Arterial hypertension is a chronic disease which is very prevalent contemporarily. The aim of this review was to investigate the impact of gut microbiota on the development and potential treatment of hypertension, taking into consideration underlying molecular mechanisms. The bacteria present in the intestines have the ability to secrete different metabolites, which might play a significant role in the regulation of blood pressure. The most important include short-chain fatty acids (SCFAs), vasoactive hormones, trimethylamine (TMA) and trimethylamine N-oxide (TMAO) and uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS). Their action in regulating blood pressure is mainly based on their pro- or anti-inflammatory function. The use of specifically formulated probiotics to modify the composition of gut microbiota might be a beneficial way of supportive treatment of hypertension; however, further research on this topic is needed to choose the species of bacteria that could induce the hypotensive pattern. Arterial hypertension (AH) is a chronic condition diagnosed when blood pressure (BP) value is elevated over 140/90 mmHg .Because of an aging population and increasing prevalence of hypertensive risk factors, such as overweight/obesity, dyslipidemia, physical inactivity, poor diet, low folate intake and excessive sodium intake, prevalence of AH increases with age: from 27% in patients aged younger than 60 years to 74% in those aged older than 80 years . The WorFirmicutes and Bacteroidetes [Lachnospiraceae, Ruminococcus and Parasutterella spp. and decrease in Lactobacillus and Oscillibacter [Emerging evidence indicates that the gut microbiota is an important factor in the etiology of hypertension. Gut microbiota, a compound and highly varied community of microorganisms, live in the digestive tracts of humans and consists of several types of bacteria, archaea, eukaryote, viruses and parasites . The gutroidetes . The gutroidetes . Moreoveroidetes . Multiplroidetes . Higher libacter ,11. Morelibacter ,13.The aim of our study is to describe the role of gut microbiota in hypertension.The impact of gut microbiota on the human body has been analyzed by scientists for a long time.Many scientific papers show that the gut microbiota could generate metabolic products, such as trimethylamine N-oxide (TMAO), that enlarge secretion of inflammatory factors, and hence, increase the risk of development of the atherosclerotic plaques ,15. MorePrevotella; on the other hand, the second one was more abundant in Bacterioides. The authors suggest that enterotype 1 of gut microbiota could be present in patients with prehypertension (pHTN) and hypertension (HTN), while enterotype 2 occurs in the healthy control group [Jing Li et al. specified two classes of enterotypes. The first enterotype was more opulent in ol group .Scientists have proven that patients with high blood pressure present a higher capacity of bacteria, which should weaken gut barrier and cause intestinal inflammation . FurtherAnaerovorax, Butyricicoccus, Vampirovibrio, Methanobrevibacter, Oxalobacter, Cellulosibacter, Mogibacterium and Sporobacter in hypertension [Alistipes finegoldii and Eubacterium siraeum could be correlated with an increase of blood pressure [Streptococcus and Parabacteroides, Salmonella and Eggerthella could increase in the population with hypertension, in comparison to normal blood pressure [Klebsiella could have the same impact on blood pressure [Desulfovibrio occurs in individuals with hypertension [Some bacteria might present higher abundance in hypertension. This correlation is presented in rtension . Moreovepressure ,21. Studpressure . Additiopressure ,22. Furtrtension ,21.Bifidobacterium, Coprococcus and Butyrivibrio could have a higher occurrence in people with normal blood pressure [Eubacterium rectale was noticed in individuals with lower blood pressure [Enterorhabdus, Romboutsia, Enterococcus, Lachnospiracea, Paraprevotella, Christensenella, Acetobacteroides and Coprobacter appeared to be increased in healthy controls [Roseburia and Faecalibacterium might be present at lower amounts in hypertensive patients [Rothia, Atopobium, Anaeroglobus, Megaspheara and Pseudocitrobacter might be present at lower quantities [Ruminococcus also could exist in enriched amounts in patients with normal blood pressure [Researchers have shown that a population of particular bacteria could be present at a lower capacity in individuals with hypertension or higher in normal blood pressure. This correlation is presented in pressure . Furtherpressure ,21. Morepatients ,22,23. Fantities . Ruminocpressure ,23.Oscillibacter—a Gram-positive bacterium—could be enriched in a normotensive population; nevertheless, Shan Shun et al. exhibited that the amount of this bacterium should be decreased in comparison to people with hypertension [Prevotella and Clostridium were described by X. Dan et al. as being decreased in individuals with hypertension; nevertheless, other authors have shown that the population of those bacteria should be elevated [Bacteroides was presented by X. Dan et al. [Bacteroides were presented by S. Kim et al. [A few bacteria present debatable changes in the healthy and hypertensive populations—included in rtension ,20. The elevated ,21,22. Tm et al. .The authors suggest that there is a need to undertake more detailed scientific research in order to define the association between the bacteria presented in Many different molecular mechanisms are involved in the process of maintaining arterial blood pressure. The most important of them are included in the following subsections.Renin is a hormone produced in the juxtaglomerular epithelioid cells and released from granules in response to a decrease in renal perfusion pressure, hypovolemia or hyponatremia. Simultaneously, angiotensinogen is released from the liver in a continuous manner and is present in excess compared to renin. Renin acts as a proteolytic enzyme that converts angiotensinogen into angiotensin I (Ang I). Furthermore, angiotensin converting enzyme (ACE) secreted from endothelial cells converts angiotensin I to angiotensin II (Ang II). Ang II acts through angiotensin receptors type 1 (AT1R) and type 2 (AT2R). Stimulation of AT1R results in vasoconstriction, activation of sympathetic nervous system, aldosterone secretion and, hence, retention of sodium and water. These mechanisms lead to elevation of arterial blood pressure. On the other hand, stimulation of AT2R has the opposite effect on blood pressure, causing vasodilation and, additionally, anti-inflammatory and anti-fibrotic function. However, AT2R plays a vital role in the developing organism of fetus, but shows limited function in adults ,25. The Arterial baroreceptors include carotid and extra-carotid baroreceptors. Carotid baroreceptors are located in the right and left carotid sinus and extra-carotid baroreceptors are found in the heart, in the aortic arch and in the pulmonary vessels . These rThe sympathetic nervous system (SNS) is of great importance in blood pressure regulation via the secretion of catecholamines that bind to adrenergic receptors (mostly α1 and β1). Stimulation of SNS results in an increase of the heart rate, total peripheral resistance and retention of sodium and water. Consequently, all these effects lead to the elevation of arterial blood pressure .The group of natriuretic peptides includes atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These molecules originate in the myocardium and act as both endocrine and paracrine mediators. Activation of relevant natriuretic peptides receptors stimulates the synthesis of cyclic guanosine monophosphate (cGMP), which is responsible for the most vital effects of natriuretic peptides . TherefoThe kinin–kallikrein system (KKS) is a complex multiprotein cascade that takes part in the activation of the intrinsic coagulation pathway and secretion of bradykinin-related peptides . BradykiThis connection is described in detail in The gut microbiota has the potential to produce a variety of metabolites that can reach the systemic circulation and act as signaling molecules that might regulate blood pressure in the host’s organism . The mosShort-chain fatty acids (SCFAs) are fatty acids that have fewer than six carbon atoms, including mostly acetate (C2), propionate (C3) and butyrate (C4) . They arAnimal studies suggested that SCFAs can have both a hyper- and hypotensive effect, depending on the receptors involved. For example, SCFAs might take part in lowering BP thanks to the vasodilating effect of stimulation of GPR43 and GPR109a, which are present in renal arteries . On the Roseburia, Rothia and Ruminococcaceaae spp. [Another mechanism in which SCFAs might regulate BP relates to the inhibition of histone deacetylase (HDAC) . Animal aae spp. ,23.Furthermore, SCFAs might also interact with central nervous system (CNS) via vagal receptors . Animal Escherichia, Lactobacillus, Bifidobacterium and Streptococcus [The studies have found that gut microbiota has the ability to produce vasoactive hormones, such as serotonin, dopamine and norepinephrine . These mtococcus . All thetococcus ,47.Escherichia coli, Klebsiella spp., Citrobacter spp., Desulfovibrio alaskensis and Proteus mirabilis [Trimethylamine N-oxide (TMAO) is another gut microbiota-derived metabolite that can be involved in the compound process of BP regulation . It