Globally hypertension in adults is among the leading preventable cause of premature death, where a graded association from the childhood hypertension is well recognised. With the concurrent rise in obesity and pediatric hypertension (HTN) during the past decade in developed countries, a parallel trend is emerging in developing countries that has a potential for exponential rise in cardiovascular, cerebrovascular and renal tragedies. A cumulative incidence of pediatric HTN in China and India is 50–70 and 23% respectively, is quite disturbing. New guidelines for the detection, evaluation and management of hypertension in children and adolescents published in 2017, where a jump in prevalence of pediatric HTN is observed, rings a call to address this under-attended burning problem; for which a review in pediatric hypertension and its management is warranted. Blood pressure (BP), is the pressure of the blood exerted on the arterial walls, produced by the contraction of the left ventricle against the resistance offered by arteries and arterioles that is required for the optimal body functioning, however, persistent high blood pressure (hypertension) is a global health issue. Globally, hypertension (HTN) is found to be major risk factor accounting for 10.2 million deaths and 208 million disability adjusted life years .Meta-analysis of more than 61 prospective studies from 1 million adults, showed that the risk of cardiovascular disease increased beginning at systolic BP levels less than 115 mmHg and diastolic BP levels less than 75 mmHg [Globally the prevalence of hypertension is increasing and more than 1 billion people are hypertensive, and the increasing trends are witnessed more in low-income and middle-income countries , 7. In oAccording to the Fourth Report  the diagBP ≥95th percentile in the office or clinical setting but <95th percentile outside of the office or clinical setting is considered as WCH which is more significant in pediatric population. It is confirmed by using Ambulatory Blood Pressure Monitoring (ABPM) where mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) are <95th percentile, in addition to SBP and DBP load are < 25%; for age, sex, and height , 19.Again with aid of ABPM, it is the presence of hypertension despite normal office BP . Obese aAlso known as essential hypertension is defined as a blood pressure (BP) ≥95th percentile without an identifiable cause. Children with primary HTN are usually ≥6 years, overweight/obese, have positive family history and usually have systolic HTN .It is the HTN with an identifiable cause, mostly seen in younger preschool children, where renal and urological disorders are the common causes and these children have usually diastolic HTN . Common Accurate BP recording is must to address the problem at hand and parental concerns. It has been observed that anxiety and recent caffeine intake are causes of isolated BP elevation, reiterating the report from a study where only 56% of sample population had same stage HTN on 3 different occasions . BP shouNormative values for blood pressure are based on auscultatory sphygmomanometry, which continues to be the preferred method for blood pressure estimation. After resting for 5-min, in relaxed environment, seated with back supported, feet on the floor, with no history of stimulant intake; a stethoscope is placed on brachial artery, proximal and medial to the antecubital fossa, below the bottom edge of the cuff, BP measurement is recorded. Age related proper sized cuff should be used for precise BP measurements in children. An estimated 80–100% length and 45–55% width of bladder to that of patients midarm circumference, while upper arm is held in neutral position with elbow flexed to 90° , 26 has Traditionally, blood pressure is assessed using the auscultatory technique (Korotkoff sounds) with the pressure in the cuff measured by mercury sphygmomanometer, which is recognised as, the ‘gold standard’. However, due to adverse environmental concerns like the maintenance and disposal problems, mercury as a component in BP measuring devices, has led to the imposition of bans in some European countries and its restricted use in health care, for which appropriate health and safety procedures should be followed including the availability of mercury spillage kits. Disposal of mercury should be performed in compliance with the appropriate environmental regulations in place.Oscillometric devices are increasingly being used as they are user friendly, automatic with no digit preference. Although these devices measure the oscillations transmitted from disrupted arterial flow by using the cuff as a transducer to determine mean arterial pressure (MAP), and interpret the relation to proprietary algorithm for the MAP calculation . These d1.Normal BP: <90th percentile in office BP with <95th percentile mean ABPM and < 25% ambulatory BP loadWCH: Office BP with ≥95th percentile with <95th percentile mean ABPM and < 25% ambulatory BP loadMH: < 95th percentile in office with ≥95th percentile mean ABPM and ≥ 25% ambulatory BP loadPrehypertension: Office BP ≥90th percentile, with <95th percentile mean ABPM and ≥ 25% ambulatory BP loadAmbulatory HTN: Office BP ≥95th percentile, with ≥95th percentile mean ABPM and 25–50% ambulatory BP loadSevere Ambulatory HTN: Office BP ≥95th percentile, with ≥95th percentile mean ABPM and ≥ 50% ambulatory BP loadABPM devices measure BP outside the office setting and provides multiple readings over a period. It provides the mean, daytime, night-time ambulatory BP and detects the hidden variations of HTN. Based on existing data, ABPM is more accurate for the diagnosis of HTN than office/clinic-measured BP and is more predictive of future BP . ABPM deAs with other clinical entities, a thoughtful history and thorough clinical examination must be the first step for the evaluation of pediatric HTN. A detailed history starting from the conception, gestational events, foetal growth patterns, birth weight, maternal hypertension,  perinataTo confirm various clues obtained from the history, physical examination starts with the assessment of general appearance like syndromic facies like , along with weight, height, BMI, waist hip ratio, head circumference, and general growth. This is followed by vital sign measurements like pulse rate, radio femoral delay, difference in blood pressure in upper and lower limbs. Presence of pallor, proptosis, adenoids, thyromegaly, hirsutism, acne, café-au-lait spots, butterfly rash, lymphadenopathy, localised chest bulge, dyspnoea, murmur, apical heave, abdominal mass, palpable kidneys, ambiguous genitalia, hematuria, joint swellings, and muscle weakness must be looked for.Screening of blood pressure should be carried if there is history of oligohydramnios, foetal USG documented renal/urological anomaly, prematurity, low birth weight, umbilical artery/vein catheterization, congenital heart disease, neurofibromatosis, tuberous sclerosis, ambiguous genitalia, recurrent urinary tract infections, features suggestive of renal disease, malignancy, organ transplant. Further action is warranted if the BP of the child or adolescent is above the values as depicted in Table However, applying this data which is extracted from the 4th report wherein overweight and obese children are excluded, will continue to serve as basic source, till quality indigenous data becomes available with us. While using the new Clinical Practice Guidelines 2017, the prevalence of confirmed hypertension among shorter children < 13 years old and taller 13+ years old children are more likely to be diagnosed with hypertension . ConcentIn general, basic work up like estimation of haemoglobin, renal functions, serum electrolytes, serum lipids, blood glucose, urinalysis routine and/or culture, spot protein to creatinine ratio and chest X-ray might be considered. In patients with BMI >95th percentile, HbA1c, ALT, AST, TSH, drug screen, and sleep study in SDB will be helpful . In addiGoals for the pediatric hypertension must include prevention of target organ damage and occurrence of adult hypertension along with optimal BP maintenance among hypertensive children and adolescents. It has consistently been proven that Dietary Approach to Stop Hypertension (DASH) diet , and gooThe goal of the treating physician is to optimise the BP while the child is on pharmacotherapy and/or DASH approach. A 4–6 weekly follow up is recommended for the dose adjustments and drug modification in patients on pharmacotherapy. Once the BP is stabilized the frequency of visits can be extended to every 3 to 4 months. However, in DASH approach a 3–6 monthly follow up is required. It has been suggested that home BP measurement and repeat ABPM  is also Rising prevalence of pediatric HTN carrying global health dimensions, needs early identification and appropriate management, a goal-oriented step wise progress with heightened awareness of this entity shall be envisioned, where primary prevention could stand tall before all measures.


