrograde A wave and two antegrade waves: first, the larger wave called S wave corresponding to systole and then a smaller one called D wave corresponding to diastole panel A,  Beaubie. In voluUnlike the hepatic veins, the walls of the portal vein are thick. When applying pulsed Doppler over the portal vein of healthy subjects, a continuous flow should be observed panel A, . In a stCardiac Doppler imaging and tissue Doppler can assess left-sided filling pressures . When fi2, tricuspid regurgitation velocity >2.8 m/s and e’ septal velocity <7 cm/s or e’ lateral velocity <10 cm/s. Patients with at least two previous conditions are likely to have diastolic dysfunction with chronic exposition to high left-side filling pressures.Recommendations for the evaluation of left ventricular diastolic function by echocardiography were updated in 2016 by the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) . DespiteUltrasound evaluation of renal blood flow in HF has become another valuable tool for congestion diagnosis and management . The objTwo indexes have been developed to quantify venous renal flow modifications secondary to elevated central venous pressures. The first, the venous impedance index (VII), quantifies the velocity changes in renal venous flow during the cardiac cycle . The second one, the venous discontinuity index (VDI), quantifies the time without blood flow in interlobar veins (high when a single flow phase in diastole is observed) .via IVC diameter). Moreover, impaired renal venous flow was correlated with less diuretic efficiency, and patients with a lower VII had a better diuretic response  ultrasound has been related to the classical jugular vein distention (JVD) sign and is a volume or pressure overload marker. Clinical evaluation might be subjective and challenging in some patients, but ultrasonography allows for identifying and quantifying this phenomenon. It should be performed with the head and neck elevated 45° and carefully to avoid IJV compression. If it is difficult to visualize, asking the patient to cough or perform a Valsalva will allow to identify it. The JVD ratio is the difference between IVJ at rest and during Valsalva. When congestion worsens, IJV diameter at rest increases. Thus, a JVD ratio <4 is abnormal, and if congestion is severe, it can decrease to <2 . A low JBioelectrical impedance analysis (BIA) measures the impedance of the body to an alternating electric current of known characteristics, this being the result of two variables: Resistance (R) and Reactance (Xc). The BIA measures the resistance of the whole body resembling a homogeneous cylinder. Though there are several commercially available devices with different characteristics (bioimpedance spectroscopy (BIS), single-frequency BIA, multifrequency-BIA (MF-BIA), bioelectrical impedance vector analysis (BIVA)), to determine the amount of intra- and extracellular water indirectly and thus estimate the degree of overhydration of congestive patients. Its results are not reliable if the patient has metal objects such as prostheses or major amputations , and it is contraindicated if the patient has a pacemaker or self-implantable defibrillator in the case of MF-BIA, BIVA, BIS or segmental BIA . MoreoveRight heart catheterization (RHC) has long been considered the gold standard to diagnose the presence of increased intracavitary filling pressures, including RAP and PCWP and for the measurement of pulmonary vascular resistances . These mRHC use in AHF decreased considerably after the publication of the ESCAPE trial, which did not show a benefit of RHC-guided therapy for patients admitted for decompensated heart failure compared with usual care; this trial, however, did not include patients in cardiogenic shock . InteresNevertheless, wireless pulmonary artery hemodynamic monitoring has shown promising results in HF patients with previous HF hospitalizations to detect subclinical congestion, leading to anticipated decongestive therapies that significantly decrease HF hospitalizations, regardless of left ventricular ejection fraction . The useThe key to managing cardiorenal syndrome should always be to solve the root issue: heart failure or kidney disease. However, most times, the root problem does not have a solution, or if it has one, it is not instantaneous. In such cases, physicians must manage congestion, which derives from either organ’s dysfunction. Herein, we discuss pharmacological and extracorporeal therapies that have alleviated congestion, reduced readmissions, and sometimes mortality. A multimodality diagnostic and treatment algorithm is proposed in Most patients who present with an