origirabilis .Although the direct role of TMA and TMAO in the development of hypertension remains uncertain , studiesOn the other hand, it is important to note that TMAO functions as a protective osmolyte against high osmotic pressure . FurtherMicrobiota-derived uremic toxins include among others indoxyl sulfate (IS) and p-cresyl sulfate (PCS) ,60,61. TBacteroides and Blautia, while Enterococcus, Akkermansia, Dialister and Ruminococcus are associated with a higher PCS level [Higher presence of bacteria correlated with a high IS level applies to CS level .Hypertension is a common human condition, historically defined as a sustained elevation of systolic blood pressure (SBP) above 140 mmHg or diastolic blood pressure (DBP) above 90 mmHg. Essential hypertension (90% of patients) is a heterogeneous disorder, typically emerging in middle or elderly age, as a cumulative result of complex gene–gene and gene–environment interactions .Luckily for the patients, there are numerous types of treatment available nowadays, mainly pharmacological, in which the leading drugs include diuretics, beta-blockers, angiotensin-converting enzyme inhibitors (ACE-I) and calcium channel blockers. Interestingly, minocycline, an antibiotic, presented a strong and positive impact on the regulation of blood pressure (BP) without harming the “healthy” microbiome  and to aNaturally, diet is one possible way of dealing with some diseases, such as diabetes mellitus (DM), allergies or hypertension. Knowing that, it is vital to mention quercetin, which alters the microbiome through metabolites such as 3-(3-hydroxyphenyl)propionic acid, which reduces BP and works as a vasodilator ,69,70.Recently, the attention of researchers from all over the world has been focused on using probiotics to treat hypertension. The idea to use probiotics was based mostly on the fact that both bacteria and fungi might be beneficial in the long term, by inhabiting intestines and improving our health by secreting specific metabolites.Our attention was focused on microbiota as well, because, e.g., enterochromaffin cells in mucosal and submucosal layer of stomach could be influenced by microbiota, as a consequence of serotonin, dopamine and norepinephrine release, which elevates BP because of changes that occur in the gut microbiome–brain axis. Recent studies discovered that in patients with hypertension (HT), dysbiosis occurs in certain bacterial families. Due to this fact, the term Firmicutes/Bifidobacterium ratio (F/B ratio) was created. It turns out that in patients who suffer from HT, that ratio is elevated; therefore, the amount of Firmicutes is larger than Bifidobacterium. Moreover, it is important to mention that the decrease of blood pressure might be a result of short-chain fatty acids (SCFA) production in bacterial cells ,64,71,72Currently, studies cannot tell exactly what the proper genome of the microbiota is; however, it is assumed that even though there are differences at the phylum level, it is possible to observe some general directions in search of the “healthy” microbiome .L. helveticus strain was indeed able to lower blood pressure [L. plantarum strain TENSIA has proven that this bacteria might be able to contribute to lowering BP in patients medicated with antihypertensive drugs, thanks to the increased excretion of water from the body [L. plantarum proved to have antimicrobial properties, and hence, it might play a protective role in maintenance of desirable “healthy” microbiome [L. animalis might be able to create biologically active types of caseins that possess ACE-I functions [It was observed that implanting a diet enriched in pressure  and the pressure . L. planthe body . Moreovecrobiome . Interesunctions .Prevotella, Klebsiella, Parabacteroides and Desluvibrio [Lactobacillus is also able to help ameliorate hypertension by secreting substances working as Th-17 lymphocytes inhibitors that decrease inflammation; furthermore, it lower the BP [L. coryniformis [Over time, many studies have been conducted, and some of them determined that in individuals with hypertension, the amount of Gram-negative bacteria could be elevated, especially of those belonging to the following genera: luvibrio ,18,21,23r the BP  and mighniformis ,79.Roseburia, Rothia and Ruminococcaceaae spp. might be able to lower blood pressure [Lactobacillus could be increased in rodents [Lactobacillus plantarum has the ability not only to lower BP, but also decrease the level of fibrinogen, leptin (gut hormone stimulating hunger) and IL-6 (main proinflammatory interleukin) [Even though still not enough studies considering the human microbiome have been conducted, it has been noticed that SCFA producers such as pressure ,22,23,80 rodents , which mrleukin) , and therleukin) .For starters, when it comes to treating many different diseases, the best way is to start low and go slow (if it is not a life-threatening state); therefore, dietary changes should be the first thing to alter, as well as psychological aspects such as behavior—e.g., avoiding stress and seeking psychiatric help if needed. Then, pharmacological therapy with the use of antihypertensives should be introduced, and, if all of the above options are currently involved, probiotics should be considered to alleviate symptoms of hypertension and augment the effects of methods that are already in use.There is room to create a set of dietary rules  for hypertensive patients that would become part of their life, and thus, it could make beneficial habits easier to follow for people regardless of their education, wealth or job.○Killing hostile microorganisms;○Developing drugs that work as growth inhibitors of unwanted bacteria species;○Creating substances that mimic function of SCFA so it could lower the price of probiotics and make it more accessible in regions where storing living organisms might be difficult (because of electricity deficiency or lower hygiene standards).Moreover, thanks to modern pharmacological technologies, we might be able to produce drugs that are precisely created to augment the proliferation and beneficial abilities of SCFA producing bacteria by:All the above-mentioned results of many studies suggest there might be a possibility to include probiotics into standard treatment of hypertension; however, further research on this topic is needed to fully establish the association between different bacterial species and regulation of blood pressure.The association between the composition of gut microbiota and the development of arterial hypertension has been widely explored in the literature lately. The potential opportunity to alleviate the symptoms, and therefore, prevent further consequences of elevated blood pressure (BP) with the use of specific probiotics, has aroused great hopes.The bacteria present in the intestines can produce and secrete different metabolites, which might play an important role in the regulation of blood pressure. The hypertensive effect is associated with increased level of microbiota-derived vasoactive hormones, trimethylamine (TMA) and trimethylamine N-oxide (TMAO) and uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS). The elevation of blood pressure might occur mostly due to the proinflammatory and vasoconstrictive function of these molecules.Roseburia, Rothia and Ruminococcaceaae spp., contributes to the hypotensive effect via the anti-inflammatory action.Short-chain fatty acids (SCFAs) also belong to the group of bacterial metabolites involved in the process of blood pressure regulation. These particles might have both hypo- and hypertensive effect depending on the stimulated receptors, but their stronger effect applies to lowering the BP. Especially butyrate, produced by, e.g., Lactobacillus  might be able to reduce the BP by promoting the anti-inflammatory phenotype.Moreover, it has been suggested that a greater population of different species of Lactobacillus and Bifidobacterium, the most commonly found in probiotics, suggests that, until more detailed research is conducted, taking these probiotics might be considered as both primary prevention of hypertension and as an addition to standard therapies for elevated blood pressure.Even though the dependence between the composition of gut microbiota and increased blood pressure has not been fully established yet, it is certain that patients with unbalanced microbial community are at a higher risk of developing hypertension. These conclusions might lead to potential new ways of supportive treatment of hypertension with the use of specifically formulated probiotics. The beneficial role in maintenance of normal BP attributed to This literature review has several limitations—it completely relies on previously published research, and even though the selection of the included data was done very meticulously, some errors resulting from previously applied methodology might occur. Moreover, the availably of non-open access research was limited due to lack of external funding.The most important positive outcome of this scientific paper is that vital molecular mechanisms known for affecting the blood pressure in accordance with the composition of gut microbiota and their metabolites were gathered and discussed. Further studies on the species of bacteria which might be used in probiotics to achieve the significant hypotensive effect might be needed to implement this kind of therapy.