Childhood hypertension is a predictor of later diseases, increases the risk for cardiovascular morbidity and mortality in adulthood and results in major economic burdens.The purpose of this study was to investigate the direct and indirect effect of anthropometric, socioeconomic and lifestyle factors on blood pressure (BP) in a large population-based sample of children and adolescents using a path analysis.This multi-centric nationwide study was performed on students aged 7–18 years. Anthropometric indices and blood pressure were measured by standard methods and demographic data, socioeconomic status, dietary habits and health related behaviors were obtained using validated questionnaires. Path analysis was applied to evaluate the relationships among the study variables and to implement the subsequent structural modeling.Totally, 7235 students  were assessed. Systolic and diastolic BP positively correlated with age , BMI  and WC . According to path analysis, age had significant direct effect on BMI, WC, and BP , which was greater for BP. BMI and WC had the greatest direct effect on BP . Education level, subjective health complaints, health-related behaviors and dietary habits had positive direct effects on BP . Socioeconomic status and positive changes in diet had negative indirect effect on BP (β = − 0.001 for both).Our findings strengthen the importance of weight and body composition in BP control. It is suggested to improve diet and health related behaviors especially in families with low socioeconomic position. High blood pressure that originates early in life is a predictor of later diseases, increases the risk for cardiovascular morbidity and mortality in adulthood and results in major economic burdens , 2. The , using path analysis method. The results of this study would be helpful for primary prevention of hypertension and consequent complications later in adulthood.Although numerous reports have documented higher blood pressure parallel to the rise in childhood obesity , it requThis survey was performed in urban and rural regions of Iran in 2015 as the fifth national study of a school-based surveillance program entitled the Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable disease (CASPIAN-V) study. The study was conducted on students in primary and secondary schools aged 7–18 years. Selection of 14,286 students was done by multistage, stratified cluster sampling method from 30 provinces of the country (48 clusters of 10 students in each province). Descriptions of sampling and operation details of the study has been published previously . The ResTwo sets of the questionnaires were completed for students and their parents. The validate and reliable questionnaires were obtained from Global School Student Health Survey (GSHS) and translated to Persian . The valThe student’s questionnaire, filled out by trained staff, had questions regarding the body image, and psychosocial environment of school, dietary habits, life-style habits and violence behavior. A team of health care professionals monitored all process.The parent’s questionnaire, completed by trained interviewers, included questions about family composition, economic and socio-demographic factors and genetic determinants , past history of student , family dietary habits were included in the parent’s questionnaire.2). We used the WHO growth charts to categorize BMI [Examinations were performed under standard protocols using calibrated instruments. The project team measured height, weight, and waist circumference using standard protocols which were described previously in details . Body marize BMI . Blood prize BMI .The method and items used for calculating family socioeconomic status (SES) were approved previously in the International Reading Literacy Study (PIRLS) . Using pFor the health-related behaviors (HRB) factor, a validated questionnaire was used for estimating physical activity (hours/day). It was classified as the mild, moderate, vigorous, and extremely vigorous activities. The screen time (ST) behaviors were defined as the sum of the number of hours per day that participants spent watching television (TV), working with personal computer, or playing electronic games .Subjective health complaints (SHC) were assessed by asking children to report the frequency of their experiences of a variety of emotional  and physical symptoms  during the past 6 months. Response options were ‘about every day’, ‘more than once a week’, ‘about every week’, ‘about every month’ and ‘rarely or never’. Then responses were categorized at weekly or more versus rarely or never. Items within the scale have shown an adequate content validity and test–retest reliability .Dietary habits (DH) were assessed by asking children to report the eating pattern of items included dairy products, animal protein, plant protein, fast foods, salt, fatty snacks, vitamins/mineral supplement, sweets/candies, vegetables, fruits and carbohydrates . HistoryAll continuous variables were checked for normality. Continuous variables were expressed as means (SD) or median (IQR) according to normal and non-normal distributions, respectively. Categorical variables were presented as number (percentage). Spearman correlation was used for evaluating the correlation between different demographic, anthropometric and physiological variables. Path analysis was applied to evaluate the direct, indirect and total effect of the study variables and to implement the subsequent structural modeling. The method of fitting of path modeling was least square (OLS). The preferred value of the fitness indices of models in path analysis including normed fit index, comparative fit index, goodness of fit index, and adjusted goodness of fit index is above 0.9. Regarding the root mean square error of approximation criteria, score ≤ 0.05 indicates a good fit, and score up to 0.08 means acceptable . SoftwarP > 0.05). The mean of BMI, SBP and DBP was 26.5 ± 5.1, 99.1 ± 13.1 and 63.8 ± 10.4, respectively. The details of socioeconomic status, subjective health complaints, health-related behaviors and demographic characteristics of the participants are presented in Table In this national population-based study, among of 14,286 participants whose information was collected, 7235 were assessed . Difference between mean age of boys (12.4 ± 3.1) and girls (12.2 ± 3.2) was not statistically significant (P < 0.05).The mean SBP and DBP against age groups are shown in Fig. P < 0.05) and had no effect on BP. Dietary habits had slight positive direct effect on both BMI and BP which was greater for BP. Positive changes in diet had positive direct effect only on BMI. Education level, health-related behaviors and dietary habits in our path models had positive indirect effect on BMI, however, their direct effects on this variable did not reach the significant threshold. Education level, SHC, HRB and DH had positive direct effects on BP . SES and PCD had small negative indirect effect on BP (β = − 0.001 for both).According to the correlation matrix of the variables, path diagram is modeled as Fig. There are a variety of fit indices to evaluate the model. All of them indicated that the model was acceptable fitted. The results of model fitness with accepted range for evaluating the validity of the model are characterized in Table Our study clarified the obvious relations among anthropometric, socioeconomic and lifestyle factors with blood pressure in children and adolescents. To determine the true independent effects of anthropometric, socioeconomic and lifestyle factors on childhood blood pressure, we performed a path analysis that provides the full range of relations between variables. The path analysis revealed that among all variables (demographic and anthropometric) age had the greatest direct effect on BP, however, in the case of anthropometric variables, BMI and WC had the greatest direct effect. Moreover, by indirect-effects analysis, BP had negative correlations with SES and PCD while they had not direct effects on BP. The direct effects of weight and WC on BP were also reported in previous studies , 21. HigIn current study, we also showed that the higher socioeconomic status and positive changes in diet can indirectly lead to beneficial effect on BP. The effect of SES indicators such as education attainment, household income or employment status on health is well established. A large body of research revealed that higher socioeconomic position individuals are healthier overall. Low education and low income are well-known causes of poor health and chronic medical diseases such as obesity, depression, and asthma –32. The The beneficial effect of healthier diet on BP, which was shown in this study, was also demonstrated in previous evidence. Dietary habit is considered one of the major modifiable determinants of hypertension and related chronic diseases in children and adolescents. Scientific evidences reveal the fact that a healthy diet pattern consisting of a daily intake of fruits and vegetables combined with a low consumption of salt, sugar, and saturated fat, in addition to industrially-produced-trans-fatty acids, is associated with a better cardio-metabolic profile both in adults and in children , 35. HigUsing path analysis for evaluating of the direct and indirect effect of anthropometric, socioeconomic and lifestyle factors on blood pressure in a large sample of Iranian children and adolescents is the strength of present study. While the cross-sectional design of our study represents a limitation for the emerged associations that cannot be considered causal. Moreover, the information on socioeconomic status and health-related behaviors was obtained by self-reporting which may affect the estimates by under- or over-reporting.Results of this study strengthen the importance of weight and waist circumference in blood pressure control. Our data also supports the need to improve dietary habits and health related behaviors especially in families with low socioeconomic position.