acute cardiorenal syndrome are volume overloaded. The only way to remove the excess fluid pharmacologically is by blocking sodium and water reabsorption at the kidney tubules with diuretics . When thIn a healthy individual, kidneys filter 180 L of plasma a day. Most water reabsorption occurs thanks to the sodium-potassium-chloride cotransporters (NKCC) in the loop of Henle, which reabsorb sodium in high quantities, increasing the solute concentration at the kidney’s medulla . This osFurosemide is the most used and cheap loop diuretic; unfortunately, its oral bioavailability is highly variable, ranging from 10 to 100%. More modern loop diuretics like bumetanide and torsemide have a higher and more consistent oral bioavailability between 80 and 100%. However, torsemide is of particular interest as it has a longer half-life than furosemide and bumetanide (3.5 vs. 1.5 h), and its effect can last up to 16 h. Moreover, torsemide has proven to significantly reduce HF symptoms by improving the NYHA functional class, increasing cardiovascular survival, and non-significantly reducing heart failure-related hospital admissions . MoreoveFurthermore, furosemide’s bioavailability can be affected by many factors, such as other medications, delayed gastric emptying, reduced systemic perfusion, or gut edema. Acute congestion can produce the last two. Hence, the most efficient way to deliver enough loop diuretics in circulation in acute congestion is intravenously. There is no clear data on which is the proper initial furosemide dose in cases of AHF . RecentlSimilarly, a post-hoc analysis of the ROSE-AHF trial associated urinary sodium at the first void <60 mmol with longer hospital stays and lower weight loss. Nevertheless, the clinical application of this “suboptimal urinary sodium excretion” needs to be better defined, as some measure it in the first 6 h, others in the first hour, and others in the first void. Likewise, the urinary sodium threshold is not well defined either, though it is usually 50—60 mmol . HoweverThe suggested initial furosemide dose in the ESC position paper on diuretic use in HF  recommenIn patients who do respond to intravenous loop diuretics, there are conflicting data on whether it is better to administer the drug in a continuous infusion or bolus . The DOSFurosemide has been reformulated for subcutaneous administration to allow an “intravenous-like” diuretics delivery in out-hospital patients.Nevertheless scarce, there is evidence that subcutaneously administered furosemide for AHF treatment . This roper se. However, in combination with a loop diuretic, they can significantly increase natriuresis and improve congestion by acting as a sequential diuretic (Thiazide diuretics act on the sodium-chloride cotransporter (NCC) located in the distal convoluted tubule. The most used thiazide diuretics are hydrochlorothiazide, metolazone, and chlortalidone. There is also available an intravenous thiazide, chlorothiazide. These agents are primarily utilized in the clinical setting as an antihypertensive medication rather than diuretics diuretic . It shoudiuretic .2, there is compelling evidence of their effectiveness in advanced CKD. For instance, chlortalidone has been proven to increase diuresis and improve blood pressure control in advanced CKD while significantly reducing albuminuria, rendering a nephroprotective effect  act by inhibiting the action of aldosterone in the principal cells of the connecting and collecting tubule, reducing the number of epithelial sodium channels (ENaC). They have a weak diuretic effect, though their efficacy is significantly augmented in cases of hyperaldosteronism related to HF or cirrhosis. Three main agents belong to this class, spironolactone, eplerenone, and, in the immediate future, finerenone.They have a more delayed onset of action than the rest of the mentioned diuretics, requiring 2 or 3 days until any effect can be seen. Blocking sodium reabsorption creates a lumen-positive electrical gradient that impedes potassium and hydrogen secretion, thus potentially leading to hyperkalemia and acidosis. Therefore, they should be used cautiously in patients with CKD stage 3b or greater. However, they are quite useful in the setting of HF as part of the sequential tubular blockade, given that this side effect balances the risk of hypokalemia and metabolic alkalosis produced by the concomitant use of loop and thiazide diuretics.Moreover, this drug class is of particular interest given that they serve as diuretics and are also cardioprotective. The RALES  and EMPHAmiloride and Triamterene act similarly to MRA though instead of indirectly blocking ENaC