While optimizing spirometry is a challenge for lung function labs, long-term variability if any between IOS (impulse oscillometry) parameters and spirometry is not clearly known in stable COPD (chronic obstructive pulmonary disease) and chronic asthma. The forced oscillation technique is increasingly employed in routine lung function testing. Our aim in this study was to determine the variability in oscillometric parameters between clinic visits over weeks or months in two patient groups during a period of clinical stability. Moreover, the research assessed relationships between IOS parameters long-term variability and COPD severity.We used data from 73 patients with stable COPD and 119 patients with stable asthma at the Shanghai Pulmonary Hospital Affiliated to Tongji University. Patients were included if they had three or more clinic visits where spirometry and IOS were performed during a clinically stable period. Data recorded from the first three visits were used. The standard deviation (SDbv), the coefficient of variation (COV), intraclass correlation coefficient (ICC) and the coefficient of repeatability (COR) were calculated, Wilcoxon Mann–Whitney test was used for data that did not conform to normality of distributions, Kruskal Wallis test was used to compare with multiple groups, post hoc comparison was analyzed by Bonferroni, Spearman correlation coefficients for non-parametric data, the multiple regression analyses to determine the relationship between long-term variability and airflow obstruction.(1) The repeatability of IOS resistance parameters with ICC values > 0.8 was high in COPD and asthma. ICC values of IOS resistance parameters were higher than IOS reactance parameters; (2) the repeatability of spirometry parameters with ICC values < 0.8 was lower than IOS resistance parameters in different GOLD  stages, the higher the stage the worse the repeatability; (3) the severity of airflow obstruction was correlated with long-term variability of R5 (R at 5 Hz) (P < 0.05) in GOLD4, not with long-term variability of R20 (R at 20 Hz) (P > 0.05) and R5-R20 (P > 0.05).IOS resistance parameters have good long-term repeatability in asthma and COPD. Additionally, repeatability of spirometry parameters is lower than IOS resistance parameters in different GOLD stages. IOS is increasingly receiving attention for pulmonary function examinations. The main advantage being its simplicity: the oscillatory signal is based on spontaneous breathing and, hence, no special patient cooperation is required .IOS is a variant of forced oscillation technique (FOT), measures respiratory impedance at multiple frequencies in a range of 5–35 Hz. Measurements are performed at tidal breathing. The principle is to measure the flow response of the respiratory tract to externally applied pressure signals. Hence, the respiratory impedance can be derived, which is expressed in its component resistance and reactance . The resIOS as a re-emerging clinical detection technology is valuable to study the minimal clinically important difference (MCID) of lung function in stable COPD and asthma. There has been suggestion that the ICC’s are high for all parameters in health, stable asthma and COPD. FOT measures are highly repeatable, day-to-day variability is due mostly to repeatability, which is correlated with airway obstruction . The betTherefore, the aim of this study was to determine the variability in IOS parameters between clinic visits over weeks or months, in stable asthma and COPD patients. The research also assessed relationship between IOS parameters long-term variability and degree of airway obstruction of stable COPD.The study protocol was reviewed and approved by the Ethics Committee of Shanghai Pulmonary Hospital. All methods including PFT (pulmonary function tests) and IOS were carried out in accordance with relevant guidelines and regulations.This study retrospectively enrolled 73 patients with stable COPD and 119 patients with stable asthma who were examined in Shanghai Pulmonary Hospital from January 2011 to December 2018. All patients were in the stable condition. The main inclusion criteria were as follows: (1) three or more clinic visits; (2) spirometry and IOS were performed; (3) no change in symptoms, no respiratory infection in the past 6 weeks and no changes in treatment. Patients were diagnosed by physicians as asthma and COPD, having a post-bronchodilator Tiffeneau index FEV1/FVC < 70  . GOLD stWe performed pulmonary function tests [including spirometry and impulse oscillation (IOS)] using standard equipment . FVC, FEV1 and FEV1/FVC were determined by standard procedure . OscilloStatistical analysis was performed using SPSS 22.0 and GraphPad Prism 5. Data are shown as mean ± SD, median (interquartile range). A two-tailed P-values less than 0.05 is considered to be statistically significant. The Shapiro–Wilk test was used to assess normality of distributions. Long-term variability was expressed as the standard deviation of the first three visit’s measurements for each subject (SDbv). The coefficient of variation (COV = SDbv/mean) was calculated and intraclass correlation coefficient  of IOS measurements of the three clinic visits. In addition, the coefficient of repeatability (COR) was calculated, defined as twice the standard deviation of the differences between two pairs of consecutive clinic visits from three clinical visits per patient or expressed as a percentage of close to maximal variation (pMV) , 15. ICCThe demographic data and the baseline lung function test results of the COPD and asthma patients are shown in Table Long-term variability of spirometry and IOS parameters is shown in Table The COR data during a period of stable disease for the two patient groups Table  are noveComparison of long-term variability of IOS parameters with the degree of airway obstruction in stable COPD.Long-term variability of PFT and IOS parameters related to COPD severity stages are shown in Table It is exciting that the higher the COPD stage the lower numerical values of ICC for spirometry parameters. Nevertheless, the ICC values of IOS resistance parameters were relatively stable and significant, and were higher than the ICC values of spirometry parameters in GOLD3 and GOLD4 stages. The ICC values of IOS reactance parameters were relatively low. Higher COPD stage had higher COR values of spirometry parameters. The COR values of IOS resistance parameters were relatively stable and lower than those of spirometry parameters in GOLD3 and GOLD4 stage, the higher the COPD stage, the lower COR values of IOS resistance parameters, the COR values of IOS reactance parameters were relatively stable.Associations between long-term variability and degree of airway obstruction of stable COPD.s = 0.61, P < 0.05), not correlated with %FEV1 in GOLD2 and GOLD3  years] patients were younger than COPD [(62.68 ± 9.57) years] patients, the spirometry parameters in COPD were lower compare to asthma (P < 0.0001), the COPD patients had higher R5, R5-R20, AX and more negative X5, except for R20 and Freq, compared to the asthma patients (P < 0.0001). These findings suggest that there were differences in pulmonary ventilation function and airway obstruction between COPD and asthma.As airway obstruction increases with disease progression and airway remodeling, characteristic changes in resistance and reactance are more pronounced. Particularly, resistance spectrum increases in direction of low frequencies. At the same time overall resistance increases but more so at low frequencies than at high frequencies , 17. ThuCOR values were less than 66% in COPD and asthma, except for Freq (69%) and X5(80%) in asthma with the relative CORs for IOS being more variable than for spirometry. However, the repeatability of IOS parameters, apart from Freq and X5, were high (> 0.80). We are not sure if this has any relationship to the difference of distal airway distensibility in the two conditions. These results suggest that despite there being higher long-term variability in IOS measurements than spirometry, IOS is still highly repeatable and stable. The high variability may be due to different baseline characteristics, the airway caliber and elastic characteristics of respiratory system, which fluctuated with time , 19.The current gold standard to assess airway limitations is spirometry. However, performing an optimal spirometry always requires good patient cooperation. Additionally, repeated forced breathing causes changes in bronchial motor tension, false positive results occur often. Studies on the quality of spirometry in elderly patients have shown that only 30% of patients are able to perform a spirometry that meets the quality standards of the European Respiratory Society/American Thoracic Society, 21. FurThe short-term variability in IOS parameters is known, particularly within-day, day-to-day or week-to-week repeatability of resistance (Rrs) and reactance (Xrs) with high ICC values (> 0.80) –27. It is = 0.61, P < 0.05). Additionally, multiple regression analyses indicated that %FEV1 is potential predictor for long-term variability of R5 and R5-R20 . Their mean values are potential