In our aim to improve patient outcome we are transitioning from a “one-size-fits-all” protocolized approach toward an individualized hemodynamic management, that is tailored to the cardiovascular (patho-)physiology and the specific clinical characteristics of each individual patient. In this narrative review an overview is provided about an individualized approach toward various neonatal hemodynamic conditions. Newborns admitted to the neonatal intensive care unit have an increased risk of hemodynamic failure for several reasons. The immaturity of the cardiovascular system in preterm infants, combined with impaired compensatory mechanisms, makes them prone to injury related to hypoperfusion and hypoxemia. Many conditions may affect the heart and vasculature, for example perinatal hypoxia-ischemia, sepsis, necrotizing enterocolitis, air leakage syndromes, and congenital anomalies, such as structural heart defects and congenital diaphragmatic hernia. Moreover, well-intended therapeutic interventions could potentially have adverse hemodynamic effects, for instance invasive ventilation with high mean airway pressure impeding venous return, iatrogenic tachycardia secondary to chronotropic properties of cardiovascular drugs limiting the filling phase (preload) of the heart, and drug-induced systemic vasodilation in case of sedation, analgesia, and muscle relaxation. It is therefor imperative that cardiovascular disturbances are detected as soon as possible or preferably prevented. The fact is, however, that this is easier said than done. It has been shown that severe systemic hypoperfusion can remain clinically undetected, irrespective of the level of experience of the health care professional , 2. ThisNowadays, we are transitioning from an empirical approach via stratified medicine toward an individualized hemodynamic management . Not allSeveral aspects of personalized hemodynamic management will be discussed for patients with highly prevalent hemodynamic conditions, namely persistent patent ductus arteriosus (PDA), shock/hypotension, and persistent pulmonary hypertension of the newborn (PPHN).. preterm infants, that should either be treated and actively closed or can be managed conservatively awaiting spontaneous closure.. Given t., 7. Seve.–10. Thes..p < 0.01) and less side-effects without causing a difference in ductal closure rate or obvious effects on mortality or incidence of chronic lung disease. In two similar studies, a subsequent dose of cyclooxygenase-inhibitor was only prescribed when ductal constriction was considered insufficient by evaluating the change in transductal diameter , less inotropic support , and a trend toward less oxygenation failure . Despite the prophylactic use of milrinone, it was observed that about 50% of patients still developed PLCS, reason why other echocardiographic parameters are studied as potential preemptive indicators of myocardial impairment. For example, a prolonged isovolumic relaxation time (IVRT) in the preoperative phase, indicating myocardial diastolic dysfunction, is associated with an increased risk of PLCS . PLCS is characterized by systemic hypotension secondary to myocardial impairment, oxygenation failure, and increased need of ventilatory support. Jain et al. observed that a left ventricular output <200 mL/kg/min in patients 1 h after ductal ligation was predictive of low cardiac output 8 h post-surgery (sensitivity (Se) 1.0; specificity (Sp) 0.89), systemic hypotension , and need for inotropes  . In a su of PLCS .As illustrated, hemodynamic management of preterm infants with a PDA can be adapted according the specific cardiovascular physiology and clinical context of the individual patient. In this way it is possible (1) to predict the hemodynamic significance of the PDA, that is associated with an increased risk of chronic lung disease and mortality, (2) to potentially reduce the number of doses of cyclooxygenase-inhibitors, and (3) to anticipate and prevent complications after surgical ligation of the ductus arteriosus.The terms shock and hypotension are obviously not interchangeable. Shock is defined as a condition characterized by an imbalance between oxygen demand and delivery on a cellular level. Oxygen delivery is mainly determined by hemoglobin concentration, arterial oxygen saturation, and cardiac output. When the amount of oxygen delivered to the peripheral tissues doesn't fulfill the demands, compensatory mechanisms will aim to redistribute blood to the vital organs in an attempt to prevent these from hypoxemic-ischemic injury. Three stages of shock are distinguished, namely (1) compensated shock, (2) uncompensated shock, and (3) irreversible shock. In the first stage, neuroendocrine compensatory mechanisms are responsible for preservation of blood (and oxygen) supply to the brain, the heart and the adrenal glands. This phase is called the compensated shock and is characterized by selective constriction of the vasculature perfusing the non-vital organs, such as kidneys, intestines, muscles, liver and skin. By the counteracting effects of constriction of non-vital organ vasculature and dilation of vessels supplying the vital organs, blood pressure can remain unaffected. There is no linear relation between cardiac output and blood pressure, as can be understood from Hagen-Poiseuille's Law. According this law, cardiac output is determined by the pressure gradient  divided by the systemic vascular resistance. This means that blood pressure can be in the normal (or even high) range during a state of low cardiac output provided that vascular resistance is increased. Systemic hypotension will occur when compensatory vasoregulatory mechanisms fail, known as the uncompensated phase of shock. Relying solely on the level of blood pressure, a “pressure-based” approach, might lead to misinterpretation of the hemodynamic status of newborns and the initial, compensated phase of shock might be missed. Neglecting the possibility of the presence of a compensated shock might have detrimental effects. There are indications that in fetuses and very preterm infants the blood vessels perfusing the cortex are not acting as high-priority vasculature and therefore not dilating in response to decreased blood flow, as would be expected for a vital organ as the brain –18. One Hence, it is imperative to detect low cardiac output already in the compensated stage of shock and not wait for intervention after systemic hypotension occurs, suggestive for the uncompensated stage of shock. This requires comprehensive hemodynamic monitoring with at least simultaneous measurement of arterial blood pressure and cardiac output. Under normal physiological circumstances both systemic blood flow and blood pressure are in the normal reference range. The combination of low cardiac output with a normal or high blood pressure suggest a compensated shock, whereas in a uncompensated shock both blood pressure and cardiac output are in the lower ranges . MeasureIncreased pulmonary blood pressure can be the consequence of either an increase in pulmonary blood flow , pulmonary wedge pressure , or pulmonary vascular resistance. Increased pulmonary vascular resistance is caused by maladaptation (reactive vasoconstriction on various stimuli), maldevelopment (remodeling of blood vessels), or underdevelopment (hypoplasia) of the pulmonary vasculature. The typical clinical presentation of a patient with PPHN is hypoxemic respiratory failure with sometimes signs of transductal right-to-left shunting  and systemic hypotension. PPHN is associated with both left and right ventricular failure –32. IncrIn a case report pulmonary vasodilation could successfully be evaluated in a patient with pulmonary hypertension with RV failure with the use of speckle tracking echocardiography . In a reBeing informed about myocardial performance is important in patients with PPHN, since hemodynamic management will be quite different in the presence of ventricular failure.The clinical scenarios discussed above illustrate the importance of a comprehensive hemodynamic assessment in order to timely diagnose cardiovascular failure, elucidate underlying pathophysiology, guide hemodynamic therapy, monitor the effects of the interventions, and adjust treatment as appropriate. This enables an individualized hemodynamic management that is optimized for the patient's specific pathophysiology and clinical situation. However, this personalized hemodynamic approach is more complex than a strict protocolized management and requiring more complicated algorithms. Moreover, accurate and precise monitoring of neonatal hemodynamics, using for example neonatologist performed echocardiography (NPE), non-invasive cardiac output assessment and near infrared spectroscopy (NIRS), is challenging . The impThis minireview is written by WB.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patients after solid organ kidney transplantation (KTX) often suffer from acute kidney injury (AKI). Parameters as serum creatinine indicate a loss of kidney function, although no distinction of the cause and prognosis can be made. Imaging tools measuring kidney function have not been widely in clinical use. In this observational study we evaluated 2-deoxy-2[18F] fluoro-D-glucose (FDG) PET/MRI in thirteen patients after KTX with AKI as a functional assessment of the graft. Twenty-four healthy volunteers served as control. General kidney performance (GKP), initial flow (IF) and renal response function (RF) were calculated by standardized uptake values (SUV) and time activity curves (TAC). The GKP measured for the total kidney and medulla was significantly higher in healthy patients compared to patients after KTX , but no difference was found for the GKP of the cortex (p = 0.59). The IF in KTX patients correlated with renal recovery, defined as change in serum creatinine 10 days after PET/MRI . With regard to the RF, a negative correlation for tubular damage was found . In conclusion, parameters obtained from FDG PET/MRI showed a possible predictive feature for renal recovery in KTX patients undergoing AKI. The most susceptible site to injury by oxygen and energy deprivation is the epithelia of the proximal tubule5. Tubular cell injury is inflicted by hours of cold ischemia time during transportation from donor to recipient site7. Among other potential factors for kidney dysfunction8 is the kidney donor profile index (KDPI)9 which most likely influences the organ-specific regenerative potential12. Furthermore acceptance of expanded criteria donor (ECD) and