channel expression by blocking aldosterone, they directly inhibit ENaC function. Amiloride is currently recommended over triamterene as it is better tolerated, and it can be administered once a day instead of twice daily. It does not have triamterene’s side effect of crystalluria, leading to cast formation and triamterene stones . Given tAcetazolamide, a carbonic anhydrase inhibitor, works in the proximal convoluted tubule by blocking the sodium–hydrogen exchanger 3 (NHE3), inhibiting bicarbonate and sodium reabsorption, causing metabolic acidosis. Its diuretic effect may be minimal due to the multiple distal compensation mechanisms; however, like in the case of MRA, this side effect is desirable to balance the metabolic alkalosis produced by the urinary chloride losses caused by both loop and thiazide diuretics . In factmacula densa, similar to the effect seen with SGLT2 inhibitors, which could be nephroprotective. Moreover, it can also improve apnea-hypopnea symptoms associated with central sleep apnea, a common disorder found in HF patients  will evaluate if the addition of intravenous acetazolamide 500 mg once daily to loop diuretics adds clinical benefit in acutely decompensated HF patients.SGLT2i also act at the proximal convoluted tubule by blocking the sodium-glucose cotransporter 2. This way, they reduce glucose reabsorption by 30%–50%  and incrIn addition to these beneficial cardiac effects, they have also proven to slow CKD progression in both diabetic  and non-Vaptans act by inhibiting vasopressin receptor type 2 at the collecting duct, the nephron’s last site of water reabsorption , making Like all other diuretics except for MRA, loop diuretics circulate in the blood bound to albumin and are, therefore, not filtered by the kidney. They can then act on the NKCC channel placed in the loop’s lumen only after being secreted by a transporter in the proximal tubule in competition with other molecules such as urea. This means that in cases of acute tubular necrosis or reduced nephron mass, there are fewer transporters available to secrete these diuretics into the lumen, which is why in cases of AKI or CKD, higher diuretic doses are required to allow for enough drug to make its way to the channel we want to block.The reduced systemic perfusion and renal blood flow in AHF mislead the kidneys into wanting to reabsorb as much volume as possible, increasing the number of transporters in the proximal and distal tubule. When the loop NKCC transporter is blocked, the concentration of sodium and chloride that reaches the distal tubule in the presence of an increased number of transporters enhances the amount of water reabsorbed at this level . This isFor many years, compensatory post-diuretic sodium reabsorption (CPSR) was thought to be the main reason for intravenous loop diuretic resistance. CPSR was described in healthy individuals as a decrease in renal sodium secretion after the loop diuretic level drops to concentrations lower than its threshold . This phThe renal tubule consists of four main segments, the proximal convoluted tubule, the loop of Henle, the distal tubule, and the collecting duct. The main concept of this approach is that when the loop diuretic effect is insufficient to achieve decongestion, we must block the rest of the tubular transporters.There is evidence that a multi-diuretic drug sequential blockade regimen benefits roughly 60% of patients with diuretic resistance . Our proInotropic agents can be of use in cases of hypoperfusion due to low cardiac output syndromes that lead to low renal blood flow, sodium retention, and less diuretic delivery to the proximal tubule. In general terms, current guidelines restrict the use of inotropes for the treatment of HF patients who are hypotensive or hypoperfused since they have been otherwise associated with a worse long-term prognosis . InotropDobutamine, a beta-adrenergic inotrope, has a renal sympathetic activity that increases renal blood flow and the glomerular filtration rate but impairs oxygenation of the medulla, increasing the oxygen demand in the kidney tissue . MilrinoLevosimendan has been used to facilitate the weaning of continuous inotropes, augment diuresis in cardiorenal syndrome, and as cardiogenic shock therapy in selected patients . VariousIn the past, dopamine was thought to increase renal blood flow and urinary sodium excretion; nevertheless, the addition of low-dose dopamine (2 mcg/kg/min) to diuretic treatment in patients with AHF and renal dysfunction has not shown significant effects on urine volume or renal function, and it is no longer used for this purpose .Therefore, in the setting of a low