Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress. When serum uric acid (SUA) levels exceed 6.8 mg/dL, the ionized forms of UA form monosodium urate (MSU). When the MSU concentration exceeds the solubility, it forms MSU crystals , which iUA is a potent antioxidant and can scavenge superoxide, hydroxyl radicals, and singlet oxygen. It can neutralize more than 50% of free radicals in human blood . Thus, aWhile the pathophysiological mechanisms of hyperuricemia are different from RHU, both conditions lead to elevated urate levels in proximal tubules. Since the filtered urate load, calculated as [SUA level] × [GFR], is increased in hyperuricemia patients, gout is often accompanied by interstitial nephritis. RHU increases the urate concentration in the proximal tubules due to impaired tubular reabsorption, and give rise to a similar situation. In fact, it has been reported that there is a J-shaped relationship between the level of SUA and the incidence of CKD ,11.This review discusses the epidemiology and genetic background of hyper- and hypo-uricemia and complications such as urolithiasis, renal tubular damage, and kidney in patients with dysuricemia including hyperuricemia, gout and hypouricemia. It also discusses the U-shaped association of SUA with impaired kidney function.Hyperuricemia is diagnosed when the concentration of SUA is >7 mg/dL based on the guidelines of the Japanese Society of Gout, Uric Acid, and Nucleic Acids. Hyperuricemia occurs in 20% of men and 5% of women in the entire Japanese population. A total of 1.25 million Japanese suffer from gout . There iHypouricemia is diagnosed when the SUA level is <2 mg/dL . HypouriBeing attributable to either increased production or decreased urinary excretion, hyperuricemia and gout are categorized as the renal overload type  and the renal underexcretion type. Several genes are reported to be associated with gout, such as ABCG2, NIPAL1, FAM35A, and ALDH1B and 2 . The devHypouricemia is attributable to the genetic impairment of UA production or reabsorption. The impairment of production is most frequently caused by mutations in xanthine oxidase (xanthinuria). Some 90% of the filtrated UA at the glomerulus is reabsorbed through UATs. Uric acid transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are localized at the apical site of the proximal tubules and at their luminal site, respectively, and play an important role in UA excretion. The impairment of URAT1 activity  causes rA typical complication in patients with hyperuricemia and gout is ureteral calculus, which is caused by monosodium urate (MSU) crystals. The prevalence of uric acid stones among urolithiasis varies depending on the population under study. It has been reported to be as low as 8% in the USA, whereas in Israel it has been reported to be 39.5% . The preInterestingly, RHU has been reported to be accompanied by urolithiasis . We repoWe recently reported that the prevalence of urolithiasis in RHU patients (18.2%) was higher than that in gout patients (6.8%) . BecauseGout nephropathy is induced by an increased urinary uric acid excretion, which accumulates in the renal tubules and interstitum  Figure . The filIt is likely that tubular reabsorption impairment in RHU elevates the urate concentration in proximal tubules and causes tubular damage . RHU wasHyperuricemia is often accompanied by chronic kidney disease (CKD), and has been reported to be a risk factor for the progression of CKD. Indeed, a recent meta-analysis reported that 24% of gout patients exhibited CKD beyond stage 3, and that hyperuricemia occurs in advanced CKD, with a prevalence of 64% with stage 3 CKD and 50% in patients with stage 4 or 5 CKD ,39,40. TRHU poses a risk of acute kidney injury. Exercise-induced acute kidney injury (EIAKI) is a major complication of RHU. The prevalence of EIAKI has been reported to be 9.4% in hereditary RHU subjects . It has While hyperuricemia and gout are associated with kidney diseases, hypouricemia is also associated with kidney injury, indicating the U-shaped association between SUA and kidney disease. A U-shaped association between SUA and loss of kidney function has also been reported. Kanda et al.  reportedIt has been reported that there is also a U-shaped relationship between the level of SUA and the incidence of cardiovascular events (CVE) . VerdeccUA infusion into the brachial artery caused impaired vasodilation of the forearm artery in response to acetylcholine in healthy volunteers , suggestkB) signaling [MSU crystals are known to enhance the production of inflammatory cytokines such as IL-1β or IL-18 in primed macrophages through the activation of the NLRP3 inflammasome, leading to local or systemic pro-inflammatory reactions. This causes vascular and kidney diseases. The CANTOS study  demonstrignaling   plays a central role in the formation of UA as well as the superoxide. XOR is composed of xanthine dehydrogenase (XDH) and xanthine oxidase (XO). XO is converted from XDH by post-translational modification and catalyzes two steps of reactions that convert hypoxanthine to xanthine, and then xanthine to UA. These reactions generate superoxide and hydrogen peroxide . The supUA concentration was extremely low (0.1 mg/dL or less) [It is assumed that the extreme reduction of SUA impairs endothelial function. The endothelial function is impaired in patients with RHU harboring homozygous/compound heterozygous mutations of URAT1. Sugihara et al. reported that patients with URAT1 gene mutations and severe hypouricemia (sUA < 0.8 mg/dL) showed a significant decrease in blood flow-dependent vasodilation response (FMD) compared to the other group with hypouricemia (sUA > 0.8 mg/dL) . Patientor less) . Interesor less) ,69. Afteor less) .UA value: 2.1 mg/dL). In the febuxostat and uricase groups, an increase in lipid peroxidation was observed, which may reflect a decrease in the antioxidant capacity of plasma. These results suggest that extremely low levels of SUA could impair vasodilation mediated by endothelium-derived highly polarized factors (EDHF) in the absence of NO. EDHF is formed through classical or non-classical pathways. The classical pathway is activated by hyperpolarization factors released from endothelial cells. They hyperpolarize the plasma membranes of smooth muscle cells, causing a decrease in intracellular Ca2+ and the activation of K+ channels and relaxation. The non-classical pathway is activated by epoxyeicosatrienoic acid (EET) derived from endothelial cells, which activates K+ channels or transporters of smooth muscle cells to induce the hyperpolarization of the smooth muscle cells, in addition to their relaxation. Although SUA inhibits epoxy hydrolase, epoxide hydrolase inactivates EET under extremely low SUA conditions, resulting in the inhibition of heat-induced endothelium-dependent vasodilation [Transient hypouricemia might impair endothelial function in the absence of NO. Becker et al. examined whether short-term hypouricemia induces the impairment of endothelial function under the condition of inhibiting NO production . Seventedilation   such as XOR inhibitors might be beneficial. The effects of XOR inhibitors on eGFR were examined ,78,79,802+ antagonist is recommended. For its protection, the avoidance of anaerobic exercise is also recommended. The oxidative stress together with the precipitation of urate in tubules might play a pivotal role with regard to EIAKI in RHU; thus, treatment with an antioxidant XOR inhibitor could be beneficial. It has been reported that an XOR inhibitor, allopurinol, may be useful for protection from EIAKI in RHU patients [A treatment to protect kidney function in hypouricemia remains to be elucidated. Because of the pathophysiology of EIAKI in RHU, sufficient hydration, together with a vasodilator or dopamine as a Capatients . The ratIn conclusion, both hyperuricemia and hypouricemia cause urolithiasis, renal tubular damage, and kidney injury. With regard to the cardiovascular events, there is likely a U-shaped association of SUA with the loss of kidney function. Its underlying mechanisms could be attributable to two types of impaired endothelial function. The first is the endothelial dysfunction induced by intracellular UA, MSU and XOR under hyperuricemic conditions, while the other involves endothelial dysfunction induced by the depletion of NO and EDHF under hypouricemic conditions. To treat kidney disease in hyperuricemic patients, ULAs are recommended. To treat kidney disease in hypouricemic patients, XOR inhibitors might be useful.