donation after circulatory death (DCD) with prolonged warm ischemia time have led to increasing incidence of DGF15. Potential nephrotoxic medication as calcineurin inhibitors required after kidney transplantation is an additional risk factor for acute kidney injury16.Within the first year after kidney transplantation (KTX) postoperative monitoring and care is crucial for patients’ outcome. Delayed graft function (DGF) and early rejection representing a subtype of acute kidney injury (AKI) are common and make up for 20–40% of cases19. Therefore renal recovery following transplantation or kidney injury due to acute events differs markedly and no reliable parameters are available in predicting the time span of allograft function regain21.Renal tubular cells are capable of replicating and can repopulate injured regions. This reflects the organ specific regenerative potential and is variable from individual to individual25. Markers such as KIM-1, IGFBP7, TIMP-2 and other have shown promising results in predicting delayed graft function prior to known laboratory tests26. However, too many factors and pathophysiological states represent the underlying causes of AKI that not one single biomarker in blood or urine could provide sufficient information for the clinician in directing the care procedures30.In case of kidney function deterioration, a core needle biopsy is inevitable to confirm the diagnosis and determine the further course. One essential focus is the establishment of diagnostic tools to identify the underlying cause of renal dysfunction and the determination of predictive markers for the restoration of renal function. Various biomarkers have been tested for their diagnostic value for partial or full organ recovery following AKI in transplant recipients32. Although most of the imaging methods are easily accessible only estimates can be provided in respect to graft structure and perfusion, but not on complex renal function35. Computed tomography (CT) on one side provides higher resolution but on the other side radio contrast should be better avoided in the early stages of transplantation36. Despite all this, core needle biopsy still remains the gold standard in detecting the reason of malfunction.Non- invasive radio imaging such as sonography is a further important surveillance tool in allograft assessment37. PET/MRI scans give information on both, accurate organ substructures and functional components38. Additionally, with dynamic scans the behavior of the tracer can be observed in the kidneys, undergoing several renal processes such as filtration, re-absorption and excretion39.In the past decade novel technology has provided additional imaging tools by combining positron emission tomography (PET) with CT or magnetic resonance imaging (MRI) using the glucose analogue radio tracer 2-deoxy-2[18F] fluoro-D-glucose (FDG)41. Using the MRI sequences to determine the localization of the renal cortex and medulla combined with the dynamic PET images, information on regional cellular functionality was obtained.In this observational study, we analyzed the functional behavior of the glucose analogue FDG by the use of novel PET/MRI technology in patients after kidney transplantation with AKI. Kidney functional parameters were compared with those from healthy volunteers, which were acquired in a previous studyIn parallel, we followed the function of the excretory kidney with parameters such as serum creatinine and additionally compared the PET/MRI results with renal biopsies taken close to the time of examination.The study was carried out at the Division of Nephrology and Dialysis in Collaboration with the Division of Nuclear Medicine at the Medical University of Vienna between 2016 and 2019. Thirteen kidney recipients admitted to hospital due to DGF or kidney function deterioration were enrolled in the study. Demographic data and routine parameters were extracted from the data base of the General Hospital of Vienna. Inclusion criteria were age above 18 years, kidney transplantation regardless the immunological risk constellation, suitable to undergo PET/MRI. Exclusion criteria were claustrophobia, existing metal prosthesis and implantation of any metal devices.All patients were monitored for their renal function by routine blood and urine testing and gave written and oral consent. The study was approved by the Local Ethics Committee of the Medical University of Vienna (protocol: 1043/2016). The study was conducted in accordance to the Declaration of Helsinki and relevant guidelines and regulations and no organs/ tissues were procured from prisoners.Tissues from fine needle biopsies were immediately fixed by Formalin and embedded in paraffin. Histological processing and diagnosis was performed at the Department of Pathology at the Medical University of Vienna according to the BANFF classification. Additional immunohistological staining was carried out for presence of C4d for evaluating antibody mediated rejection (ABMR).42.On a daily base, blood samples were drawn from all patients before and after PET/MRI examinations, from which serum creatinine was determined and eGFR was calculated according to CKD-EPI formulaA positive recovery was defined when serum creatinine decreased by >10% ten days after the PET/MRI examination, a negative recovery when serum creatinine increased by >10% ten days after the PET/MRI examination and an unchanged status was classified when the change was between ± 10%.Directly before scan start, around 3 MBq/kg body weight FDG  were injected. The PET/MRI  acquisition started immediately after tracer injection and continued for 24 minutes, PET data sets were reconstructed (Siemens e7 tools) into a dynamic sequence of 60 × 5 s, 19 ×60 s a 172 × 172 × 127 matrix using the ordinary Poisson ordered subsect expectation maximization (OP-OSEM) 3D algorithm . Scatter correction along with Dixon based MR-attenuation correction was performed. The MR imaging protocol consisted of a T1 weighted MRI sequence .The MRI images were used to delineate volumes-of-interest (VOIs): 1) aorta descendens , drawn by hand in several layers (2) left kidney, (3) right kidney, (4) left kidney cortex (5) right kidney cortex, (6) left kidney medulla and (7) right kidney medulla. VOIs (2–3) were carefully drawn by hand in each layer; all other VOIs were delineated randomly in about 30% of all layers by a threshold VOI selection tool. After image fusion, the FDG concentrations in the according VOIs were measured in units of standardized uptake values (SUV); the time activity curves (TACs), reflecting the tracer concentration over time, were exported for further analysis. In Fig.  aorta de40. Additionally, the renal response function (RF) was calculated in order to obtain the collected net tracer concentration over the first minute. The calculation was performed via a deconvolutional analysis as commonly applied on renogram curves from renal scintigraphies. The AIF and the total kidney TAC, from which a response function is obtained, reflect the net tracer concentration in the kidneys44.To evaluate renal processes, the initial flow (IF) was determined, which is a measure used to assess the renal blood flow. IF is acquired by dividing the maximum measured tracer concentration by the total collected tracer amount in the kidney within the first 60 seconds and can be used to assess the effective renal plasma flow47. Recently, it has been published that this parameter is also affected after sodium-glucose linked transporter-2 inhibitor therapy in patients with type 2 diabetes mellitus48.Furthermore, the total renal tracer uptake within the second and third minute of tracer injection was used to quantify the general kidney performance (GKP), see also Fig. Statistical analysis was performed with Gnumeric  and LibreOffice Calculator . Correlations were calculated with Pearson’s correlation coefficient r, from which a corresponding p value was derived. The significance of the differences between groups, as well as between healthy and transplant kidneys was assessed by the student’s t test with p < 0.05 considered as a statistically significant difference.A total of 13 renal transplant recipients were recruited and followed for a minimum of 6 weeks after the PET/MRI scan. Baseline characteristics, underlying renal disease and comorbidities are summarized in Table With regard to kidney transplantation, information on the sex and age of the graft, data on immunological risk and mismatch are listed in Table Ten patients had an eGFR <30 ml/min/1.73 m² at the day of the PET/MRI examination, 3 patients presented with an eGFR > 30 ml/min/1.73 m². Patients were treated for DGF, rejection and AKI, accordingly. Six patients showed a positive recovery, i.e. the serum creatinine decreased by > 10%  ten days after PET/MRI examination; 4 patients had a negative recovery, i.e. an increased serum creatinine by in average 55% (from 2.0 mg/dl to 3.4 mg/dl); 3 patients showed no or minimal changes between ± 10%  in serum creatinine.As depicted in Fig. −1) and higher in patients with negative recovery (1.7 min−1), but this difference was not statically significant (p = 0.051).The initial flow showed a strong correlation with the change in serum creatinine 10 days after the PET/MRI . The averaged IF was lower in patients with positive recovery and stable kidney function  indicates the net amount of FDG within the first minute. The average RF in healthy kidneys did not differ from the average RF in patients after kidney transplantation (p = 0.9). However, patients with severe tubular damage had lower RF (p = 0.0004) whereas patients with no or only mild tubular damage had a significantly higher RF (p < 0.0001).. Transplanted kidneys with a higher degree of tubular damage showed lower RF compared to no or only slight tubular damage according to renal histology (p = 0.006) .Upon closer examination, a negative correlation between RF and tubular damage was found within the transplant cohort  Fig. . Transpl06) Fig. .Figure 2With regard to the prognosis of renal recovery 10 days after PET/MRI, a lower RF was associated with a decrease in serum creatinine, but was not significant . Regarding GKP, IF and RF, no influence of the donor’s age, sex or time point of transplantation could be found.In this prospective observational study 13 patients after KTX with kidney injury underwent radio imaging based on a PET using 2-deoxy-2[18 F] fluoro-D-glucose combined with 3-Tesla MRI. Accordingly, a kinetic model based on the tracer distribution was assessed and high quality