cardiac output-induced cardiorenal syndrome, we propose that levosimendan may be the first inotrope treatment option .Albumin has been broadly prescribed for critically ill patients, although it has no known mortality benefit. It increases intravascular oncotic pressure and produces fluid mobilization from the interstitium to the intravascular space, which is thought to improve diuresis. The hypothesis that co-administration of furosemide and albumin can achieve a better diuresis response than diuretics alone has been debated. In theory, given that furosemide travels albumin-bound in the circulation, good renal perfusion and albumin are required for furosemide to arrive and be secreted at the tubular lumen of the proximal tubule. Hence hypoalbuminemia could decrease furosemide diuretic efficacy. Different trials showed inconsistencies in published results on this topic. A retrospective analysis  in intenThe combination of hypertonic saline infusion, ranging from 1.4% if serum sodium greater than 136 and 4.6% if lesser than 125, with high-dosed furosemide has been proposed to mitigate renal dysfunction and promote natriuresis . A meta-Despite the wide heterogeneity between different analyses, and the lack of an adequately powered, multi-center, randomized, blinded trial, we believe that hyponatremic and hypochloremic patients with diuretic resistance may benefit from the co-administration of hypertonic saline infusion and intravenous diuretics.Natriuretic peptides such as atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) are cardiac hormones. ANP exerts diuretic, natriuretic, and vasodilatory effects that help maintain water-salt balance and regulate blood pressures by reducing preglomerular vascular resistance stimulating diuresis and natriuresis . PleiotrPeritoneal dialysis (PD) is mainly known as a renal replacement therapy technique. However, it has also been used as a tool for volume removal for more than 50 years. It consists of the infusion of osmotically active solutions in the peritoneal cavity, where these solutions ultrafiltrate both free-water and sodium through the peritoneal membrane . The mosIn summary, despite the lack of clinical trials evaluating PD effect on mortality and other hard cardiovascular outcomes, we recommend it as a valuable option in autonomous patients with CKD and frequent readmissions due to AHF. This therapy allows them more independence, renal function preservation, and improved quality of life with fewer HF hospital readmissions .Given the side effects and limitations of diuretic treatments, there has been growing interest in a non-pharmacological management approach to congestion. There is conflicting evidence on whether ultrafiltration (UF) brings any benefit on top of a proper diuretic regimen. The CARESS-HF trial by However, there are reports showing that UF slightly reduces rehospitalizations within 30 days of an acute decompensated HF episode and helps achieve greater weight reduction if an individualized rather than a fixed UF rate is used. For instance, in the CUORE trial , the UF In summary, isolated UF is useful, particularly in patients who have trouble achieving sufficient decongestion with diuretic therapy, though one should not forget the implications of such a therapy. There could be bloodstream catheter-associated infections and potential bleeding complications derived from the anticoagulation required to perform this technique.The interplay between the heart and the kidney has been a matter of concern for a long time. Still, it has gained interest recently, leading to the constitution of cardiorenal units with a multidisciplinary approach. Recent advances have highlighted the need for the pre-clinical and multiparameter diagnosis of congestion, with the integrated use of biomarkers and bedside ultrasound. Multiple treatment strategies have been studied: diuretics in different doses or combinations have been the cornerstone of congestion treatment, but newer drugs and less conventional pharmacological and non-pharmacological approaches are becoming available to clinical practice. The lack of strong scientific evidence for many of these strategies contrasts with the clinical need to implement them for the increasingly diagnosed refractory congestion.There is an urgent need for collaborative research in the field of heart and kidney failure, especially in the setting of congestion. Better diagnostic techniques to identify a pre-clinical state may lead to anticipated and effective treatment. A multidisciplinary approach, led by cardiology and nephrology, will eventually answer the needs of this increasing patient population.