predictor for long-term variability of R5, R20 and R5-R20 (P < 0.05). The severity of airflow obstruction significantly was correlate with long-term variability of R5 and R5-R20, not with long-term variability of R20.Significant correlations at baseline between FEV1 and R5 (P < 0.05) but not with R20 has been reported and during 1-year follow up. The changes in R5 and R20 did not significantly correlate with FEV1. Additionally, the R20 is unrelated to the severity of airflow obstruction in patients with COPD . We founOne potential limitation of this study was that the groups were not matched by sex and age in different diseases and GOLD stages. There was one female in GOLD1, 20 male and 2 female in GOLD2, 25 male and 6 female in GOLD3, 18 male and 1 female in GOLD4, 58 male and 61 female in asthma. There is long-term disease progression in stable diseases , our maxThis study revealed that IOS resistance parameters have high long-term repeatability as shown by high ICC values (P > 0.80) in asthma and COPD with lower ICC values < 0.8 in GOLD3 and GOLD4. Higher long-term variability seen in COPD was related to airflow obstruction. These findings help determine thresholds for MCIDs. IOS can support routine lung function testing to monitor disease progression, disease activity, disease progression or treatment response over a long period of time. IOS will not replace spirometry anytime soon as the two tests measure very different things. However, when IOS is used as a complimentary test to spirometry for long term follow up, proves to be clinically very useful.


Among the problems caused by hypertension, early renal damage is often ignored. It can not be diagnosed until the condition is severe and irreversible damage occurs. So we decided to screen and explore related risk factors for hypertensive patients with early renal damage and establish the early-warning model of renal damage based on the data-mining method to achieve an early diagnosis for hypertensive patients with renal damage.With the aid of an electronic information management system for hypertensive out-patients, we collected 513 cases of original, untreated hypertensive patients. We recorded their demographic data, ambulatory blood pressure parameters, blood routine index, and blood biochemical index to establish the clinical database. Then we screen risk factors for early renal damage through feature engineering and use Random Forest, Extra-Trees, and XGBoost to build an early-warning model, respectively. Finally, we build a new model by model fusion based on the Stacking strategy. We use cross-validation to evaluate the stability and reliability of each model to determine the best risk assessment model.According to the degree of importance, the descending order of features selected by feature engineering is the drop rate of systolic blood pressure at night, the red blood cell distribution width, blood pressure circadian rhythm, the average diastolic blood pressure at daytime, body surface area, smoking, age, and HDL. The average precision of the two-dimensional fusion model with full features based on the Stacking strategy is 0.89685, and selected features are 0.93824, which is greatly improved.Through feature engineering and risk factor analysis, we select the drop rate of systolic blood pressure at night, the red blood cell distribution width, blood pressure circadian rhythm, and the average diastolic blood pressure at daytime as early-warning factors of early renal damage in patients with hypertension. On this basis, the two-dimensional fusion model based on the Stacking strategy has a better effect than the single model, which can be used for risk assessment of early renal damage in hypertensive patients. According to the 2020 international society of hypertension global hypertension practice guidelines, hypertension is related to cerebrovascular disease and ischemic heart disease. It is also a major risk factor for the incidence and death due to chronic kidney disease . HyperteIn China, the number of uremic patients caused by hypertension reaches 1.5 million every year . FurtherIn clinical practice, it is hard to realize the early diagnosis of the high-risk population of hypertensive renal damage and guide different patients to choose the most suitable scheme to receive treatment in time. Because of few or no symptoms in the early stage of chronic kidney disease (CKD), most patients with renal damage fail to get a timely diagnosis. Many hypertensive patients who look healthy may have developed CKD, and current methods fail to diagnose these patients fully. We intend to establish an early-warning model based on data mining to evaluate the risk of early renal damage by integrating the relevant factors. The factors including cardiovascular risk factors, blood pressure parameters, biochemical blood indicators, and related biomarkers –5. Then In order to achieve the early diagnosis of a high- risk population with hypertensive renal damage, we will screen the early-warning risk factors of early renal damage by feature engineering . Based oFrom November 2011 to May 2013, Beijing Anzhen Hospital of Capital Medical University (Beijing Institute of Heart Lung and Blood Vessel Diseases), Third Xiangya Hospital of Central South University (Hunan Hypertension Research Center), and Chenzhou No.1 People’s Hospital of Hunan Province  received 513 patients without complications who have initially diagnosed hypertension. They aged between 35 and 64, including 319 males and 194 females. None of the patients had ever taken any antihypertensive drugs before their visit. According to their albumin- to-creatinine ratio(ACR) levels, the patients are divided into two groups: positive group (30-300mg/g), which is the early renal damage group, and control group (< 30mg/g), which is the normal renal function group. The number of patients in the two groups is 191 and 322, respectively.P <0.05). The levels of sex ratio, body mass index(BMI), high-density lipoprotein(HDL), low-density lipoprotein(LDL), blood urea nitrogen(BUN), and serum creatinine(Scr) are similar. The differences are not statistically significant (P > 0.05). See Table In the comparison of the data of the two groups of patients, the levels of fasting blood glucose(FBG), triglyceride(TG), uric acid(UA), and red cell distribution width(RDW) in the positive group are greatly higher than those in the control group. Furthermore, the differences between the two groups are statistically significant  and unimportant can be deleted. Features with fewer missing values can be filled. We can use statistics to fill in mean, median, and mode. It is recommended to use the median for continuous values, excluding the influence of some large or small outliers. For discrete values, we can use mode to fill in.Personal information features: height, weight, age, sex, BMI, smoking or not, and body surface area(BSA).Ambulatory blood pressure features: 24-h average SBP, 24-h average DBP, 24-h average heart rate, day average SBP, day average DBP, day average heart rate, night SBP drop rate, night DBP drop rate, blood pressure circadian rhythm, night average DBP, and night average SBP.Blood biochemical and routine features: HDL, TG, FBG, UA, LDL, RDW, and BUN.Based on the information obtained from data analysis and combined with the understanding of hypertensive renal damage, we analyze and construct the following features.Feature selection is also called feature subset selection or attribute selection. It refers to selecting a subset of features from all features to make the constructed model best . In the Using the variance selection method, we calculated the variance of each feature and then eliminated the feature with variance more minor than the threshold.P-value between each feature and the target value using the correlation coefficient method.We calculated the correlation coefficient and Using the variance inflation factor to determine the correlation between variables to perform multicollinearity detection.Using the random forest as the base model to train to get the importance of different features for selection.For feature selection, we use the following methods:We use the K-Fold function for cross-validation in the scikit-learn(Python package) to divide the data into five sets of train sets and test sets to perform 5-fold cross-validation . It can In order to determine the best prediction model, we use Random Forest, Extra-Trees, and XGBoost to train the data. During model training, we use grid search to adjust and optimize model parameters. Grid search is a model parameter optimization method  whose esAfter the above model training is completed, we use the Stacking method to integrate the above models to build a new model to improve the prediction effect. The Stacking model fusion strategy is based on the idea of K-fold cross-validation, whose essence is a hierarchical model integration framework to stack the learning ability of different models for different features. However, as the number of layers increases, there is a risk of overfitting. Therefore, we usually use a two-layer model to reduce the number of data repeat training. The