morphology on the kidney was used for anatomical allocation. This data was then compared to 24 healthy subjects undergoing the same PET/MRI imaging protocol.51.One major finding was a significantly higher GKP in healthy subjects compared to the transplant patients. Interestingly, the medulla and total kidney GKP were significantly higher, whilst the purely cortical GKP showed no difference between the cohorts. This finding indicates that FDG as a glucose analogue is less accumulated in the proximal tubule or even glomeruli, which is also supported by the fact that RF, a parameter which can be understood as measure of the blood entering the kidneys within the first minute, was also higher in patients with a positive recovery. Novel data has previously demonstrated that the Henle’s loop and the capillary system are involved in AKI and its potential recovery, which is supporting our present findingsWhen looked at the initial flow, a predictive value for serum creatinine development within 10 days after PET/MRI could be seen. Additionally, RF seems of high relevance when classifying tubular damage, as significantly higher RF values were observed in patients with no or mild tubular damage. Although also medulla and total kidney GKP were higher in patients with mild tubular damage, these results were not significant.53. However, no commercially accessible tools are available for prediction of DGF and subsequently no estimation on prognosis can be made. In recent years biomarker- guided diagnostic approaches for renal impairment have gained importance. In respect of KTX patients, well investigated markers such as IL-18, NGAL, IGFBP7 and TIMP-2 have shown an association with DGF and worse transplant outcome55.In the early phase of kidney transplantation many risk factors due to graft characteristic, warm and cold ischemia time and immunological risk can lead to delayed graft function as a subtype of acute kidney injury. Until now, clinical decisions are based on standard care procedures including close laboratory screening, adequate immunosuppression, avoidance of nephrotoxic medication and maintaining optimal fluid balanceNon- invasive radio imaging of renal allograft allows assessment of morphology, perfusion and urologic abnormalities. However, few data regarding functional measurements exist and are yet not implicated in clinical routine. The gold standard for diagnosis of glomerulopathies, tubular damage, interstitial fibrosis and allograft rejection remains the histopathology.56. One study has shown a predictive value for allograft dysfunction and fibrosis using a multiparametric 1,5 Tesla magnetic resonance imaging with specific diffusion weighted- imaging and T1 sequences57. Another study using functional MRI to assess interstitial fibrosis by arterial spin labeling and apparent diffusion coefficient was able to discriminate between <50% and >50% fibrosis accordingly to histopathology58. Clinical trials for ultrasound and MRI have attempted to diagnose acute rejection, but have not been able to discriminate accurately between different pathologies. Imaging protocols with e.g. specific nano-sized particles as contrast agents to identify immune cells as macrophages and T cells have been established, but yet are in experimental stages and only been investigated in murine models59.A study performing T1 mapping with MRI in patients early after kidney and lung transplantation showed that the renal cortical relaxation time is longer in patients after kidney transplantation compared to healthy controls60.In a recently published paper the use of FDG PET combined with CT in kidney transplant recipients managed to distinguish between stable graft function and the diagnosis of subclinical rejection in the early phase of transplantation. The level of inflammation proved in allograft biopsies seemed to correlate with the FDG uptake and together with the urinary expression of chemokine CXCL9 and urine creatinine a high negative predictive value on subclinical rejection could be demonstrated. However, these results need to be confirmed in further clinical studiesTo date, no kinetic model in order to evaluate subunits of the kidney and the capillary system has been verified. Therefore, we tried a novel approach based on FDG PET and MRI to not only look at the morphology but shed light to a functional aspect of allograft kidneys.In the present study we found a potential non- invasive diagnostic tool for prediction of kidney repair according to GKP, IF and RF measured by FDG PET/MRI. The repair mechanism at the renal site, in particular at the proximal tubules requiring glucose as energy supply might be of relevance. Higher FDG uptake might translate into higher energy turnover and cellular repair mechanisms indicating regain of kidney function. However, more prospective studies are required to confirm these findings and evaluate its relevance.Dynamic FDG PET/MRI parameters showed a positive correlation with serum creatinine development within 10 days in kidney transplant recipients after AKI and DGF.40, they are certainly not in small VOIs, mainly the aorta and the medulla, which leads to higher errors. Therefore, the RF was not calculated for the medulla or the cortex VOIs. Although even the GKP from the uncorrected medulla VOI delivered better results, total kidney VOIs might be sufficient to study GKP or RF.No partial volume or motion corrections have been applied on the obtained VOIs. While these effects are insignificant in total kidney VOIs1 from an applied kinetic model. The non-negligible partial volume and motion effects hamper the application of a kinetic model, thus IF was chosen as a rough estimate.Furthermore, a better parameter to determine initial renal processes would certainly be the rate constant KWe did not compare the level of total inflammation (ti) as stated in histology with the FDG uptake due to limited number of patients baring a ti score >1. Another limitation of this study is the small cohort size and further studies are needed to validate these results.


Background and objectives: Type D personality, characterized by two stable traits , is associated with adverse cardiovascular events. A possible mediating factor for this association could be hypertension. Previous research has shown that individuals with Type D personality were associated with an increased risk of hypertension. However, the association of negative affectivity and social inhibition on blood pressure in normotensive individuals has not yet been reported. Therefore, the aim of this study was to investigate whether negative affectivity and social inhibition were associated with systolic and diastolic blood pressure in normotensive middle-aged and older Taiwanese adults. Materials and Methods: A cross-sectional study design was used. Individuals attending general health examination at a regional hospital in southern Taiwan who were 40 to 75 years old were recruited. Patients with self-reported hypertension or currently receiving antihypertensive medication were excluded. Negative affectivity and social inhibition were assessed with the 14-item Type D Scale-Taiwanese version. Multiple linear regression analyses were conducted to determine the association of Z-score transformed negative affectivity and social inhibition on blood pressure. Results: A total of 92 patients with a mean age of 51.5 years were included in the study, and 15 (16.3%) were defined as having a Type D personality. The Z-score transformed negative affectivity score  and Z-score transformed social inhibition score  were significantly associated with a higher systolic blood pressure. In addition, the Z-score transformed negative affectivity score  and Z-score transformed social inhibition score  were significantly associated with a higher diastolic blood pressure. Conclusions: Negative affectivity of the Type D personality was significantly associated with higher systolic and diastolic blood pressure, with a medium effect size, in apparently healthy middle-aged and older adults. Assessment of negative affectivity may be clinically useful in identifying individuals at risk of hypertension. A distressed personality type or Type D personality is characterized by the joint tendency to experience negative emotions towards themselves and others, and to inhibit these emotions while avoiding social interaction. These dimensions are referred to as negative affectivity (NA) and social inhibition (SI), respectively . The preMost previous research on Type D personality has focused on patients with various diseases rather than on healthy individuals. For example, Type D personality was found to be significantly associated with hypertension, after adjusting for sex, age, body mass index, family history of hypertension, living condition, education, and employment . HoweverThe study protocol was approved by the Institutional Review Board of Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation . Informed consent was obtained from all participants in the study.A cross-sectional study design was used to recruit individuals undergoing a general physical examination at a regional hospital in southern Taiwan from November 2009 to June 2010. Patients aged 40 to 75 years old were included in the study. Exclusion criteria included patients with self-reported hypertension or those who were currently receiving antihypertensive medication. In addition, patients with cardiovascular disease, stroke, and cancer were also excluded from the study.The 14-item Type D Scale-Taiwanese version (DS14-T)  was usedInformation of the patients, including age, sex, body weight, body height, educational level, marital status, family history of hypertension, exercise, smoking habit, and alcohol use were obtained from a questionnaire distributed at the start of the general health examination. Body mass index was calculated by dividing body weight in kilograms by body height in meters squared. Resting systolic and diastolic blood pressure were measured by trained staff using a vTrust 701DH digital handheld non-invasive blood pressure monitor , with patients in a seated position.2) was calculated by r2/(1 − r2). Values of f2 near 0.02, 0.15, and 0.35 could be defined as small, medium, and large, respectively [p value of <0.05 was considered statistically significant.Continuous variables were expressed as means with standard deviations, and categorical variables were expressed as numbers with percentages. Independent t-test and Chi-square test or Fisher’s exact test were used to compare patients