The etiology of Bell’s palsy (BP) is currently unknown, and the findings from previous studies examining the association between seasonal or meteorological factors and BP have been inconsistent. This research aims to clarify this relationship by analyzing a larger dataset and employing appropriate statistical methods. Data from 5387 patients with BP treated at Zhejiang Provincial Hospital of Traditional Chinese Medicine in Hangzhou, Zhejiang Province, from May 1, 2018, to June 30, 2023, was gathered. We assessed the temporal distribution of meteorological factors and the incidence of BP across seasons and months. A distributed lag non-linear model was used to further investigate the lagged and overall effects of temperature and air pressure on the onset of BP. The temporal distribution of BP incidence revealed the highest average number of cases occurring in December and the lowest in June. A correlation existed between BP episodes and temperature or air pressure. The model revealed a higher relative risk during periods of low temperature and high air pressure, characterized by a time lag effect. This correlation was notably more pronounced in female patients and individuals in the young and middle-aged groups. Our findings suggest that exposure to low temperatures and high air pressure constitute risk factors for BP development. Viral infections, in particular, have garnered substantial attention as a significant causative factor, supported by pathological evidence3. Meteorological factors such as temperature have been found to influence the processes of multiple viral invasions and the body's autoimmune responses5, implying that meteorological conditions may indirectly impact the development of BP. In our retrospective study of hospitalized patients, over 33.9% exhibited clear signs of wind or cold exposure to the face preceding the onset of the disease. Collectively, these findings lend support to the potential correlation between BP and meteorological factors.Bell's palsy (BP), recognized as idiopathic peripheral facial paralysis, represents the most prevalent form of facial nerve paralysis. Despite extensive research, the complete etiology and pathogenesis of BP remain elusive. Potential pathogenesis includes factors related to the anatomy of the facial nerve, viral infections, local ischemia and inflammation, exposure to cold, and autoimmune responses9, which may be more pronounced in men10. However, some studies have reported that the peak incidence does not necessarily coincide with the coldest months of the year13 or that BP does not exhibit a clear correlation with seasonal variations or specific months15. These discrepancies may be attributed to regional variations in meteorological factors across different seasons. Therefore, it is imperative to delve further into the relationship between temperature, atmospheric pressure, atmospheric pollutants and other meteorological factors with BP. Some studies found associations between BP incidence and low temperatures coupled with low relative humidity11, high wind speeds16, sustained high atmospheric pressure or rapid temperature fluctuations17, wind chill factor8, or elevated concentrations of nitrogen dioxide in atmospheric pollutants18. Nevertheless, the inclusion of other common meteorological factors in these studies did not yield evidence of the relevance, resulting in divergent conclusions. This discrepancy may be attributed to limitations in previous research, including a limited number of cases, the absence of more precise subgroup analyses, and statistical methods that do not account for lagged effects of meteorological factors. These emphasize the necessity of further research in this field.Numerous epidemiological studies have investigated the association between the onset of BP and seasonal or meteorological factors in recent years, but the findings have exhibited inconsistencies. The majority of studies indicate a higher incidence of BP in colder environments or during winterTo address these uncertainties and provide more conclusive insights, we conducted a retrospective study that rigorously examined temporal and geographical parameters associated with each included BP case. Cases with unclear onset times, uncertain geographic locations, or incomplete data were excluded from our analysis. In addition, we employed a distributed lag non-linear model (DLNM) with cross-basis computations to thoroughly investigate the relationship between essential meteorological factors and the onset of BP.The data for the BP patient study were retrieved from the electronic medical records of Zhejiang Provincial Hospital of Traditional Chinese Medicine, strategically situated in Hangzhou City , the capital city of Zhejiang Province, renowned for its four distinctive seasons. This dataset encompassed individuals diagnosed with BP who sought medical evaluation across various clinical settings, including the emergency room, outpatient clinics and inpatient wards. Data collection spanned from May 1, 2018, to June 30, 2023, exclusively including cases in which BP diagnoses had been conclusively established by clinicians.To ensure data precision, a stringent data curation process was implemented. Firstly, we excluded cases involving individuals with the same illness but follow-up visits. In instances where patients transitioned from outpatient to inpatient care, preference was granted to inpatient data due to its comprehensive nature, with the concurrent exclusion of redundant outpatient records. Moreover, recognizing that some patients did not promptly seek medical attention or referral to our hospital following the onset of illness, resulting in discordance between onset time and visit time, a meticulous assessment of BP onset time was carried out on a case-by-case basis. Cases marked by uncertain or unknown onset times were judiciously omitted from the dataset. Additionally, we verified the location of outpatients' health insurance and the contact addresses of inpatients, subsequently excluding cases with onset outside the Hangzhou area or marked by incomplete information. In total, our rigorous data curation process yielded a dataset comprising 5387 BP cases, further categorized into 1763 inpatients and 3624 outpatients.Our study received the ethical nod from the Ethics Committee of Zhejiang Provincial Hospital of Traditional Chinese Medicine . The study was conducted in accordance with the Declaration of Helsinki and followed relevant guidelines and regulations. Due to the retrospective nature of the study and the de-identification and anonymization of patient data within the cohort, informed consent was waived by the Ethics Committee of Zhejiang Provincial Hospital of Traditional Chinese Medicine.In our analysis of specific meteorological variables, we meticulously selected factors with a high likelihood of demonstrating a robust correlation with the onset of BP. This selection was guided by clinical expertise and previous research findings. Simultaneously, we considered the accessibility of meteorological data to the general populace in their daily lives, emphasizing its practical significance in guiding strategies for disease prevention and post-incidence protection of the facial nerve. Based on these considerations, we ultimately chose to investigate the correlation between the four common meteorological factors: temperature (°C), air pressure (hPa), wind speed (m/s), and humidity (%), and the incidence of BP. The meteorological parameters investigated in this study were obtained from publicly accessible data provided by the China Meteorological Administration for the Hangzhou region. The aggregated data represent the mean derived from eight daily measurements taken at 2:00 AM, 5:00 AM, 8:00 AM, 11:00 AM, 2:00 PM, 5:00 PM, 8:00 PM, and 11:00 PM.Seasons were categorized based on traditional Chinese festivals. In accordance with the traditional Chinese 24 solar terms, spring initiates with the 'Beginning of Spring' typically between February 3rd and 5th. Summer commences with the ‘Beginning of Summer,’ which generally falls between May 5th and 7th. Autumn initiates with the 'Beginning of Autumn,' commonly around August 7th to 9th, and winter starts with the 'Beginning of Winter,' typically between November 7th and 8th.20. We incorporated significant variables into this model by analyzing the time-series distribution of meteorological parameters, the number of BP cases, and the results of the Spearman correlation. The final model was constructed as follows:Yt represents the number of BP cases with daily onset in the city at time t, and cb denotes the cross-basis function of each meteorological factor describing the exposure-lag-response relationship. We defined 4 degrees of freedom (dfs) for the natural cubic spline curves of temperature and air pressure in the exposure dimension and 6 degrees of freedom (dfs) for the lag effect. Referring to the results of similar studies, we established the lag range to 0–21 days to encompass potential delayed effects adequately. To remove the long-term trend associated with BP, we employed a natural cubic spline function with 7 dfs/year. The day of the week is represented by Week, while the season of the year was represented by Season, thereby controlling for the effects of day of the week and season. The median value of each exposure variable served as the reference for calculating relative risk.We employed the Spearman correlation to examine the relationship between the incidence of BP and meteorological factors. As meteorological effects on health outcomes are frequently reported to be non-linear and delayed, we modelled the meteorological-BP association using DLNM, which is often applied in studies where disease is associated with meteorological