first layer model comprises several base learners whose input is the original train set. Moreover, the second layer model uses the output of the first layer model as the train set to retrain. The structure of the Stacking model fusion strategy is shown in Fig. We use the two-dimensional fusion model based on the stacking strategy. The first layer model uses the combination of random forest, extra trees, and XG-Boost as the base learner to train the data, and the second layer model uses XGBoost to train the output of the first layer model.The steps of feature selection are shown in Fig. The precision, recall, F1 score results of 5-fold cross- validation for each model are shown in Table The precision of each fold in 5-fold cross-validation for each model is shown in Fig. In screening CKD patients and monitoring renal function in the treatment, the main clinical index is serum creatinine. But serum creatinine assessment is not sensitive to detecting early subclinical changes and predicting renal function decline after treatment. In the preclinical stage of CKD, we need new monitoring indicators to evaluate such patients. Early renal damage can be judged by microalbuminuria and glomerular filtration rate (GFR). However, the role of urinary microalbumin has not been deemed significant due to red measurement errors. GFR is affected by many factors. Even though nuclear medicine method measurement is a gold standard, it is seldom carried out due to the complexity of cost and operation. The estimated GFR can not reflect the real renal function because the formula is complicated, and the results of different formulas are pretty different. This part of the study aims to understand the early renal damage of untreated hypertension patients, screen the relevant risk factors, and find out specific high-risk factors. It also provides quantitative indicators  for early renal damage hypertension patients and cardiovascular clinicians to prevent CKD’s progress better.The comparison results between the two groups show that the patients in the early renal damage hypertension group are older than those in the control group. Moreover, their HDL and BSA are lower, and their blood pressure index is higher than the control group. Especially the nighttime blood pressure level and blood pressure variability. Further analysis shows that abnormal blood pressure rhythm in the two groups is quite different. In the early renal damage group, the proportion of non-dipper type, reverse-dipper type, and deep dipper type account for 75.9%, 14.1%, and 3.1%, respectively, while the normal rhythm is more petite than 10%. In contrast, 72.4% of the patients in the control group have normal blood pressure rhythm. The blood pressure circadian rhythm analysis indicates that the difference in nighttime blood pressure drop rate between the two groups is statistically significant. The drop of nighttime blood pressure is weakened in the early renal damage group.P < 0.05) to indicate that the higher the blood pressure level, the higher the incidence of ACR. In addition, our study also concludes that the drop rate of nighttime systolic blood pressure and the average diastolic blood pressure in the daytime are risk factors for ACR occurrence. Furthermore, it shows that controlling blood pressure levels is significant for patients with hypertension.Cheng Dong et al.  found thPeople’s blood pressure is higher in the day and lower at night. That is to say, the blood pressure drops during sleep at night and is the lowest in the early morning; the blood pressure starts to rise in the early morning and then presents the first peak. In normal people and patients with arytenoid rhythm hypertension, sympathetic activity, cardiac output, and blood pressure decrease during sleep. Huijuan et al.  found thThis study suggests that the ambulatory blood pressure level of patients with early renal damage of hypertension increases with the increase of urinary microalbumin, which is manifested by the increase of nighttime blood pressure, significantly the increase of nighttime diastolic blood pressure. The study also finds that the early renal damage of hypertension is often accompanied by abnormal blood pressure circadian rhythm, and it has existed in hypertensive patients without microalbuminuria.In comparison with the control group, the patients with dipper and non-dipper rhythm, the patients with anti-dipper rhythm have higher ACR, night SBP, night DBP, and night PP. While the decrease of eGFR is more prominent than the control group. It suggests that anti-dipper rhythm plays a relevant and independent role in the occurrence and development of early renal damage in hypertension, regardless of whether the clinic blood pressure level and dynamic blood pressure level are the same. In addition, nighttime blood pressure level and circadian rhythm are positively correlated with ACR but not with eGFR. It suggests that the anti-dipper blood pressure circadian rhythm is independently correlated with microalbuminuria in patients with hypertension. Our study finds that all patients in the anti-dipper rhythm group have early renal damage, which may be due to a small sample size or a biased selection. However, it is enough to show that the early renal damage in the anti-dipper rhythm group is more severe than in the control group. In the future, we need larger samples and more evidence to confirm the causal relationship between the anti-dipper rhythm and early hypertensive renal damage.A series of studies confirmed the correlation between RDW(Red cell Distribution Width) and hypertension. Tanindi et al.  found thThis study finds that RDW is associated with early renal damage in hypertensive patients, and the ACR ratio also tends to increase as RDW increases. Combined with the data in this group, hypertensive patients have different degrees of early renal damage. RDW is a sensitive indicator for the diagnosis of early renal damage in hypertensive patients, and RDW is a common item of routine blood examination. The method is convenient, fast, and inexpensive. Of course, RDW, as an indicator of risk assessment of early renal damage in hypertensive patients, still needs evidence support from prospective studies in the future.When we use the Stacking method for model fusion, the corresponding results may be different when the model combination of each layer is different. In order to determine the best combination of models, the first layer model uses the random combination of Random Forest, Extra-Trees, and XGBoost as the basic learner, and the second layer uses XGBoost. Then, we carry out 5-fold cross-validation on the data. Through comparison, we can find that the average precision of two-dimensional fusion model based on Random Forest is the best. However, the random combination of Random Forest, Extra-Trees, and XG- Boost is the most stable. And the F1 and recall of two- dimensional fusion model based on XGBoost, Random Forest and Extra-Trees is the best. Therefore, the random combination of Random Forest, Extra-Trees, and XGBoost is the best. The results of 5-fold cross-validation for each model combination are shown in Table There are some limitations in current research. In the aspect of screening risk factors of renal damage in hypertension, due to the inherent limitations of a case-control study, to further clarify the relationship between the above risk factors and early renal damage in hypertensive patients, it needs to be further confirmed by more centers, larger samples, and prospective studies. In establishing an early warning model of renal damage, a small sample is a severe limitation, which will affect the precision and generalization ability of the model. However, the small sample and data imbalance are common in clinical research. How to apply the model to clinical research still needs further exploration.In order to overcome the limitations of this study, we should collect more data about hypertensive patients with early renal damage to validate and optimize the model. Moreover, we may solve small sample limitations by few-shot learning. In addition, we could fuse other models with better effects to get the better result .This study mainly carries out the application research of data mining combined with routine clinical items in early warning of renal damage in hypertensive patients. We then use feature engineering and risk factor analysis to screen for risk factors such as the drop rate of systolic blood pressure at night, red blood cell distribution width, blood pressure circadian rhythm, and the average diastolic blood pressure at daytime as early renal damage’s warning sign. On this basis, the early-warning model of early kidney damage constructed by the Stacking model fusion strategy has a better effect than the single model. This model can diagnose renal damage in hypertensive patients and has important significance for screening high-risk populations. We can try to fuse the better model and test its prediction effect in the future. At the same time, the methods and ideas of this research can also provide new methodological references for similar early-warning research and evaluation.