with or without Type D personality. To aid the interpretation of the results for NA and SI, their values were transformed into Z-scores with a mean of zero and a standard deviation (SD) of 1. Simple and stepwise multiple linear regression analyses were conducted to determine the association between blood pressure and independent variables, including Z-score transformed NA and SI, age, sex, body mass index, educational level, marital status, family history of hypertension, regular exercise, current smoking, and current alcohol use. Effect size of regression  reported that they did not have hypertension or were not receiving antihypertensive medications. These 92 patients were included in subsequent analyses.The basic characteristics of the study participants, divided into Type D and non-Type D, are shown in p = 0.025). For diastolic blood pressure, body mass index  and family history of hypertension  were significant factors. In addition, current smoking was marginally associated with a higher diastolic blood pressure. Both Z-score transformed NA and SI scores were not significantly associated with systolic or diastolic blood pressure. However, as shown in p = 0.035) when adjusting for other significant covariates in the regression model (age and body mass index). It was also significantly associated with diastolic blood pressure  when adjusting for other significant covariates in the regression model . Conversely, the Z-score transformed SI score was associated with systolic blood pressure with only a marginal significance , and not significantly associated with diastolic blood pressure  in the regression models. The f2 for all four models were above 0.15, which could be interpreted as a medium effect size.Age, sex, body mass index, educational level, marital status, family history of hypertension, regular exercise, current smoking, and current alcohol use were evaluated in the stepwise multiple linear regression model development. The Z-score transformed negative affectivity score and social inhibition score were forced to retain in their respective model.Age and body mass index were other significant covariates in the systolic blood pressure model, whereas age, body mass index, and family history of hypertension were other significant covariates in the diastolic blood pressure model.This cross-sectional study showed that NA, a tendency to experience negative emotions, was significantly associated with systolic and diastolic blood pressure in normotensive middle-aged and older Taiwanese adults. To the best of our knowledge, this is the first study to report this association. Previous research generally focused on comparing Type D personality between hypertensive patients and healthy individuals. Denollet  reportedRegarding the mechanism of how type D personality could affect blood pressure, Kupper et al. suggested that type D personality was associated with exaggerated α-adrenergic vasoconstriction to the cold pressor test, which might increase the risk of hypertension later in life . In our Because Type D classification represents both NA and SI, it is impossible to determine if the association with blood pressure reflects either of these two traits. This study separately explored the two constructs of Type D personality and found that the NA was more strongly associated with blood pressure compared with SI in normotensive adults. NA, the tendency to perceive emotions as negative, could activate the sympathetic–adrenal–medullary system and the hypothalamic–pituitary–adrenal–cortical axis system, which could increase blood pressure through increased serum levels of catecholamines and cortisol ,23. Our Previous research suggested that emotional dysregulation and coping styles in individual might affect blood pressure ,27. PatiOur study has several limitations. First, this study was based on a relatively small sample size of patients attending general health examination at one regional hospital. Second, because of the cross-sectional design of our study, the temporal relationship between blood pressure and Type D could not be established.This cross-sectional study of normotensive Taiwanese patients showed that NA was associated with a higher blood pressure. Assessment of NA may be clinically useful in identifying individuals at risk of hypertension. In addition, research on personality traits, such as forgiveness , or redu


This study tested the hypothesis that reduced Na+ and increased K+ excretion will positively associate with lower blood pressure in salt sensitive (SS) and salt resistant (SR) participants in the Dietary Approaches to Stop Hypertension Sodium Trial (DASH–Sodium). Via the NHLBI BioLINCC we accessed the DASH-Sodium dataset for data on systolic blood pressure (SBP), 24-h urinary Na+ and K+ excretion at screening  and post DASH diet . The relationships between SBP, urinary Na+ and K+ excretion, and Na+/K+ ratio were assessed via linear regression. At screening elevated urinary Na+ excretion positively associated with SBP in SS (1 g increase in urinary Na+ excretion = +1 0 ± 0.4 mmHg) but not SR participants, and urinary K+ excretion of <1 g K+/day was associated with higher SBP in SS and SR participants. Urinary K+ excretion ≥1 g/day, or a decreases in urinary Na+/K+ ratio, was not associated with lower SBP. Post the DASH–sodium diet intervention, SBP was reduced in SS and SR participants. However, no correlation was observed between reduced SBP and urinary K+ excretion or the urinary Na+/K+ ratio irrespective of the salt sensitivity of blood pressure. Our data support the DRI recommendation not to establish a K+ DRI and suggest further evidence is required to support a reduced Na+/K+ ratio to lower SBP.The 2019 National Academy of Science, Engineering and Medicine Dietary Reference Intakes (DRI) for Sodium (Na The impact of dietary Na+ intake on blood pressure has been investigated in multiple dietary intervention trials generating evidence that reduced dietary salt intake in controlled settings leads to reductions in blood pressure [+ restriction with reductions in blood pressure suggesting there is a health benefit in both normotensive and hypertensive individuals irrespective of the salt sensitivity of blood pressure [Hypertension, the most common non-communicable disease worldwide, represents a significant global public health issue. Based on the 2017 American Heart Association (AHA) guidelines, the prevalence of hypertension among US adults is estimated to be 46%  ~90% of  the AHA . Given tpressure . Furtherpressure .+) intake. Increasing dietary K+ intake appears to counteract the effects of dietary Na+ intake on increasing blood pressure [+ intake, the 2019 National Academy of Science, Engineering, and Medicine DRI for sodium and potassium Report did not establish a DRI for K+. This report concluded that more evidence is required to support a DRI of K+ with particular reference to a lack of K+ dose-response trials limiting the evidence to establish a K+ DRI [+:K+ ratio has a stronger association with blood pressure than Na+ or K+ independently [+ to K+ molar ratio of <1 has been recommended [+ intake this would necessitate dietary, or other means, of K+ supplementation—for which a DRI has not been established [+ intake in combination with either a control or DASH diet  on blood pressure. This study demonstrated substantial effects of dietary Na+ reduction and the DASH diet on reducing blood pressure, with more significant blood pressure lowering effects with the combination of a DASH diet plus dietary Na+ reduction than dietary Na+ restriction alone in individuals with higher than optimal blood pressure [+ intake by increasing dietary intake of fruits and vegetables in combination with modifying daily dietary Na+ intake, examining the potential interaction between dietary Na+ and K+ intake on blood pressure in the DASH trial will provide valuable insight into the potential influence of dietary K+ on blood pressure.Recent evidence suggests the salt sensitivity of blood pressure may be modulated, in part, by dietary potassium  in participants from the DASH–Sodium trial during the initial screening period in which participants were consuming their regular diet without dietary intervention. The secondary goals of this study were to investigate: (a) the impact of the salt sensitivity of blood pressure on these responses and (b) the impact of the DASH–Sodium dietary intervention, which lowers SBP and increases dietary K+ intake, on these potential associations. Our analysis reports that in the DASH–Sodium study cohort: (1) a daily excretion of <1 g K+/day is associated with elevated SBP, (2) urinary K+ excretion of >1 g/day does not correlate with a reduction in SBP and, (3) a reduction in the urinary Na+:K+ excretion ratio is not associated with lower SBP irrespective of the salt sensitivity of blood pressure. Collectively our data support the recent DRI recommendation not to propose a DRI for K+ and suggest that further evidence is required to support the establishment of a Na+/K+ excretion ratio that would reduce SBP in the general population.The primary goal of this study was to analyze urinary Na+, K+, and SBP values from study participants. The design of the DASH–Sodium trial has been described in detail previously [+ intake to ~120 mmol/day (4.7 g K+/day). Each dietary arm was further randomized in a crossover design resulting in each participant receiving their respective diet (control or DASH) containing low , intermediate , or high  Na+ content, for 30 days each in a randomized order. Several measures, including incentives , daily diary, and clinical staff monitoring ensured dietary compliance [The National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) provided access to the DASH–Sodium trial data on urinary Naeviously . In briempliance .Fig. 1StTwenty-four-hour ambulatory blood pressure recordings were taken during two screening periods and during the last nine days of each dietary intervention period. The data used for analysis represent the average cleaned SBP measured over each specified period. 24-h urine samples were obtained during screening and during the last week of each dietary intervention feeding period. Prior to storage at −80 °C urine samples were mixed to ensure a uniform sample and aliquoted in 5 ml volumes with 2 drops of 6 N HCl added per aliquot.