factorsp-values were two-sided, with p < 0.05 considered statistically significant.In addition, we performed subgroup analyses to identify potentially susceptible subgroups and to evaluate whether the association between environment and BP varied by age and sex. We conducted sensitivity analyses to assess the robustness of our findings. We adjusted the delay period from 21 to 14 or 28 days, and the results remained consistent Fig. . Data weAfter meticulous verification and exclusion, our study included a total of 5387 cases of BP in the Hangzhou region. Table To comprehend the dynamics of meteorological factors and the incidence of BP, we illustrated the time-series distribution of monthly mean meteorological parameters alongside monthly mean number of BP cases throughout the study duration Fig. . The numFigure Given the influence of various factors on seasonal and monthly variations, Fig. To gain deeper insights into the lag effect of meteorological factors, we incorporated temperature and air pressure into the DLNM. The results are visually depicted through 3D plots in Fig. p = 0.609).In addition, the dataset consisting of records from 1763 hospitalized patients documented the precise onset of their illnesses, including the triggers of BP. The triggering factors for the onset of illness, in descending order, include exposure of the face to windy or cold conditions, fatigue, and nocturnal sleep deprivation. The prevalence of BP associated with exposure to cold or windy conditions during the spring to winter seasons stood at 30.89, 35.93, 33.51, and 35.80% of the overall count of hospitalizations, respectively, which was not a significant difference (3. This study aspires to elucidate the true relationship between meteorological factors and the incidence of BP. Such insights hold significant implications for the prevention of BP preceding its onset, the preservation of facial nerve function following its occurrence to enhance treatment efficacy or reduce sequelae.The etiology and pathogenesis of BP remain unclear. Although BP is generally considered a self-limiting condition, up to 30% of afflicted patients may not achieve full recovery or may experience severe sequelae adversely impacting their life11. Nevertheless, we acknowledge that categorizing the disease by seasons possesses certain limitations due to the limited differentiation of meteorological factors between the seasons. Our study results suggest that a monthly breakdown provides a more nuanced representation of the interplay between meteorological factors and disease incidence. Although BP cases in our study exhibited a higher incidence in autumn, it is noteworthy that this elevated incidence coincided with months characterized by lower temperatures, thus supporting the hypothesis that low temperatures may constitute a risk factor.The investigation of the seasonal correlation of BP onset has been extensively explored in the existing literature. In our study, we observed that BP outbreaks were most prevalent during the autumn season, exhibiting a higher occurrence during autumn and winter compared to spring and summer. This is consistent with the outcomes of a Korean study, which concluded that a significant temperature drop during autumn had a more pronounced impact on BP outbreaks than cold temperatures during winter21. Autoimmunity is also considered to be associated with the development of BP2. Those indirect evidences support that the utilization of indoor air-conditioning in summer may heighten the risk of developing the disease. While DLNM model demonstrated high temperature as a risk factor for BP onset at lag = 0, the univariate analysis of temperature did not yield statistical significance regarding its overall effect on onset. This observation needs further investigation for validation.In our study, the occurrence of BP during the summer months was not infrequent, and the number of BP triggered by exposure to cold or windy conditions in the summer ranked second only to that in winter. We posit that, despite the prevailing high temperatures during the summer season, the common use of indoor air-conditioning in Hangzhou creates a notable temperature differential between indoor and outdoor environments. It has been proposed that prolonged exposure to air-conditioning during the summer months may lead to reduced levels of vitamin D and melatonin, potentially impacting immune system function10. Furthermore, combined with the outcomes derived from our established DLNM, we identified low temperature and high air pressure as risk factors for the development of BP, with a certain time lag. A parallel study has previously indicated that mean temperature may influence the course of BP, while mean air pressure is correlated with the severity of clinical symptoms associated with BP16. Additionally, another investigation suggested that prolonged periods of high air pressure may elevate the risk of BP17. Nonetheless, the results of other studies do not uniformly support this conclusion18.Although this study is not the first to investigate the correlation between meteorological factors and the onset of BP, it stands out for the inclusion of a substantial number of cases and its focused examination within a geographically confined and small area. These factors contribute to the generation of more authentic evidence for the examination of this issue. Through a comparative analysis of temperature, air pressure, and case distribution, we observed that the incidence of BP exhibited a similar pattern to the mean air pressure, while demonstrating an inversely proportional relationship with the mean temperature. This finding aligns with the results of two prior studies1. It may induce peripheral vasoconstriction, potentially resulting in microvascular ischemia of the facial nerve and subsequent morbidity, with a more pronounced effect in diabetic patients17. Furthermore, some studies have proposed that the association between BP and hypothermic seasons may be linked to heightened activation of the HSV-1 virus22. Regarding the influence of high air pressure, it has been postulated that an increase in atmospheric pressure may elevate middle ear pressure, potentially amplifying the risk of morbidity17. High air pressure has demonstrated an impact on certain vascular diseases24, and it may also contribute to the pathogenesis of BP by influencing vasoconstriction processes. Subgroup analyses unveiled that females and young and middle-aged patients with BP, exhibited heightened sensitivity to temperature and air pressure. Similar investigations into various diseases and meteorological factors have indicated that women and the elderly tend to be more responsive to environmental changes27. In the case of the elderly, we hypothesize that their greater propensity to remain indoors and reduce outdoor activities during extreme weather conditions contributes to their decreased risk, as they have fewer hours of exposure to weather extremes. However, subgroup analyses may be limited by reduced case numbers, necessitating further evidence to substantiate these findings.Drawing upon theories and research findings, we believe that low temperature and high air pressure constitute influential factors in BP. Low temperature can manifest in various scenarios, including prolonged cold exposure during winter, significant temperature drops in autumn, or substantial temperature differentials between indoor and outdoor environments in summer. Some scholars share a similar view and suggest that cold stimulation can lead to the change of secretory factors from fat cells increasing the risk of BP, and it is also believed that low temperature tends to change the microenvironment of facial microvascular neuron28, potentially linked to the known association of the novel coronavirus with facial nerve involvement29. Some reports indicate that COVID-19 vaccination has increased the incidence of BP30. Moreover, during the COVID-19 pandemic, patients experienced heightened negative emotions31, along with specific treatment limitations that were unfavorable for BP recovery. Future research should delve deeper into the specific relationship between COVID-19 and BP.While this study encompassed a dataset of 5387 BP cases collected over a 5-year period, it has some potential limitations. The entirety of BP patient data was sourced from a single medical center, and due to the exclusion of cases with incomplete data, it may not fully represent the complete BP incidence in Hangzhou. Additionally, due to the study period coinciding with the COVID-19 pandemic, the incidence of BP was affected by the pandemicThis study suggests that low temperature and high air pressure serve as risk factors for the onset of BP with a certain time lag. Implementing preventive measures to mitigate the risks associated with exposure to low temperatures and high-pressure environments has been empirically validated as advantageous. It is imperative for individuals to remain vigilant regarding daily weather fluctuations, both in the interest of averting the onset of BP and for safeguarding the facial nerve following its occurrence. Protective measures may encompass reducing outdoor exposure and limiting the duration of outdoor activities during inclement weather, alongside ensuring adequate warmth for the head and face. Patients with BP are also advised to exercise discretion regarding engagement in high-pressure environmental activities, such as air travel or diving, when circumstances permit. Furthermore, we contend that exploring the correlation between specific months and the onset of BP offers a more dynamic perspective and better reflects real-world outcomes compared to analyzing solely based on seasonal correlations.Supplementary Figure 1.