There is a growing population of patients who require chronic noninvasive ventilation. While these patients often have no parenchymal lung disease, the use of positive pressure ventilation itself predisposes to both initial and recurrent pneumothoraces. Furthermore, generally accepted pneumothorax management strategies, such as removing a chest tube after liberation from positive pressure ventilation, are not possible in this population. Despite this, there is a lack of clear guidance on management of pneumothorax in the chronically ventilated patient. In this case series, we discuss the management of pneumothoraces in patients requiring chronic noninvasive mechanical ventilation in our Assisted Ventilation Clinic (AVC). Our experience suggests a potential role of definitive treatment of the initial pneumothorax to prevent reoccurrence. AVCAssisted Ventilation ClinicPPVPositive Pressure Ventilation1Barotrauma, resulting in alveolar rupture and subsequent pneumothorax, is a potentially serious complication of positive pressure ventilation (PPV) in patients with neuromuscular respiratory failure. In patients with cervical spinal cord injury, the recommendation is to ventilate with higher tidal volumes if there is not a contraindication, which is a risk factor for barotrauma . When pn10.13039/501100005613AVC) at the 10.13039/100007270University of Michigan provides multidisciplinary care to patients with chronic neuromuscular respiratory failure utilizing chronic invasive and non-invasive ventilatory support. Here, we discuss six cases of initial pneumothorax that have occurred among patients of the UM AVC 2010–2019  of 5 cm H2O, in addition to cough assist. Chest tube was placed with resolution of his pneumothorax, and he has had no reoccurrence since.The second case is a 19-year-old male with Central Core Myopathy who presented with a left sided pneumothorax after being bagged for a mucous plug at his school. Prior to presentation, his ventilator settings Pressure Control/Average Volume Assured Pressure Support (PC/AVAPS) mode with a tidal volume of 450 mL and a positive end expiratory pressure of 8 cm H2O, in addition to cough assist. A chest tube was placed with some, but not complete pneumothorax resolution. Pleurodesis was not performed given concern for lack of pleural apposition. Two weeks later, the patient presented with a pneumothorax, for which a chest tube was placed. Video-assisted Thoracoscopic Surgery (VATS) left blebectomy and additional tube thoracostomy placement was performed. Pleurodesis was not performed due to increased bleeding/friability of lung tissue. Patient has been without pneumothorax recurrence since VATS procedure.The third case is a 25-year-old male with Duchenne Muscular Dystrophy who presented with a large upper-left pneumothorax and a 3.1 cm left apical bleb. Prior to presentation, his ventilator settings PC/AVAPS mode with a tidal volume of 400 mL and a positive end expiratory pressure of 8 cm H2O, in addition to cough assist. A chest tube was placed with resolution of pneumothorax. He stopped using his cough assist. He died 1 year later of multiorgan failure and shock in the setting of an infected pleural space.Our fourth case is a 30-year-old male with Duchenne Muscular Dystrophy who presented with a left lateral pneumothorax. Prior to presentation, his ventilator settings were assist control with a tidal volume of 950 mL and a positive end expiratory pressure of 5 cm H2O, in addition to cough assist. Chest tube was placed with resolution of pneumothorax, however, it reoccurred in the same admission, so another tube was placed with resolution. She improved and was discharged but died unexpectedly a week later.Our fifth case is a 46-year-old female with Facioscapulohumeral Muscular Dystrophy who presented with a left lateral pneumothorax during an admission for tracheostomy placement. Prior to presentation, her ventilator settings were assist control with a tidal volume of 275 mL and a positive end expiratory pressure of 5 cm H2O, in addition to cough assist. His 1 cm pneumothorax was at first managed conservatively with increased oxygen, however, it expanded, so a chest tube was placed and talc pleurodesis performed and he was discharged. Two days later, he was noted to have a pneumothorax, so was admitted, and had a chest tube followed by a VATS. He did develop a persistent hydropneumothorax which was managed with observation until his death 2 years later.Our sixth case is a 21-year-old male with Duchenne's Muscular Dystrophy who presented with a right sided pneumothorax. Prior to presentation, his ventilator settings were Intelligent Volume