+ and K+ interactions with baseline blood pressure. In order to assess potential interactions of urinary Na+ and K+ with SBP in response to changes from the HS to the LS DASH diet, we assessed SBP only, and urinary parameter values from participants from which all three urine samples  were available for analysis. This resulted in the analysis of 71 SS and 119 SR participants.In the current study, we utilized screening values for SBP and urinary laboratory parameters from 222 SS and 186 of SR participants to evaluate Na+ reduction within the control diet and the DASH diet were assessed using the Holm method, and the resulting P value < 0.05 was determined to be significant [+ and K+ excretion (mg/day) data obtained during the screening and run-in feeding period (referred to as baseline), and following 30-days LS and HS intake on either the control or DASH diet were provided to the authors via BioLINCC.In the original DASH–Sodium trial, the baseline blood pressure used for analysis was the mean of value recorded during screening and the run-in period, and the blood pressure for the intervention period was the mean of the last five measurements at the end of each intervention. Baseline blood pressure and the clinical centers were represented as fixed effects, and the intervention periods were represented as random effects. The generalized estimating equation module of Stata was employed to compute power, and the residual variance estimate value and standard deviation for each estimate were provided. As has been previously reported the DASH–Sodium trial was sufficiently powered to detect changes evoked by the dietary interventions on SBP and DBP. The effects of Nanificant . All SBPSalt sensitive: Participants with SBP being at least 5 mmHg higher after HS intake compared to the values after the LS intake; Salt resistant: Participants whose SBP differed by <5 mmHg between HS and LS intakes; Independent variables: Urinary Na+, Urinary K+ and Na+:K+ excretion ratio; Dependent variable: SBP; Categorical variable: Participants were categorized into groups on the basis of increments of 1 g/day in urinary Na+ and K+ excretion to evaluate the linear trends+ and K+ excretion with SBP. For Figs. + and K+ excretion. In order to quantify the effectiveness of increasing urinary Na+ and K+ excretion relative to SBP, Cohn’s Effect Size was calculated. In Figs. +:K+ excretion ratio with SBP. In Fig. p < 0.05 . Data are presented as mean ± SD.Generalized linear models were employed for linear regression analysis (Pearson’s R correlation) to assess the association of urinary NaAmong study participants analyzed, 53% of SR and 62% of the SS participants were female, 51% of SR and 63% of SS participants were African-American  or SR (R2 = 0.02) participants  and the SR (0.49) group. However, when assessed across the entire range of observed K+ excretion we observed no correlation between K+ excretion and SBP in either SS (R2 = 0.001) or SR (R2 = 0.008) participants  or SR (R2 = 0.002) participants  vs. SR participants  there was a significant (p < 0.05) reduction in SBP on the DASH-LS diet compared to the baseline screening SBP value (Table N = 119) there were significant (p < 0.05) reductions in SBP on both the DASH-HS and DASH-LS diets compared to the baseline screening SBP value (Table p < 0.05) increase in urinary K+ excretion and reduction in the urinary Na+:K+ ratio (that was greater during the LS intervention), in both SS and SR participants  or SR  participants  significant differences in sample size and racial backgrounds of the participants and (2) the potential differences in methods to assess urine content of 24-h urine collection compared to an estimation from a single morning spot urine sample in the DASH-Sodium versus PURE Study respectively. Our data support guidelines to limit dietary Na+ intake [In contrast to the PURE , INTERSAn the US . In contn values . The dif+ intake on blood pressure remains controversial, with conflicting data emerging from multiple clinical studies [+ intake was increased by dietary intake (via fruit and vegetable intake) or direct K+ supplements. In this study increased K+ intake up to 40 mmol/day had no impact on blood pressure [+ at 64 mmol/day for a 4-week period as either potassium chloride or bicarbonate—in this study there was no effect of K+ supplementation on office blood pressure [+ at 3 g/day and a diet relatively low in Na+ reported a reduction in SBP of 3.9 mmHg. Beyond the highly controlled trials discussed above the PURE study reports that for each increment of 1 g/day of urinary K+ excretion there is a reduction of 0.75 mmHg in SBP across the excretion range of <1.25 to 3 g K+/day [+ excretion was below 1 g/day. However, we did not observe any correlation between urinary K+ excretion and SBP or an impact of urinary K+ excretion on SBP over the range of <1 to >3 g K+ excretion per day. We speculate that discrepancy between the PURE study data and our own analysis of the DASH-Sodium data may reflect the difference in SBP response to urinary K+ excretion reported in PURE between Chinese and non-Chinese participants. Chinese participants exhibited a large reduction in SBP with increased urinary K+ excretion versus a smaller SBP effect in participants from the rest of the world. As the DASH-Sodium trial did not contain Chinese participants this may have influenced the outcome.The influence of K studies . In a rapressure , 26. A spressure . Participressure . In contg K+/day . In the + intake may be dependent on dietary Na+ intake [+ excretion and SBP, during the patient screening visit or during DASH dietary intervention when Na+ intake was modified, suggesting an independence of the effects of Na+ and K+ on SBP in this study. The 2019 DRI Report concluded that there is insufficient evidence on the effects of K+ on blood pressure and did not establish a DRI of K+ [+ supplementation may not significantly reduce blood pressure in the general population.Further, several studies have suggested that the blood pressure reduction evoked by K+ intake , 29. In RI of K+ . Our dat+/K+ excretion. The TAIM randomized control trial in hypertensive participants on a pharmacological intervention reported no significant difference in DBP between the control diet group and a low Na+/high K+ diet group during a six month period [+/K+ ratio there are several limitations to be considered. A multicenter study by Suppa et al. conducted in hypertensive participants reported a significant reduction in SBP following 4 weeks of modified low sodium high potassium salt intake compared to participants receiving a normal salt intake [+/K+ ratio and blood pressure reported a loss of statistical significance of the correlation in 44 of the 52 centers after adjustment for covariates including age, sex and BMI [+/K+ ratio is limited by the modest correlation the use of single morning urine sample [+/K+ ratio and SBP, that was maintained after covariate adjustment, with the greatest SBP observed with the highest estimated K+ and lowest estimated K+ excretion [+ excretion of <1 g/day is associated with elevated SBP we observed no association between the urinary Na+/K+ excretion ratio and SBP at screening or following DASH-dietary intervention in SS or SR participants. In conjunction with the study by Zanetti et al. [+ and low K+ excretion may increase the likelihood of having increased SBP. However, the lack of association between urinary Na+/K+ ratio and SBP in our data do not support a urinary Na+/K+ molar excretion ratio of 1:1 as a mechanism to lower blood pressure [At present there is conflicting evidence regarding the potential blood pressure lowering effects of a reduction in urinary Nah period . This sut intake , yet allt intake . Further and BMI , 33. In e sample . The PURxcretion . Althougi et al. , our datpressure , 17.+ intervention allowed participant’s to serve as their own control and diminished inter-person variability, (3) 24-h ambulatory blood pressure recordings were taken, (4) absence of the confounding effects of antihypertensive mediations, and (5) 24-h urine sample collection. The major limitation of the present study is the relatively modest sample size that may have decreased our statistical power to detect modest effects of urinary Na+, K+, and Na+:K+ ratio on SBP. While we did not observe an imbalance in baseline characteristics, residual confounding in our analysis is possible.The current study has several strengths: (1) The DASH -Sodium trial was a carefully controlled feeding study and compliance was continuously monitored, (2) The crossover design for Na+ supplementation is not associated with lower SBP and that the reductions in SBP observed following DASH dietary intervention occurred independently of a decrease in the urinary Na+/K+ excretion ratio irrespective of the salt sensitivity of blood pressure. Our data do not support the establishment of a 1:1 molar excretion ratio of Na+/K+ as blood pressure lowering strategy in US African American and non-African Americans and support the DRI recommendation not to propose daily K+ intake guidelines. Given the limitations of the current analysis and the ongoing controversy regarding the role of dietary K+ on blood pressure future carefully controlled studies are required to elucidate the potential impact of dietary K+ and urinary Na+/K+ excretion ratio on blood pressure in both hypertensive and normotensive SS and SR participants.In conclusion the current analysis of the DASH–Sodium Trial demonstrates that dietary KSeveral clinical trials, including the Dietary Approaches to Stop Hypertension (DASH) – Sodium trial have established significant effects of dietary sodium reduction on lowering blood pressure.Increased potassium intake in combination with reduced sodium intake appears to lower blood pressure and a urinary sodium to potassium molar ratio of <1 has been proposed to improve blood pressure control.Although potassium potentially modulates blood pressure, the 2019 National Academy of Science, Engineering, and Medicine Dietary Reference Intakes for Sodium and Potassium Report states that more evidence is required to establish a daily potassium intake level.Urinary potassium excretion ≥1 g/day does not correlate with lower SBP irrespective of the salt sensitivity of blood pressure in DASH–Sodium trial participants supporting the recent DRI recommendations not to propose potassium intake guidelines.The reduction in SBP in salt sensitive and salt resistant individuals following the DASH dietary intervention occurred independently of a reduction in urinary sodium to potassium excretion ratio. These findings do not support the establishment of 1:1 molar excretion ratio of urinary sodium to potassium for blood pressure reduction.