Children with chronic kidney disease (CKD) are at high risk of mineral bone disorder (MBD), which leads to fractures, growth retardation, and cardiovascular disease. We aimed to comprehensively understand the relationship between renal function and factors related to MBD and evaluate the prevalence and distribution characteristics of MBD, specifically among Korean patients from the KNOW-PedCKD cohort.From the baseline data of the KNOW-PedCKD cohort, we examined the prevalence and distribution of MBD in 431 Korean pediatric CKD patients, including the level of corrected total calcium, serum phosphate, serum alkaline phosphatase, serum intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF-23), serum vitamin D, fractional excretion of phosphate (FEP), and bone densitometry Z-scores.The median serum calcium level remained relatively normal regardless of the CKD stage. The levels of 1,25-dihydroxy vitamin D, urine calcium-to-creatinine ratio, and bone densitometry Z-score significantly decreased with advancing CKD stage, while those of serum phosphate, FGF-23, and FEP significantly increased with CKD stage. The prevalence of hyperphosphatemia  and hyperparathyroidism  significantly increased with the CKD stage. Prescriptions of medications, such as calcium supplements , phosphate binders , and active vitamin D  significantly increased with CKD stage 3b, 4, and 5, respectively.The results demonstrated the prevalence and relationship of abnormal mineral metabolism and bone growth according to CKD stage in Korean pediatric CKD patients for the first time. Mineral bone disorder (MBD) represents a systemic disorder manifested by either one or a combination of abnormal mineral metabolisms, abnormal bone growth or strength, making bone more vulnerable to fracture and extra-skeletal calcification, all of which are closely interrelated and contribute to the morbidity and mortality of patients with chronic kidney disease (CKD), including those with cardiovascular disease . In 2006Mineral metabolism exerts a more profound influence in children with CKD as the development and maturation of the skeletal and vascular systems occur during childhood. CKD-MBD in children causes bone deformity and growth failure and may be accompanied by extra-skeletal cardiovascular calcifications with serious outcomes –5. Thus,Therefore, the objectives of this study were to comprehensively understand the relationship between renal function and factors related to MBD and change in bone mass and evaluate the prevalence and distribution characteristics of MBD, specifically among Korean patients from the KNOW-PedCKD cohort.From April 2011 to April 2016, a total of 469 patients < 20 years of age with CKD stages 1–5 were enrolled in the KNOW-PedCKD study, a nationwide, 10-year prospective and observational cohort study from seven major pediatric nephrology centers in Korea. Patients undergoing kidney replacement therapy or those who had cancer or had been treated for cancer within the previous five years were excluded from this cohort. The KNOW-PedCKD study is registered at ClinicalTrials.gov with the designation number NCT02165878  and was approved by the Institutional Review Boards of all participating centers.The detailed study protocol for comprehensive assessment of clinical findings and structured follow-up has been reported previously . The aut2)  or GFR < 60 ml/min/1.73 m2 (stages 3–5) lasting more than 3 months /chronological age × 100. The bone densitometry Z-score was calculated based on the reference values from the study by Lim et al. (The estimated glomerular filtration rate (eGFR) was calculated using the bedside CKiD formula . Accordi3 months . For pat3 months , 10. The3 months . While t3 months . Hyperph3 months . Serum im et al.  as demonP-value < 0.05 was considered to be statistically significant. We performed all statistical analyses using SAS version 9.4  and IBM SPSS Statistics for Windows, version 25.0 .Continuous variables are presented as the mean ± standard deviation and median (range). We compared the level of each variable according to the CKD stage using the Kruskal–Wallis test. The incidence of disordered mineral metabolism and distribution of medication intake were compared using the Chi-square test or Fisher's exact test. The relationship between variables and the eGFR was analyzed using linear, inverse, and compound models. The correlation between MBD and prescribed medications for MBD was analyzed using a multivariate analysis of covariance (MANCOVA). A P < 0.001) with advanced CKD stages; the median serum phosphate level (mg/dl) was 4.60, 4.90, 5.10, and 5.80 in CKD stages 3a, 3b, 4, and 5, respectively, and the levels of iPTH, FGF-23, and FEP constantly increased as the CKD stage advanced from stage 1 to 5 (P < 0.001). In contrast, the levels of 1,25-dihydroxyvitamin D, urine calcium-to-creatinine ratio, and bone densitometry Z-scores decreased with advancing CKD stages; the median 1,25-dihydroxyvitamin D level decreased as the CKD stage advanced from stage 1 to 4 (P < 0.001). The urine calcium-to-creatinine ratio and bone densitometry Z-scores significantly decreased (P < 0.001) as the CKD stage advanced from stage 1 to 3. The ΔBone age % consistently showed negative values across all CKD stages, with no statistically significant difference between stages.The patterns of mineral metabolism according to the CKD stages and the distribution of patients are described in P = 0.0627), although not statistically significant. Likewise, there was a tendency for an increasing prevalence of hypocalcemia in patients with advanced CKD stages , although to a lesser extent than hypercalcemia. Furthermore, the prevalence of hyperphosphatemia and hyperparathyroidism significantly increased (P < 0.001) with CKD stage .The prevalence of disordered mineral metabolism, including hypocalcemia, hypercalcemia, hyperphosphatemia, hyperparathyroidism, vitamin D deficiency, and prescribed medication according to the CKD stages, is presented in P < 0.001). The prevalence of active vitamin D supplements  also showed significant increase (P < 0.001) through all CKD stages . Multivariate analysis of covariance (MANCOVA) was performed to determine whether there was a statistically significant difference between the patients who received medications  and non-users on CKD-MBD variables controlling for GFR , while the linear associations between corrected total calcium level and eGFR, and between 25-hydroxyvitamin D3 and eGFR were not significant. Moreover, 1,25-dihydroxyvitamin D showed a statistically significant exponential relationship with the eGFR . Serum phosphate, serum iPTH, FGF23, and FEP showed statistically significant inverse relationships.We further investigated the relationship between each variable of mineral metabolism and the eGFR . The uriMBD is a crucial complication that should be closely monitored in pediatric patients with CKD. This study first demonstrated the prevalence of disordered mineral metabolism and its relationship with the eGFR in Korean pediatric patients with CKD for the first time in Asia.2  , correspα-hydroxylation of 25-hydroxy vitamin D owing to progressive damage to the proximal renal tubule with advancing renal deterioration, leading to a decline in the 1,25-dihydroxy vitamin D level  , and onl D level , where tMANCOVA results showing the correlation between phosphorus binders or vitamin D and CKD-MBD variables are confusing in The increase in the FGF-23 level with the decrease in renal function observed in our study was similar to previous findings from studies with children , 26, 27.As CKD progresses in children, more patients are at risk of decreased bone density caused by CKD-MBD. For the first time, we demonstrated the progressive deterioration in bone density as CKD progressed from stages 1 through 3 . Althougper se” can also influence the factor. Fourth, we did not analyze baseline cardiovascular parameters in this study due to the low prevalence of detectable extra-skeletal calcifications. Finally, owing to the multicenter study design, there may have been potentially significant inter-study variations among individual center settings. However, the strength of this study lies in that this is the first nationwide cohort study of pediatric CKD-MBD and the first prospective and most extensive pediatric CKD cohort study in Asia, demonstrating the distribution and prevalence of CKD in Asian ethnicity and presenting the relationship between eGFR change and variables associated with CKD-MBD in a pediatric population. As Korea has good access to CKD-MBD-related medications and a relatively well-established reimbursement system, the management of