Assured Pressure Support (IVAPS) with a tidal volume of 615 mL and a positive end expiratory pressure of 7 cm H3Pneumothoraces have relatively high rate of recurrence, with estimates of recurrence ranging from 30 to 50% . PneumotThese cases demonstrate the importance of exploring more definitive treatment to prevent recurrence of pneumothorax for patients who require chronic ventilation. Parenchymal lung disease, such as emphysema, is considered a clear etiology of secondary pneumothorax. However, there seems to exist an ambiguity in defining pneumothorax in the setting of chronic ventilation as primary or secondary in nature, and this ambiguity may lead to sub-optimal management. Out of our 6 cases, 3 (50%) developed reoccurrence despite no primary known parenchymal lung diseases. Out of the three cases that did not develop reoccurrence, one died shortly after initial admission. A second died a year later in the setting of an infected pleural space.Previous case reports have emphasized the need for clinicians to have a higher suspicion for pneumothorax in patients using non invasive ventilation devices . In halfAnother prior case study pointed out a link between positive-pressure ventilation devices, namely those that utilize “air stacking” to facilitate pulmonary clearance, and incidence of pneumothorax. The report argues that patients with a known pulmonary pathology should avoid, or exercise caution, using cough assist and similar devices . All six4•These cases demonstrate the need for a stronger recommendation of definitive treatment to prevent recurrence of pneumothorax in chronically ventilated patients.•Appropriate management of pneumothorax could lead to decreased hospital admissions and associated morbidities. One suggestion would be to include chronic NIPPV as a criterion of diagnosing secondary spontaneous pneumothorax to encourage treatment that will help prevent recurrence.•Further study of pneumothorax incidence, recurrence, and overall morbidity in chronic NIPPV patients who receive only tube thoracostomy versus those receiving tube thoracostomy plus VATS, thoracotomy, or pleurodesis may be warranted.The authors have no conflicts of interest.Authors AJK, AH, BHS participated in collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.


Internal validation suggested a good predictive performance of the models. Males, those with a smoking habit, LVH, and high-normal clinic BP are indicators of MUCH and models including these factors provide good diagnostic accuracy in identifying this ambulatory BP phenotype.The aim of this study was to provide prediction models for masked uncontrolled hypertension (MUCH) detected by ambulatory blood pressure (BP) monitoring in an Italian population. We studied 738 treated hypertensive patients with normal clinic BPs classified as having controlled hypertension (CH) or MUCH if their daytime BP was < or ≥135/85 mmHg regardless of nighttime BP, respectively, or CH or MUCH if their 24-h BP was < or ≥130/80 mmHg regardless of daytime or nighttime BP, respectively. We detected 215 (29%) and 275 (37%) patients with MUCH using daytime and 24-h BP thresholds, respectively. Multivariate logistic regression analysis showed that males, those with a smoking habit, left ventricular hypertrophy (LVH), and a clinic systolic BP between 130–139 mmHg and/or clinic diastolic BP between 85–89 mmHg were associated with MUCH. The area under the receiver operating characteristic curve showed good accuracy at 0.78 (95% CI 0.75–0.81,  Masked uncontrolled hypertension (MUCH), that is, normal clinic but high out-of-office blood pressure (BP), in treated patients has been broadly studied in the past two decades ,25,26,27We studied 738 treated hypertensive patients with normal clinic BPs selected from 2264 sequential treated individuals aged 30 to 90 years who were prospectively recruited from December 1992 to December 2012. All patients had been referred to our hospital outpatient clinic for evaluation of BP control. One hundred and three patients were lost during follow-up. Subjects with secondary hypertension were excluded. All subjects underwent clinical evaluation, electrocardiogram, routine laboratory tests, echocardiographic examination, and non-invasive ambulatory BP monitoring. The study population came from the same geographical area . Clinic BP was recorded by a physician using a mercury sphygmomanometer and appropriate-sized cuffs. Measurements were performed in triplicate, 2 min apart after at least 5 min of rest, and the mean value was used as the BP for the visit. Clinic systolic BPs (SBP) and diastolic BPs (DBP) were defined as normal when <140/90 mmHg.Ambulatory BP monitoring was performed with a noninvasive recorder  on a typical day, within 1 week of the clinic visit. Technical aspects have been previously reported . We eval2.7 and LV hypertrophy was defined as LV mass/height2.7 > 50 g/m2.7 in men and >47 g/m2.7 in women [Left ventricular (LV) measurements and calculation of LV mass were made according to standardized methods . LV massin women . t test for continuous variables and Pearson’s Chi-square or Fisher’s exact test for categorical variables. Univariate and multivariate logistic regression analyses were used to estimate potential predictors of MUCH by odds ratio (OR) and corresponding 95% confidence interval (CI). Variables that were significantly associated with MUCH in univariate analysis were included in multivariate analysis. A prediction scoring system for MUCH was produced using the ORs of predictors. The largest among the ORs of predictors was set as the higher value and the other ORs were rescaled relative to the maximum point. The total score was calculated as the sum of the points assigned to all predictors. A receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic accuracy of the models, including the variables that were associated with MUCH in multivariate analysis and by the created scoring systems. The goodness of fit was evaluated using the Hosmer–Lemeshow test. Sensitivity and specificity were calculated at an optimal cut-off point derived from Youden’s J-index. We also performed internal validation of the models using k-fold cross validation. The original sample was randomly partitioned into 10 equal sized subsamples for ROC curve comparison of the predictive model. The mean ROC for each k-fold was then reported with 95% CI. Statistical significance was defined as p < 0.05. Analyses were made with the SPSS 21  and STATA 17 .Descriptive analysis was carried out using mean and standard deviation for the quantitative variables and percentage values for the qualitative variables. Normality distribution for quantitative variables was assessed using the Shapiro–Wilk Test. Comparison between CH and MUCH according to various definitions was performed using an unpaired Student’s We detected 215 (29%) patients with daytime MUCH regardless of nighttime BP (42 had daytime MUCH only and 173 had daytime and nighttime MUCH) and 275 (37%) patients with 24 h MUCH regardless of daytime or nighttime BP .Characteristics of patients with CH, daytime MUCH regardless of nighttime BP, and 24 h MUCH regardless of daytime or nighttime BP are shown in BP values and the therapeutic strategy of study groups are reported in Use of aspirin and statin was not different between patients with CH and MUCH for each definition . In univariate logistic regression analysis, male sex, smoking, LV hypertrophy, clinic systolic BP in the range of 130–139 mmHg, and clinic diastolic BP in the range of 85–89 mmHg were significantly associated with MUCH defined by both thresholds .p = 0.43; MUCH defined according to 24 h BP, Chi-square = 6.0, p = 0.65).All variables that were significant in the univariate analysis, except smoking habit for MUCH defined according to 24 h BP threshold which approached significance, remained significantly associated with MUCH . The HosTen-fold cross validation showed that cross-validated mean AUC, standard deviation, and bootstrap bias corrected 95% CI were 0.77 ± 0.06 and 0.72–0.79, respectively, for the model predicting MUCH defined according to daytime BP threshold, and 0.77 ± 0.05 and 0.73–0.80, respectively, for the model predicting MUCH defined according to 24 h BP threshold .When we applied to our population the prediction model suggested by Kim et al. , the AUCThe present study shows that: 1) male sex, smoking habit, LV hypertrophy, a clinic systolic BP in the range of 130–139 mmHg, and/or a clinic diastolic BP in the range of 85–89 mmHg are associated with MUCH defined by both daytime and 24 h BP thresholds; (2) prediction models based on the abovementioned variables were appropriate in identifying the presence of MUCH; (3) internal validation indicated a good predictive performance of the models. Though characteristics of patients with MUCH have been described in previous studies  male sex,31,32,33Male sex, smoking habit, presence of LV hypertrophy, and high-normal clinic systolic and/or diastolic BPs are predictors of MUCH and models including these factors appear to provide good diagnostic accuracy in identifying this ambulatory BP phenotype and show a good predictive performance. The suggested prediction models may be a useful tool to select patients eligible for out-of-office BP evaluation.