Nighttime blood pressure (BP) and an abnormal nocturnal BP dipping profile are important cardiovascular risk factors in patients with hypertension. This post hoc analysis investigated the effects of sacubitril/valsartan on 24‐hour BP in patients with mild‐to‐moderate hypertension and in patient subgroups based on nocturnal BP dipping status.P<0.01 and P<0.001). Between‐group differences in the BP control rate were greatest in the nondipper subgroup .Data from a randomized clinical trial comparing the BP‐lowering effects of 8 weeks of treatment with sacubitril/valsartan (200 or 400 mg/d) and olmesartan (20 mg/d) in Japanese patients with mild‐to‐moderate hypertension were analyzed. The primary end point was change in 24‐hour, daytime, and nighttime BP in patient subgroups based on nocturnal BP dipping status . Six hundred thirty‐two patients with baseline and follow‐up ambulatory BP data were included. Both sacubitril/valsartan dosages reduced 24‐hour, daytime, and nighttime systolic BP, and 24‐hour and daytime diastolic BP, to a significantly greater extent than olmesartan in the dipper and nondipper groups. However, between‐group differences in nighttime systolic BP were more significant in the nondipper group (difference [95% CI] for sacubitril/valsartan 200 and 400 mg/d versus olmesartan 20 mg/d: –4.6  and −6.8  mm Hg, respectively; This analysis highlights the value of sacubitril/valsartan therapy in patients with a nondipper profile of nocturnal BP and confirms this agent's potent 24‐hour BP‐lowering effect in Japanese populations with hypertension.https://www.clinicaltrials.gov; Unique identifier: NCT01599104.URL:  DBPdiastolic blood pressureSBPsystolic blood pressureThese are the first data on the differential 24‐hour blood pressure (BP)‐lowering effects of sacubitril/valsartan in patient subgroups based on the nocturnal BP dipping profile.Nondipper patients showed the most significant decreases in ambulatory BP  during sacubitril/valsartan versus olmesartan treatment.Given the contribution of nighttime BP and an abnormal nocturnal BP dipper pattern to cardiovascular risk, treatment with sacubitril/valsartan impacts multiple mechanisms that could improve cardiovascular outcomes in patients with hypertension.A substantial body of evidence shows that nocturnal hypertension is a significant risk factor for developing cardiovascular disease and the occurrence of cardiovascular disease events.Despite this, management of nocturnal hypertension remains an unmet medical need, because most current antihypertensive medication is given once daily in the morning. Unfortunately, this leaves a therapeutic blind spot in the early morning hours, where drug levels (and BP‐lowering effects) are at their lowest point before morning drug dosing. One approach to overcoming these issues is bedtime dosing of antihypertensive therapy.One of these newer agents is the angiotensin receptor neprilysin inhibitor sacubitril/valsartan, which has recently been approved in Japan to treat hypertension.Therefore, this post hoc analysis of randomized clinical trial data evaluated the antihypertensive effects of sacubitril/valsartan compared with olmesartan on 24‐hour, daytime, and nighttime ambulatory BP in patients with mild‐to‐moderate hypertension and in patient subgroups (phenotypes) based on nocturnal BP dipping status.The data that support the findings of this study are available from Novartis AG upon reasonable request.ICH Harmonized Tripartite Guidelines for Good Clinical Practice  and the ethical principles laid down in the Declaration of Helsinki. All patients provided written informed consent before initiation of all study procedures.This post hoc analysis used data from a multicenter, randomized, double‐blind, parallel‐group study comparing the BP‐lowering effects of sacubitril/valsartan and olmesartan in Japanese patients with mild‐to‐moderate essential hypertension (NCT01599104), conducted from June 2012 to April 2013.pm–6 am) ambulatory BP fall of ≥10% versus daytime (6 am–10 pm) ambulatory BPDipper: mean nighttime . Secondary end points included the following: change from baseline to 8 weeks in 24‐hour BP; change from baseline to 8 weeks in levels of NT‐proBNP ; changes from baseline to 8 weeks in 24‐hour, daytime, and nighttime BP in patient subgroups based on baseline characteristics; rates of BP control at 8 weeks, where BP control was defined as 24‐hour SBP <130 mm Hg and 24‐hour diastolic BP (DBP) <80 mm Hg; safety in patient subgroups based on nocturnal BP dipping status; and between‐group differences in change from baseline to 8 weeks in the daytime and nighttime SBP.Ambulatory BP measurement over 24 hours was conducted at 2 time points in a subset of participants in the original study. The first 24‐hour ambulatory BP measurement was performed after a patient had qualified for randomization based on office BP measurement but before administering the first dose of double‐blind study medication. The second ambulatory BP measurement was performed at week 8. Patients who withdrew from the study before week 8 did not need to have ambulatory BP measurements performed. At each 24‐hour ambulatory BP assessment period, the measurement device was attached to the nondominant arm, and both BP and heart rate were measured at study‐specified intervals. Readings were downloaded from device memory and then analyzed by a central laboratory.t test for continuous variables and a χ2 test for categorical variables. In addition, summaries with estimates and corresponding 95% CIs are presented, as appropriate. BP and laboratory baseline were defined as the measurements taken at the randomization visit. The follow‐up measurement of BP was obtained at 8 weeks.The analysis population included patients with ambulatory BP data at baseline and all follow‐up visits. Demographics and baseline characteristics are presented using descriptive statistics, including mean±standard deviation, minimum, first quartile, median, third quartile, and maximum values for continuous variables, and frequencies and percentages for categorical variables. Between‐group differences were determined using an independent ANCOVA was used to assess treatment effects on changes from baseline to 8 weeks in 24‐hour ambulatory BP in patient subgroups based on nocturnal BP dipping status. A repeated measures ANCOVA model with treatment, postdosing hours (time elapsed since drug administration), and treatment by postdosing hour interaction as fixed‐effect factors, and mean 24‐hour ambulatory SBP/DBP at baseline and 8 weeks as repeated measures was used. In addition, between‐group differences in mean change in 24‐hour ambulatory BP from baseline to 8 weeks with 95% CIs were determined.t test , 632 patients  had ambulatory BP data at baseline and follow‐up and were included in this analysis . TreatmeChanges in 24‐hour, daytime, and nighttime ambulatory SBP and DBP from baseline to week 8 were more significant with both dosages of sacubitril/valsartan compared with olmesartan Figure . The proP=0.022 and P<0.001, respectively) and nighttime DBP  to a significantly greater extent in nondippers compared with dippers , both overall and in patient subgroups based on dipper profile of nocturnal BP . In addition, BP control rates at week 8 were higher in both sacubitril/valsartan groups than with olmesartan in the nondipper subgroup, whereas differences between sacubitril/valsartan and olmesartan were less marked in the dipper subgroup , although reductions in nighttime BP were slightly greater than the other 2 measures. This indicates consistent BP‐lowering effects throughout 24 hours with good antihypertensive coverage overnight and in the early morning predosing period.In the current analysis, reductions from baseline in 24‐hour, daytime, and nighttime ambulatory SBP over 8 weeks of treatment with sacubitril/valsartan exceeded 12 mm Hg, and DBP reductions were all above 7 mm Hg Figure , which mOverall, the number of responders to treatment with sacubitril/valsartan was significantly higher than the number of responders to treatment with olmesartan, indicating the superior 24‐hour BP‐lowering efficacy of sacubitril/valsartan. Although a small proportion of patients had a change in 24‐hour BP of <5 mm Hg, most had reductions of ≥5 mm Hg, and some had a substantial response, with a ≥20 mm Hg reduction in 24‐hour BP during treatment Figure . It woulThe novel finding of this study is the differences in the BP‐lowering effects of sacubitril/valsartan between patients with a dipper versus nondipper profile of nighttime BP Figures  and 3. AThis study was conducted in Japanese patients, and there is evidence to suggest that angiotensin receptor neprilysin inhibitor drugs may be ideally suited for the treatment of hypertension in Asian populations.Although the data used were generated in a randomized controlled clinical trial, the post hoc analysis was not prespecified. The post hoc nature of this analysis means that potential sources of bias cannot be excluded. Therefore, the findings require confirmation in a prospective clinical study. In addition, only a single midrange dose of olmesartan was used as the comparator, and therefore both agents studied were not investigated across their full dosage range. Another limitation of the study was the single ethnicity population (Japanese), limiting the external generalizability of the findings.Sacubitril/valsartan has recently been approved in Japan and China for the treatment of hypertension. This analysis provides the first data on the differential effects of treatment with sacubitril/valsartan on ambulatory BP in patient subgroups based on the nocturnal BP dipping status. It also confirms the potent 24‐hour BP‐lowering effects of sacubitril/valsartan in Asian populations with hypertension. Strict reduction in 24‐hour BP and maintaining the dipper pattern of nocturnal BP are critical components of strategies designed to achieve perfect 24‐hour BP control, which is essential to attenuate or prevent hypertension‐mediated target organ damage and associated conditions.This study was funded by Novartis.Dr Kario has received speaker's honoraria and consulting fees from Novartis Pharmaceuticals and Daiichi Sankyo, and a research grant from Daiichi Sankyo. In addition, Dr Rakugi served as the external medical expert for this study and has received consulting fees from Novartis Pharmaceuticals. D. Yarimizu, Dr Morita, S. Eguchi, and Dr Iekushi are employees of Novartis Pharma K.K., Tokyo, Japan.Data S1Tables S1–S3Figures S1–S5Click here for additional data file.