Korean pediatric CKD patients closely conforms to universal guidelines, and thus the results of this study may be applicable worldwide. Therefore, the baseline study of mineral metabolism is meaningful as a cornerstone of future research. We will follow the study participants for ten years. We expect further studies regarding dynamic changes in mineral metabolism and growth, including analysis by underlying etiologies in children with CKD from the full-length cohort data to be available.This study has several limitations that warrant discussion. First, missing data or unavailable information, a different number of patients for each CKD stage might have caused biased results, skewing the tendency of mineral concentration across the CKD stages. Second, the level of dietary restriction and compliance with each patient's medications, which may have impacted the serum mineral or hormone levels, were not included. Third, risk factor analysis was not conducted, nor the subgroup analysis according to different etiology was not performed as the cohort was composed of patients with heterogeneous etiologies  and progression rates. Therefore, we determined that it was unconvincing to demonstrate the association of a single factor with CKD-MBD progression since CKD “Among Korean pediatric patients from the baseline data of the KNOW-PedCKD cohort, the median calcium level remained relatively normal with increasing use of calcium supplements and active vitamin D across the CKD stages. Disordered mineral bone metabolism with respect to serum phosphate, serum FGF-23, hyperparathyroidism, and bone densitometry Z-score was evident with advancing CKD stages. Further study with follow-up data showing the trajectory or course of CKD-MBD stratified with underlying CKD etiologies might elucidate the progression and the impact of medical management on CKD-MBD in pediatric patients. Furthermore, a comparative study and consensus on what modality should be used for assessment of bone disease, growth, and extra-skeletal calcification are needed.


Ureteropelvic junction obstruction (UPJO) is one of the most frequent causes of congenital hydronephrosis. It is essential to distinguish UPJO which needs surgical treatment. fMRU combines high quality morphological details of the kidney and excretory pathways with functional data.This study aims to introduce a new radiological score based on fMRU findings to be able to differentiate surgical from non-surgical kidneys.We retrospectively selected patients with hydronephrosis due to UPJO who underwent fMRU (January 2009–June 2018). A multidisciplinary team identified a list of fMRU morpho-functional predictive variables to be included in the analysis. To evaluate the role of different independent variables in predicting the outcome, a multivariable logistic regression model has been performed; the outcome variable was the surgical intervention. For each predictive variable, Odds Ratio and 95% Confidence Intervals were calculated. The likelihood ratio test was used to assess the significance of the variables. Using the regression model, we assigned a numerical value to each predictive variable, rounding up the beta-coefficients. The cut-off value of the total score was obtained from the ROC curve analysis.A total of 192 patients were enrolled, corresponding to 200 pathological kidneys. All of them underwent fMRU; 135 were surgically treated, while 65 underwent ultrasound or MRU follow-up. Predictive variables significantly associated with surgery resulted to be the urographic phase, the presence of abnormal vessels, and a baseline anterior-posterior pelvic diameter >23 mm. Beta coefficients of the logistic regression model were then converted in scores. The ROC curve of the score showed high sensitivity (84.3%) and specificity (81.3%) with a cut-off > 2.5.We propose a new fMRU score able to identify surgical vs. non-surgical kidneys with UPJO. Congenital hydronephrosis is diagnosed in 3–5% of all prenatal ultrasounds (US) . While mUreteropelvic junction obstruction (UPJO)  is a congenital anomaly associated with hydronephrosis that can be corrected through surgery .UPJOs are classified as intrinsic or extrinsic causes. Intrinsic forms usually arise from an adynamic ureteral segment or cicatricial post-operative factors whereas extrinsic types are characterized by aberrant crossing vessel (CV), kinkings or adhesions over the ureteropelvic junction (UPJ). UPJOs may result from both intrinsic and extrinsic obstruction .It is essential to distinguish between forms that may be resolved spontaneously from those that require surgical treatment to prevent further loss of renal function .International guidelines  are baseThe use of functional Urographic Magnetic Resonance Imaging (fMRU) has progressively increased in the assessment of Congenital Anomalies of Kidneys and Urinary Tract (CAKUT) –16. fMRUTherefore, the aim of this study is to introduce a fMRU score to identify patients with UPJO who require surgical correction based on quantitative data. The study compares fMRU results to surgical findings and outcomes in a single pediatric center over 10 years.Between January 2009 and June 2018, we retrospectively analyzed all patients who underwent fMRU for hydronephrosis, diagnosed through renal US   are also considered indications for surgery.All the resected UPJ were analyzed by a pathologist.Follow-up was performed by fMRU or US in both groups . The parameters taken into consideration during the follow-up were: APD (variation >5 mm), calicectasia (grade and extension) and renal parenchymal thickness. Based on the fMRU and/or sonographic appearance of these features the pediatric radiologist defined three categories for clinical outcomes: improved, stable, or worsened.As the study was observational and retrospective in design and did not examine patients' personal information, ethical committee approval was not required.U-test as data were not normally distributed. Normality of variables was tested by means of the Shapiro-Wilk test.Firstly, descriptive statistics were performed, categorical variables were reported in terms of absolute frequencies and percentages while quantitative variables were reported in terms of mean values with SD or in terms of median values and first and third quartiles (1st−3rd q). Statistical analysis of frequencies was carried out using the chi square test or Fisher's Exact test (if expected frequency was <5). Comparison of quantitative variables between 2 groups  was done by means of the non-parametric Mann-Whitney example: age at first MRI, SRF AUC, DAP pre-Furosemide administration, antero-posterior diameter evaluated at baseline) were dichotomized based on the best cut-off value obtained by means the ROC curve method. This method allows to obtain the best cut-off value that can discriminate between subjects who had to be operated or not . Clinically relevant or statistically significant variables evaluated at bivariate analysis were included in the model. Some quantitative variables ; the correlation has been evaluated by means of the Spearman's Rank order coefficient (rS).Some quantitative variables were not included into the logistic regression model as they were auto-correlated (The odds ratios (ORs) with their 95% CI have been calculated and reported. The log-likelihood ratio test (LR test) has been used for testing variables statistical significance. The backward approach (that consists in removing non-significant variables from the saturated model) has been used for evaluating the model. The area under the ROC curve of the model has been used as an indicator of goodness of fit.x 0.5 value or to the nearest integer, a score has been calculated for each significant variable. All these scores were summed up to obtain for each patient a “total prediction score”. Finally, the best cut-off that could discriminate between patients who should undergo surgery or not has been calculated by means of the ROC curve method.Rounding up the regression coefficient (beta) of the statistically significant variables in the logistic regression model to the nearest P-value < 0.05 was considered statistically significant. Statistica”  was used for all the bivariate analyses; MedCalc was used for the ROC curve analysis; “Stata”  was used for the Fisher's exact test, for the Cohen's k and for the multivariable logistic regression model.All the statistical tests were two-sided and a According to our inclusion and exclusion criteria, 192 patients  were enrolled in the study, corresponding to 200 pathological kidneys, with a median age at fMRU of 5.1 years . The affected side was the left one in 124 and the right one in 76 cases with a