Research into dietary factors associated with hypertension has focused on the sodium component of salt. However, chloride has distinct physiological effects that may surpass the effect of sodium on blood pressure. This study aims to separate the specific effects of chloride and sodium intake on blood pressure.We studied 5673 participants from the Prevention of Renal and Vascular End-Stage Disease(PREVEND) study. Urinary chloride(uCl) and sodium(uNa) were measured in two 24-hour collections. We used generalized-linear-regression to evaluate the relation of uCl and uNa with baseline blood pressure and Cox-proportional-hazards-analysis to assess the association with hypertension. Multicollinearity was assessed with Ridge regression.r = 0.96). UCl and uNa had similar non-significant positive and linear associations with blood pressure. In 3515 normotensive patients, 1021 patients developed hypertension during a median follow-up of 7.4 years. UCl and uNa had a comparable but non-significant J-shaped effect on the risk of hypertension. Adding both uCl and uNa to the same model produced instability, demonstrated by Ridge coefficients that converged or changed sign. The single index of uNa minus uCl showed a non-significant higher risk of hypertension of 2% per 10mmol/24-hour difference .Baseline 24-hour uCl was 135±39mmol and uNa was 144±54mmol. The correlation between uCl and uNa was high (Pearson’s UCl and uNa had similar positive but non-significant associations with blood pressure and risk of hypertension and their effects could not be disentangled. Hence, the alleged adverse effects of high salt intake could be due to sodium, chloride or both. This encourages further study into the effect of chloride in order to complement dietary recommendations currently focused on sodium alone. Hypertension is an important modifiable risk factor for renal and cardiovascular disease. ResearcDespite the focus on sodium, the accompanying anion–chloride–may also play an important role. Chloride is associated with plasma renin suppression, metabolic acidosis and vasoconstriction of the afferent arteriole of the glomerulus and a subsequent reduction in the glomerular filtration rate,9. PreliRestricting sodium intake without lowering chloride intake disregard the pathophysiological effects of chloride and may have unintended effects on blood pressure. Since sodium reduction will mostly be effectuated by lowering salt (i.e. sodium chloride) intake, the beneficial effects of sodium reduction in previous studies could also result from concurrent chloride reduction. Although sodium restriction is assumed to result in a similar reduction in chloride, analysis of various food demonstrated that sodium and chloride contents can be different,25. In an = 410), with missing urinary chloride values (n = 134), with an estimated GFR <15 ml/min (n = 2) and those without available follow-up data after the second study visit (n = 12), leaving 5673 participants for analysis of urinary electrolyte excretion. Urinary sodium and potassium were available for at least one urinary collection for each participant. The association with blood pressure at baseline was evaluated in 4655 participants who did not use antihypertensive drugs. The risk of developing hypertension was evaluated in 3515 patients without hypertension at baseline. The PREVEND study has been approved by the medical ethics committee of the University Medical Center Groningen. Written informed consent was obtained from all participants.The Prevention of Renal and Vascular End-stage Disease (PREVEND) study is a prospective, general population-based cohort study investigating the association of albuminuria with renal and cardiovascular disease. Details of this study are described elsewhere. In totaThe procedures at each examination in the PREVEND study have been described previously. In brieDetermination of urine electrolyte concentration was performed on the 24-h urine specimens by indirect potentiometry with a MEGA clinical chemistry analyzer . Serum and urinary creatinine, serum total cholesterol, triglycerides, and glucose were determined by using Kodak Ektachem dry chemistry . Body mass index was calculated as weight in kilograms divided by height in meters squared. Smoking status was categorized as current or never/former and alcohol intake as rarely (≤4 drinks/month), regularly (>4 drinks/month and < = 3 drinks/day) or often (≥4 drinks/day). Education was categorized as low , average (higher secondary education), and high . Diabetes mellitus was defined as a fasting plasma glucose ≥7.0 mmol/L or the use of antidiabetic medication. Hypertension was defined as systolic blood pressure (SBP) of ≥140 mmHg, a diastolic blood pressure (DBP) of ≥90 mmHg, or both or the use of antihypertensive agents. Estimated glomerular filtration rate (eGFR) was calculated from the Chronic Kidney Disease Epidemiology Collaboration equation.The urinary chloride, potassium and sodium concentration were multiplied by urine volume to obtain a value in millimoles per 24-hours (24-h). Correlations between 24-h electrolyte concentrations evaluated with Pearson’s correlation coefficient. Second, we evaluated the association between 24-h chloride and sodium excretion and blood pressure at baseline using generalized linear models. Restricted cubic splines were used to examine the optimal functional form of the covariables. Models containing splines were compared with the linear model using conditional likelihood ratio tests. Model assumptions of homoscedasticity and normal distribution of errors were verified graphically by residual versus predicted plots and Q-Q plots. The base models were adjusted for sex and age. Further, fully adjusted models included urinary creatinine, urinary potassium, body mass index, eGFR, current smoking, alcohol consumption, family history of premature cardiovascular disease, and educational attainment. By adjusting for urine creatinine, we adjusted indirectly for both muscle mass and body dimension. We did not adjust for the presence or absence of albuminuria since we considered this covariable as potential intermediary factor in the development of hypertension. Third, the association with development of hypertension was evaluated with multivariable Cox proportional hazards regression. We evaluated the presence of Interaction between uCl and age, sex, albuminuria, C-reactive protein, eGFR, smoking, BMI and family history of premature cardiovascular disease by a likelihood ratio test of the model including a cross-product term. Further, the proportional hazard assumption was verified by correlating scaled Schoenfeld residuals and time and no violations were observed. Since previous analyses demonstrated that the effect of sodium intake on incident hypertension was strongest in patients with albuminuria (defined as ≥15mg/L), we performed a separate analysis in this stratum as sensitivity analysis[In order to detect potentially influential multicollinearity between sodium and chloride in the constructed models we calculated the variance inflation factor (VIF). This parameters indicates how much the variance of a given covariable is increased compared to complete absence of correlation  and is generally agreed to indicate potential model instability if higher than ten. To quanData were missing in 2.3% of participants for HDL-cholesterol and triglycerides and <2% for all other variables. Missing data were imputed by single imputation methods using predictive mean matching. StatistPatient characteristics are displayed in r = 0.96, p<0.001), as illustrated in r = 0.52, p<0.001).In the 5673 participants who attended the second screening visit, there was a very high correlation between 24-h uCl excretion and uNa excretion (Pearson’s p for interaction <0.001). When specifying tertiles of albuminuria, an increased effect for uCl was observed in the middle tertile but a decreased effect in the highest tertile. Higher age increased the effect of uCl on systolic BP whereas it decreased the effect on diastolic BP (p for interaction <0.001).Urinary chloride excretion was nearly linearly related to systolic and diastolic BP in 4655 patients without antihypertensive medication at baseline . In the The model combining both uCl and uNa was hampered by high collinearity (VIF = 12) resulting in opposite associations for chloride and sodium with systolic and diastolic BP . When app<0.01); therefore uCl was modelled as a spline. The spline of uCl was significant in the base model (p = 0.01) but not in the full model (p = 0.16). The risk of hypertension was lowest at a uCl level of 151 mmol in the fully adjusted model. The constructed tertiles of uCl excretion showed a trend towards an increased risk of hypertension in both the lowest and highest tertile  and is the alleged culprit of the adverse effects on blood pressure and cardiovascular disease. The most abundant accompanying anion, chloride, has received little attention but could have a pivotal role. In this study we showed the difficulty of disentangling the effects of sodium and chloride because sodium and chloride urinary excretions were highly correlated. Nonetheless, differences in sodium versus chloride excretions occurred at an individual level. Higher 24-h uCl excretion was positively but not significantly associated with baseline BP and development of hypertension similar to and inseparable from the effect of higher uNa excretion. Therefore, we argue that the role of chloride cannot be discarded and should be considered in clinical studies and dietary recommendations on salt intake.p-values[In this observational cohort study, we tried to separate the collinear effects of both ions with different analytical methods. The negative effects of multicollinearity in statistical models primarily pertain to inadequate estimates of uncertainty such as confidence intervals and p-values. Furtherp-values. Potentip-values,29. In tp-values. Nonethep-values. In the p-values,35. A pop-values.NonethelThe focus of current dietary recommendations on sodium follows from the selective evaluation of cations in dietary studies thus far. The present study is the first to attempt to separate the effects of the cation and anion and showed their high correlation and comparable effects on blood pressure. The current recommendations on selective sodium restriction are based on the large observational studies such as INTERSALT, INTERMAP and PURE,37–39. FTo our knowledge this is the first study to quantify the correlation between sodium and chloride excretion and their association with BP and risk of hypertension in a large prospective Western cohort. Strengths of the current study include the large number of participants, the long follow-up time and the availability of two 24-h urine collections per individual to reliably predict electrolyte intake. In addiIn conclusion, the adverse effects of chloride and sodium measured by 24-h urinary excretion were difficult to disentangle due to their high correlation and comparable non-significant effects on blood pressure and risk of hypertension. Hence, the alleged adverse effects of a high salt intake could be due to sodium, chloride or both. An intervention study with different combinations of cations and anions would be required in order to understand their relative contribution to the development of hypertension. For now, guidelines committees should consider formulating sodium chloride targets rather than sodium targets alone.S1 FigAdjusted for age and sex, with density plot. SBP, systolic blood pressure; DBP, diastolic blood pressure.(PDF)Click here for additional data file.S2 FigRelated to baseline systolic blood pressure  and diastolic blood pressure , with density plots.(PDF)Click here for additional data file.S3 FigWith base model (left) and fully adjusted model for urinary creatinine, urinary potassium, smoking, body-mass index, history of diabetes, family history of premature cardiovascular disease, educational attainment, alcohol and estimated glomerular filtration rate (right). HR; hazard ratio.(PDF)Click here for additional data file.S4 FigBase model (left) and after further adjustment for covariables (right). HR; hazard ratio.(PDF)Click here for additional data file.