These findings suggest that even serum uric acid concentrations over 5 mg/dL may affect the prevalence of hypertension-related complications among patients with very high cardiovascular risk.Hypertension remains a global threat to public health, affecting the worldwide population. It is one of the most common risk factors for cardiovascular disease. Today’s treatments focus on creating a hypotensive effect. However, there is a constant search for additional factors to reduce the potential of developing hypertension complications. These factors may act as a parallel treatment target with a beneficial effect in specific populations. Some studies suggest that uric acid may be considered such a factor. This study investigated the potential effect of uric acid concentrations over 5 mg/dL on the incidence of hypertension complications among patients with very high cardiovascular risk. A total of 705 patients with hypertension and very high cardiovascular risk were selected and included in the analysis. The patients were divided and compared according to serum uric acid levels. The study showed a higher occurrence of heart failure (OR = 1.7898; CI: 1.2738–2.5147;  Hypertension is a global problem affecting nearly 1.13 billion people worldwide, and it is estimated that by the year 2025, this number will reach over 1.56 billion. The World Health Organization data show that it is linked with 13% of deaths globally [Even though prevention and treatment are continuously developing, hypertension remains the primary risk factor for cardiovascular diseases. Its complications that lead to death are still significant public health and clinical challenges .Furthermore, this condition is a significant cause of premature death worldwide, mainly due to coronary artery disease (CAD) development. Nowadays, focusing on prevention and antihypertensive treatment is essential for dealing with hypertension. These actions were recently enhanced by tightening the target blood pressure (BP) for hypertensive patients and by intensifying the pharmacological treatments using initial one-pill combined therapies . HoweverUric acid (UA), which is the end-product of purine mononucleotide metabolism, has been the target of studies for many years. Purines can be synthesized endogenously or delivered from dietary sources. UA homeostasis is regulated by the balance between the rate of UA generation (determined by purine catabolism), renal excretion, and intestinal secretion. Balance disruption leads to an increase in serum uric acid (sUA) concentration, defined as hyperuricemia, which may consequently result in gout ,6.Many studies suggest that a higher concentration of sUA decreases hypertension treatment effectiveness and decreases cardiovascular complications and total number of deaths. However, despite several studies, the treatment of hyperuricemia remains unclear and inaccurate. Whether the treatment of asymptomatic hyperuricemia is cost-effective and whether the benefits of it prevail over the risks are still a matter of debate. A similar problem applies to the cut-off point for starting the treatment, the choice of the drug, its dosage, and the target value ,7,8.The cut-off value for hyperuricemia recognition is 6 mg/dL in men and 7 mg/dL in women. However, some sources show that lower values may be beneficial for a specific group of patients . AsymptoThe aim of our study was to assess the effect of hyperuricemia (UA > 5 mg/dL) on the prevalence of hypertension complications among patients with very high cardiovascular risk.The analysis was conducted from 27 December 2007 to 30 May 2016 as a case–control study. Data were collected by the Invasive Cardiology Department of the Medical University of Bialystok. The sample size consisted of 3291 patients with chronic coronary disease (CCD) with a Canadian Cardiovascular Society (CCS) Angina Score from I to III, and from this group, 705 patients were selected. The calculated sample size with a 5% margin of error and confidence level of 95% was equal to 316 . Inclusion criteria were admission for further invasive diagnostic process or invasive treatment, hypertension and echocardiography performed during hospitalization. Exclusion criteria were acute myocardial infarction, unstable angina, tumor lysis syndrome or in induction phase of chemotherapy. Our study population was divided into two subgroups—(I) uric acid in serum > 5 mg/dL and (II) uric acid in serum ≤ 5 mg/dL—according to the recommendations of Polish experts on treating asymptomatic hyperuricemia . Laboratt-test. The Mann–Whitney U-test was performed to compare nonparametric continuous variables and to compare categorical variables; the Odds Ratio Altman calculation was used. The statistical analysis was performed using Statistica 10. p-value ≤ 0.05 was considered significant.Continuous variables are expressed as median ± standard deviation. Categorical variables are expressed as percentages (number of patients). All parameters were tested for a normal distribution using the Kolmogorov–Smirnov test. To compare parametric continuous variables, we used the student’s 2, and over 65% had lipid disorders. Moreover, a history of myocardial infarction and heart failure occurred in almost half of the population . Other frequent complaints were diabetes mellitus (35.03%), chronic kidney disease (13.82%), atrial fibrillation (8.83%), and chronic obstructive pulmonary disease (4.26%).The median age of the patients was equal to 67 ± 9.85 y.o. Males constituted 65.81% of the study population. Our group was characterized by typical coronary artery disease comorbidities . Over 80p < 0.001), BMI > 25 kg/m2 , chronic kidney disease  and chronic obstructive pulmonary disease  were more frequently connected with uric acid > 5 mg/dL (Most of our study population (71.51%) had serum uric acid concentrations above 5 mg/dL. In 192 cases (27.35%), the level was over 7 mg/dL, and only 18 patients (2.56%) demonstrated high, over 10 mg/dL, levels in the serum. In our study, we noticed that male gender  and atrial fibrillation  occurred more often in patients with uric acid in serum > 5 mg/dL (p = 0.551), myocardial infarction history , carotid artery stenosis , limb ischemia  and stroke history  were not statistically significant (p = 0.028), without an effect on the number of affected vessels   . Therefop = 0.947), systolic blood pressure , diastolic blood pressure  and blood glucose level  between subject with sUA concentrations ≤ 5 and >5. Furthermore, the patients with sUA levels over 5 had higher heart rates and more atherogenic lipid profiles .However, we found no difference in age , and larger diameters for the left atrium , ascending aorta and both left and right ventricles (p = 0.061) was noticeable . It is an especially important implication because the HR over 80 beats/min was included in factors influencing cardiovascular risk in patients with hypertension by the European Society of Cardiology and the European Society of Hypertension . Also, tIn our study, patients with elevated sUA concentrations had an increased prevalence of atrial fibrillation (AF). Most atrial fibrillation cases occurred in the group with sUA levels > 5 mg/dL (88.70%). Moreover, the sUA level was significantly associated with AF in the general Japanese population . HyperurAnalyzing the results, we discovered that patients with sUA concentrations above 5 mg/dL are significantly more likely to have chronic kidney disease. The relationship between asymptomatic hyperuricemia and CKD is confirmed by other researchers ,23. MoreMoreover, our study shows that uric acid level was not related to the development of limb ischemia, carotid artery stenosis, or stroke. Numerous reports have shown that peripheral arterial disease (PAD) is found more often in patients with a higher concentration of uric acid in the serum ,28. LangAs mentioned earlier, sUA