predominance (62%) of the left side. The anatomical features of pathological kidneys are shown in After fMRU, 135/200 kidneys underwent surgery while 65/200 kidneys underwent instrumental follow-up (US or fMRU). In one case the UPJ stenosis was not confirmed by intraoperative ascending pyelography.In 6/192 patients, Gadolinium-based contrast medium (Gadoteric Acid) was not administered due to counter-indications. In 31/192 patients  it was not possible to perform the functional phase, while in 1/192 cases the urographic phase was not performed due to early interruption of the examination.The median age at surgery was 5.1 (1st−3rd q: 1.4–11.4) years with a median interval between fMRU and surgery of 2 months. Patients who underwent surgery had a mean follow-up of 25 months (SD: 24 months), while non-surgical patients had a mean follow-up of 30 months (SD: 26 months) from first fMRU.All the resected UPJ were analyzed by pathologist who confirmed the diagnosis.At a bivariate analysis  the morpFinally, to evaluate the role of different independent variables in predicting the surgical intervention, a multivariable logistic regression model was performed. As shown in Beta coefficients of the logistic regression model were then converted in scores , roundinFor each kidney, the total score  was then calculated; the best cut-off score was calculated by means of an ROC curve, using the surgical intervention as the outcome variable (yes/no). The best cut-off score able to predict surgical intervention was > 2.5 .Outcome data at the end of the follow-up was available on 148/200 kidneys (74%). The median length of follow-up was 1.73 years (1st−3rd q: 0.90–3.40 years) in the surgical group, and 1.69 years (1st−3rd q: 0.91–4.49 years) in the non-surgical group.P < 0.0001). Moreover, analysis of the observed outcome at the end of follow-up showed that diagnosis of UPJ Intrinsic Obstruction (UPJ-IO) is the subtype that had the greatest improvement after surgery ; similar data were observed for the diagnosis of Intrinsic Cicatricial UPJ (UPJ-IC) and Extrinsic Vascular UPJ (UPJ-EV) without reaching statistical significance due to the small numbers in the two diagnostic subgroups. Data of the outcome at last follow-up was available for only one kidney with the diagnosis of Extrinsic Adherential UPJ (UPJ-EA) and therefore no statistical test could be performed for this diagnostic subgroup; it was only observed that this case had improved.As shown in The diagnosis of congenital hydronephrosis has increased in incidence since the 1980s due to the greater diffusion of prenatal US. In published literature, about 50–75% of hydronephrosis are resolved or stabilized without treatment; the remaining cases need corrective surgery as chronic dilation of the calico-pyelic system induced by permanent obstacle to urinary outflow determines an incomplete morpho-functional development of the affected kidney , 25.Research has shown that early diagnosis of hydronephrosis improves the overall management in the postnatal phase , 26. No The most frequent cause of UPJO (62–75%) is the presence of an aperistaltic segment adjacent to the pyelo-ureteral junction. Initially, the obstruction is only functional, however, with time tissue alterations can occur, causing scarring and reduction of the pyelo-ureteral caliber –32. The Identification of the abnormal vessel in preoperative imaging remains an important step in UPJO surgical planning  avoidingDRS is the gold standard for the functional evaluation of hydroureteronephrosis and to guide therapeutic decisions; fMRU provides a radiation-free morphological and functional assessment with remarkably high spatial and contrast resolution , 40. RecFurthermore, in recent years, several studies have been published on the development of imaging-based scores for the assessment of hydroureteronephrosis, able to objectively predict the need for surgery and to evaluate the resolution of the obstruction , 41.In this study, we focused on the role of fMRU in guiding surgical or conservative approach in UPJO proposing a quantitative score. The score was obtained using the classical statistical methodology but also taking into account clinical considerations.First, variables considered as items of the score were chosen on a clinical basis. Subsequently, the considered variables were evaluated according to a standard statistical method with a multi-variable logistic regression analysis, also being used to identify the best predictors of surgical interventions. The beta coefficients of the best-fitted logistic model were considered as points of the score for each significant variable. Finally, all these scores were then added up to obtain a “total prediction score” for each individual patient.In our bivariate model analysis between surgical and non-surgical kidneys, the presence of an abnormal vessel obstructing the UPJ (93.8%) showed to be the morphological parameter with the greatest statistical significance. Other parameters, such as morphology and rotation of the pelvis and ureteral dilation were not found to be statistically significant when comparing the two groups. Interestingly, our analysis highlighted the role of dilation of the calyxes and renal pelvis measured both pre and post-hydration and Furosemide injection. Surgical kidneys had a considerably greater dilation than non-surgical ones, which worsened after water load and Furosemide injection.The subclass of extrinsic juntopathy resulted to be the major condition candidate to surgery.A substantial concordance was found between surgical findings and fMRU, consistent with published data , 42.At follow-up, the hydronephrosis and the morphology of the pathological kidney were evaluated as improved, stable, or worsened. An important finding of our analyses is that surgical kidneys improved significantly in 88.1% of cases, while non-surgical kidneys improved in 52% of cases or remained stable in 44% of cases. Intrinsic UPJOs have the most statistically significant improvement after treatment. Moreover, UPJ-EV is always treated surgically with an improvement of the hydronephrotic condition.Based on the regression model, the significant predictive variables were pelvic dilation, fMRU diagnosis, and the urographic phase. Functional curves, significant at the bivariate analysis, were excluded from the final score because of their direct correlation with other variables.The scores attributed to each predictive value are shown in The more delayed the detection of obstructive disease, the more likely the patient will undergo follow-up instead of surgery; conversely, very young patients have a higher risk of undergoing surgery.The best cut-off value obtained by the ROC curve method, able to discriminate between subjects who had to be operated or not, was calculated. The ROC curve demonstrates the reliability of our score in discriminating surgical/non-surgical patients with a cut-off >2.5, a sensitivity of 84.3%, and specificity of 81.3%.However, our study has some limitations. Within the surgical kidney group, we had few patients with UPJ-EA. Furthermore, we had fewer cases with available follow-up data in non-surgical kidneys; however, the median of the follow-up of the non-surgical and surgical groups, is substantially overlapping (1.7 and 1.3 years) and represents an adequate period to express clinical judgments on the pathological kidney .Finally, this new radiological score still needs to be applied to a wider different population to be validated.In conclusion, by means of a bivariate and multivariate analysis, we evaluated the predictive role of fMRU findings in the discrimination between surgical and non-surgical patients.Based on our experience we propose a new highly sensitive and specific fMRU score able to identify surgical vs. non-surgical kidneys in patients with UPJO.We believe that this score can help surgeons in patients' management, however it needs to be clinically validated in a large cohort of patients. Hopefully, a wider use of this score will further improve its clinical use. Considering that the main goal of pediatric urology is to preserve long term renal function with the least invasive approach, we strongly believe that this tool may be useful in guiding clinical decisions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.MBD and FS wrote the original draft of the paper. AP performed statistical analyses. MCYW, IC, MC, LB, LA, MB, GP, GMG, and GM made contributions. All authors approved the final version of the paper.This work was supported by ministerial funds (MSALRF DEL68/21) as it is part of the project precision medicine in CAKUT.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.