concentration is a risk factor for cardiovascular diseases, including hypertension ,7,8. So The relationship between lipid profile and serum uric acid remains unclear; a similar study concerning patients with very high risk found no correlation between uric acid and triglycerides . HoweverA novel approach of using Sodium-Glucose Cotransporter 2 (SGLT-2) inhibitors to lower uric acid was suggested, and this effect was proposed as one of the possible components of SGLT-2 inhibitors’ pleiotropic effects on cardiovascular diseases by anti-inflammatory actions . The SGLOur study shows that even a slight increase in uric acid concentration (even over 5 mg/dL) in patients with hypertension and very high cardiovascular risk further increases the risk of organ complications. Therefore, early hyperuricemia treatment and sUA level monitoring to prevent multiple organ complications among those patients should be considered. Large prospective, double-blind studies designed to assess the effect of decreasing sUA early among hypertensive patients with very high cardiovascular risk should be conducted.The study was performed in a single center, the subjects originate from Eastern Europe and all participants were Caucasian; thus, the results cannot be generalized to other ethnicities.The study analyzed the difference between groups with sUA concentrations ≤ 5 mg/dL and >5 mg/dL, and the possible effect of hyperuricemia treatment on hypertensive patients must be verified by prospective randomized trials.An additional limitation of our study is that the analysis did not take sex into account.The retrospective aspect of the study, based on data acquired from medical documentation does not allow for including the whole initial population due to lack of data regarding sUA concentrations.


Kidney disease is an important comorbidity in people living with HIV(PLWH), and is associated with poor outcomes. However, data on renal function of PLWH are limited in China so far. In this study we assessed the prevalence of kidney disease in patients either on antiretroviral therapy (ART) or not respectively in a single center in China and explored the possible risk factors associated.2, and/or isolated hematuria, proteinuria, microalbuminuria. We calculated the prevalence of kidney disease and used logistic regression to assess its associated risk factors.In the cross-sectional study, we recruited hospitalized adult PLWH. Demographic characteristics, clinical information and laboratory variables were collected. Kidney disease was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, 53 (10.6%) patients with hematuria, 11 (2.2%) patients with proteinuria, and 40 (8.0%) patients with microalbuminuria. 297 (59.3%) patients were receiving ART. The patients on ART had a higher prevalence of renal disease than those had not been administrated with ART . On the multivariate logistic regression analysis among patients not on ART, lower haemoglobin  were significantly associated with kidney disease. While among those on ART, older age , lower haemoglobin  and lower albumin  were significantly associated with kidney disease.A total of 501 adult PLWH were enrolled, 446 (89.0%) males and 55 (11.0%) females. The median age was 39 (IQR 30–50) years old. The prevalence of kidney disease was 19.0%, 22 (4.4%) patients with eGFR < 60 mL/min/1.73 mThe prevalence of kidney disease among hospitalized PLWH in China is high, especially in patients on ART. A larger scale study on Chinese outpatient PLWH should be conducted, so as to precisely assess prevalence of kidney disease in general Chinese PLWH. Ying Cao et al. [Kidney disease is an important comorbidity in people living with HIV (PLWH) and is associated with poor outcomes –4. Lene o et al.  found thPrevious studies indicated that contributing factors to kidney disease in PLWH include older age, hypertension, diabetes mellitus, co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, poor virological control, low CD4 count and nephrotoxic drugs , 11. TenHowever, data on renal function among PLWH are limitedly reported in China. The aim of our study was to assess the prevalence of kidney disease among PLWH in China involving those either on ART or not and to identify its associated risk factors.We conducted a cross-sectional study on PLWH. The patients were all with Chinese nationalities. PLWH above 18 years old who were admitted to Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University from February 2019 to January 2020 were observed consecutively. Exclusion criteria as follows: (1) Pregnant women, participants who were suffering from urinary tract infection, patients who had urinary tract malignancy, renal tuberculosis, kidney stones or other obstructive nephropathy; (2) The patients who had missing data which were required to describe kidney damage.This study was approved by the Ethics Committee of Beijing Ditan Hospital, Capital Medical University. The approval number was Jdlkz 2019-056-02. We obtained informed consent from each participant.Demographic characteristics, clinical information and laboratory variables were collected from electronic medical records, including the following parameters: sex, age, weight, height, comorbidities including hypertension, diabetes mellitus, HBV co-infection, HCV co-infection, Syphilis, or tumor, duration of HIV infection, antiretroviral regimen and duration, plasma HIV viral load, CD4 + T-cell count, serum creatinine, urine protein, urine microalbumin, serum concentration of hemoglobin (Hb), albumin (Alb), uric acid (UA), homocysteine (Hcy), procalcitonin (PCT), C reactive protein (CRP), triglycerides (TG), total cholesterol (CHOL), high density lipoprotein cholesterol (HDLC) and low density lipoprotein cholesterol (LDLC). Body-mass index (BMI) was calculated (kg/m²). All laboratory tests were conducted at Clinical Laboratory Department in Beijing Ditan Hospital, Capital Medical University. Serum creatinine was measured using enzymatic assay. The eGFR was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation .Comorbidities, such as hypertension, diabetes, HBV co-infection and HCV co-infection were collected from “past history” in medical records. HBV/HIV co-infection means PLWH with a positive hepatitis B antigen, with a HBV history. HCV/HIV co-infection means those with a positive hepatitis C antibody, with a HCV history. So it contains both chronic HCV infection and prior exposure to HCV. Syphilis refers to patients who had syphilis in their medical history and were positive for Treponema pallidum particle agglutination (TPPA) test or denied history of syphilis, but both toluidine red unheated serum test (TRUST) and TPPA test were positive.Presence of ≥ + 1 protein or ≥ + 1 occult blood on a spot urine specimen was defined as abnormality on urine dipstick. To minimize the influence of urine sample contamination, patients with abnormal urinalysis were asked to repeat the test. Those with confirmed ≥ + 1 protein or ≥ + 1 occult blood were classified as having proteinuria and haematuria, respectively. Urine microalbumin was measured using immunoturbidimetry with normal reference range < 1.9 mg/dL. Patients who presented with urine microalbumin ≥ 1.9 mg/dL for twice consecutively were classified as having microalbuminuria.2, hematuria, proteinuria, or microalbuminuria.Patients with at least one of the following disorders were considered to have kidney disease: eGFR < 60 mL/min/1.73 mAll analyses were performed using Statistical Package for Social Sciences (SPSS) 20.0 software . We conducted One-Sample Kolmogorov-Smirnov test for homogeneity of quantitative data. We presented data with normal distribution as mean ± standard deviation (SD), including BMI, Alb and LDLC. Data without a normal distribution was presented as median (interquartile range), including age, duration of HIV, antiretroviral duration, plasma HIV viral load, CD4 T-cell count, serum creatinine, Hb, UA, Hcy, PCT, CRP, TG, CHOL and HDLC. Categorical variables were presented as frequency and percentage. Chi-squared test was used to compare prevalence of kidney disease in patients on ART and those not on ART. Univariate and multivariate logistic regression analyses were carried out to estimate associations between potential risk factors and the development of kidney disease. A two-tailed P values < 0.05 were considered statistically significant.2 had missing data for urine test, leading to impossibility to identify whether they had kidney disease. Finally, 501 (88.99%) Chinese adult PLWH were enrolled , 16 (3.2%), and 139 (27.7%) patients, respectively. 40 (8%), 39 (7.8%), and 37 (7.4%) patients had hypertension, diabetes, and tumor, respectively. Median duration of HIV was 8 (IQR 0–57.5) months.There were 446 (89.0%) males and 55 (11.0%) females. Median age was 39 (IQR 30–50) years old, and the youngest patient was 19 years old, while the oldest one was 83 years old. BMI was 21.65 ± 3.57 kg/mThe longest duration of HIV was 276 months. 153 (30.5%) patients were newly diagnosed with HIV infection (diagnosed within 1 month). 297 (59.3%) patients were receiving antiretroviral therapy, of whom 239 (47.7%) patients were receiving TDF-containing regimen. The majority of these patients  were prescribed ART with a combination of TDF, lamivudine (3TC), and efavirenz (EFV). 65(13.0%) patients were receiving protease inhibitors (PIs)-containing regimen. 64(12.8%) patients were prescribed with lopinavir/ritonavir and one patient with boosted darunavir. None of the patients were prescribed with atazanavir. 46(9.2%) patients were administered with TDF in combination with PIs. In the patients on ART, median duration of ART was 12 (IQR 2–47) months. The longest duration of ART was 216 months. 161 (54.2%) patients had HIV viral load < 20 copies/mL or undetectable. Median CD4 + T cell count was 215 (IQR 66–458) cells/µL, with 143 (48.1%) patients presenting with a CD4 + T cell count < 200 cells/µL. More information is available in Table 2, 53 (10.6%) patients had hematuria, 11 (2.2%) patients had proteinuria, and 40 (8.0%) patients had microalbuminuria. Some patients had two or more disorders simultaneously, so the total number is not equal to 95. The patients on ART had a higher prevalence of renal disease than those not on ART.Of the total study population, 95 patients had kidney disease. The prevalence of kidney disease was 19.0%. 22 (4.4%) patients had eGFR < 60 mL/min/1.73 mP = 0.013) were significantly associated with kidney disease.Table P = 0.032), lower haemoglobin  and lower albumin were significantly associated with kidney disease.Table In this study, we assessed the prevalence of kidney disease in Chinese adult PLWH and assessed the associated risk factors of kidney disease in this population. Similar to previous studies , our stuMajority of the patients on ART received TDF-containing regimen, which is one of the possible reasons why the prevalence of kidney disease among patients on ART was higher than those not on. Prior studies –18 confiYing Cao et al.  ascertaiEduardo Shahar et al.  reportedConsistent with previous studies , 22, lowPrior studies found that kidney disease is significantly associated with hypertension, diabetes mellitus, duration of HIV, ART, CRP, and CHOL –26. ThroOur study has following advantages. Firstly, we used enzymatic method to quantify serum creatinine, which is more accurate than Jaffe method . SecondlHowever, our study also has limitations. Firstly, we used CKD-EPI creatinine equation to calculate eGFR, which may underestimate the prevalence of renal dysfunction compared to CKD-EPI creatinine-cystatin C equation . SecondlIn conclusion, the prevalence of kidney disease in hospitalized PLWH in China is high, especially in the patients on ART. A larger scale study on Chinese outpatient PLWH should be conducted, so as to precisely assess prevalence of kidney disease in general Chinese PLWH.


The metabolic syndrome (MS), a cluster of clinical and biochemical abnormalities including insulin resistance, dyslipidemia and hypertension, is often diagnosed in chronic kidney disease (CKD) children. Left ventricular hypertrophy (LVH) is a major target organ damage in hypertension and an important cardiovascular risk factor in CKD patients. We aimed to identify the most significant risk factors of LVH in children with CKD.Children with CKD stage 1-5 were enrolled in the study. MS was diagnosed according to De Ferranti (DF) as ≥3 from 5 criteria. Ambulatory blood pressure measurements (ABPM) and echocardiographic evaluation were performed. LVH was defined as ≥95th percentile of LV mass index related to height and age. Clinical and laboratory parameters included: serum albumin, Ca, HCT, cystatin C, creatinine, estimated glomerular filtration rate (eGFR) based on Schwartz formula, triglycerides, high-density lipoprotein (HDL), proteinuria, BMI standard deviation score (SDS), height SDS, waist circumference, ABPM data.71 children (28 girls/43 boys) with median age 14.05 (25%-75%:10.03-16.30) years and median eGFR 66.75 (32.76-92.32) ml/min/1.73m2 were evaluated. CKD stage 5 was diagnosed in 11 pts (15.5%). MS (DF) was diagnosed in 20 pts (28.2%). Glucose ≥ 110 mg/dL was present in 3 pts (4.2%); waist circumference ≥75th pc in 16 pts (22.5%); triglycerides ≥ 100 mg/dL in 35 pts (49.3%); HDL < 50mg/dL in 31 pts (43.7%) and BP ≥ 90th pc in 29 pts (40.8%), respectively. LVH was detected in 21 (29.6%) children. In univariate regression the strongest risk factor for LVH was CKD stage 5  and low height SDS . In stepwise multiple logistic regression analysis (logit model) of the most important risk factors for LVH in CKD children, only three were statistically significant predictors: 1)MS diagnosis based on DF criteria ; 2), high mean arterial pressure (MAP SDS) in ABPM  and 3) low height SDS .In children with chronic kidney disease LVH is associated with the cluster of multiple factors, among them the components of MS, hypertension, stage 5 CKD and growth deficit were the most significant. PatiIn the general population, the occurrence of MS is associated with obesity . In chilIn our study, we compared the associations of metabolic syndrome and the clustering of its components with target organ damage - LVH in children and adolescents with chronic kidney disease.2The prospective study was conducted between January 2016 and March 2017. The study was performed in accordance with the Declaration of Helsinki of 1975 for Human Research and approved by the Bioethical Committee of Jagiellonian University no. 122.6120.280.2015. The parents and patients were educated as to the objective and method of performing the study and gave their written informed consent.2.1Patients aged 0-18 years with diagnosed chronic kidney disease were included. The exclusion criteria were lack of consent of the patient or parents, congenital heart defects or other primary heart diseases, acute infections during measurements, acute damage or failure of other organs.2.2Blood samples for basic research were taken on routine admission for diagnostic check-up in all patients (fasting for 12 hours). Biochemical analyses were performed and blood count, electrolytes, urea, creatinine, cystatin C, glucose, insulin, parathormone (PTH), venous blood gas, and lipids were measured. HOMA index was calculated. 24-hour urine collection with the albumin and protein concentrations were performed. Based on serum creatinine estimated glomerular filtration rate (eGFR) with the Schwartz  and Fill2.3Metabolic Syndrome (MS) was diagnosed according to De Ferranti (DF) when ≥3 from the 5 following criteria were met: High glucose >110 mg/dl (6.1 mmol/l); Waist circumference >75 pc; triglycerides (TGL) >100 mg/dl 1.13 mmol/l); Low high density lipoprotein (HDL) ≤50 mg/dl (1.3 mmol/l); High blood pressure (BP)>90th pc  was calculated. Growth age was calculated. Ophthalmological examination with fundus assessment was done. Ambulatory blood pressure measurements (ABPM) with SpaceLabs 90207 device and cuff of appropriate size were performed. BP was measured every 20 minutes during the day and every 30 minutes during the night. Mean values of systolic (SBP), diastolic (DBP) and mean BP  were calculated. Hypertension was defined as BP values equal to or exceeding the 95th percentile for gender, age and height. BMI and BP values were analyzed and expressed in standard deviations (SD).2.5Echocardiographic examinations were performed by an experienced cardiologist using HP 5500 unit with S4 and S8 variable frequency probes. In children on chronic hemodialysis echocardiography was performed on the day between two hemodialysis procedures, while in children on peritoneal dialysis, it was performed during the daily exchange, with a low volume of dialysate in the peritoneal cavity. LV mass (LVM) was calculated using the formula described by Devereux and Reichek . LVM ind2.6p <0.05 was considered significant in all statistical analyses.Data were collected in MS Excel database and analyzed with Statistica 13 StatSoft. Clinical and biochemical parameters of CKD, LVH and MS as continuous or categorical variables were compared. Because data of the majority of variables did not show normal distribution, they are presented as median and interquartile range . In statistical analysis nonparametric tests were used . Univariate and multivariate regression for LVH were performed. A value of A univariate regression analysis of risk factors for LVH was performed for every clinical and biochemical parameter with calculation of Odds ratio (OR), 95% Confidence Interval (CI), with significance p<0.05.In a stepwise multiple logistic regression analysis (logit model) with LVH as dependent variable and all important multiple variables of clinical interest as predictors, including those with borderline p value of 0.05. Collinearity was excluded for any multivariable logistic regression covariates.3Group of 71 children  with CKD stage 1 to 5 was enrolled in the study. The patients’ median age was 14.05 (IQR:10.03-16.30) years and median eGFR based on serum creatinine  was 66.7Stage 1 CKD was observed in 18 (25.4%) patients; stage 2 in 23 (32.4%), stage 3 in 14 (19.7%), stage 4 in 5 (7%) patients. CKD stage 5 was diagnosed in 11 pts (15.5%).Statistical analysis was performed in 3 defined groups according to eGFR value as follows:≥60 ml/min/1.73m2 in 41 pts (57.7%); 15-59 ml/min/1.73m2 in 19 pts (26.8%) and <15 ml/min/1.73m2 in 11 pts (15.5%).Clinical data and basic kidney function parameters depending on eGFR group are presented in Patients with eGFR <15 ml/min/1.73m2 (stage 5 CKD) had decreased hemoglobin  and increased phosphates , albuminuria , urine albumin/creatinine ratio , parathormone  and calcium times phosphate product  compared to pts with eGFR 15-59 and ≥60 ml/min/1.73m2, respectively (LVH was detected in 21 (29.6%) children. Patients with LVH had significantly higher BMI SDS (p=0.012), TGL level (p=0.04), proteinuria (p=0.0005), and MAP 24 SDS (p=0.04), and lower height SDS (p=0.00026) Table 2.MS (DF) was diagnosed in 20 pts (28.2%). High glucose ≥ 110 mg/dL was present in 3 pts (4.2%); Central obesity based on waist circumference >75th pc in 16 pts (22.5%); triglycerides > 100 mg/dL in 35 pts (49.3%); decreased high-density lipoprotein (HDL) ≤ 50mg/dL in 31 pts (43.7%) and high blood pressure > 90th pc in 29 pts (40.8%) were found, respectively. Hypertensive retinopathy (Ist degree) was present in 8 patients (11.3%).In our study 13 pts (18.3%) were overweight . Obesity was found in 4 pts . All obese patients were diagnosed with MS. Among overweight children 8 out of 13 did not meet the criteria for the metabolic syndrome. In obese children 2 (50%) – 1 female and 1 male had LVH in echocardiography.Patients with MS had lower eGFR, more pronounced lipid abnormalities, and increased uric acid, insulin, HOMA-IR, 24-hour mean arterial pressure and LVMI compared to those without Table 2.ABPM was performed in 62 patients. Due to young age ABPM was not used in 9 children. The analyzed parameters of arterial blood pressure and heart rate in the studied groups are provided in LVH patients significantly more often presented with MS , as for low HDL-DF , high TGL-DF , presence of HT- DF  or cluster of low HDL+ high TGL+HT . In LVH patients CKD stage 5 occurred significantly more often .In univariate regression analysis the strongest risk factor for LVH was CKD stage 5  and low height SDS . Among other LVH risk factors significant associations for diagnosis of MS according to DF , BMI SDS ;, proteinuria , HDL ≤50 mg/dl/1.3 mmol/l  and 24-hour MAP SDS  were found Table 4.In a stepwise multiple logistic regression analysis (logit model) of all important risk factors for LVH in CKD children, only three of them were statistically significant predictors Table 5:diagnosis of MS based on DF criteria ;high mean arterial pressure SDS (MAP SDS) in 24hABPM low height SDS .The diagnosis of metabolic syndrome (DF criteria) increased 24 times the risk of left ventricular hypertrophy in CKD patients diagnosed with height deficit and high MAP in in 24 hours ambulatory blood pressure monitoring.4In the study population, metabolic syndrome was diagnosed based on the De Ferranti definition in as many as 28.2% of children with chronic kidney disease and LVH in 29.6%.Cardiovascular risk factors defined as metabolic syndrome in children are most often associated with obesity. However, they can also occur in patients with CKD regardless of body weight. As such, they seem to be an important factor influencing myocardial remodeling and LVH. Left ventricular hypertrophy is an established cardiovascular risk factor and an important intermediate step in the cardiovascular continuum. Both obese children and CKD patients are at risk of developing LVH, which is confirmed by data from clinical trials. In obese children without hypertension, LVH was found in 47.2% and correlated with WHtR . In a laIn an important, long-term study evaluating the impact of risk factors in childhood on cardiovascular complications in adults, it was shown that each of the 5 tested factors: BMI, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking significantly increased its risk. In addition, it should be emphasized that the change in the combined-risk z score between childhood and adulthood were associated with fatal and non-fatal cardiovascular events in midlife . This coIn the adult population, CKD significantly increases the risk of cardiovascular morbidity and mortality. In the pediatric population, this risk is also elevated, and LVH is found not only in children with end-stage renal disease, but also in the early stages of the disease , 21. TheIn the present study a univariate analysis revealed that an eGFR below 15 was the strongest factor increasing the risk of LVH in children with CKD. Despite modern conservative treatment, children with eGFR <15 ml/min/1.73 m2 were characterized by severe metabolic disorders increasing the cardiovascular risk, such as anemia, elevated phosphate levels, CaxP product, proteinuria, albuminuria and increased heart rate in ABPM.z-score on the basis of age and gender and presence of LVMI >95pc was analyzed. The dependence of LVH on growth retardation may result from the increased uremic toxemia in these patients and the influence of various compounds and their metabolites that accumulate in advanced renal failure. Adjustments or different formulas for LVH may be required for children with short stature due to chronic kidney disease (It is noteworthy that the simultaneous presence of lipid disorders in the form of high TGL and low HDL with hypertension increased the risk of LVH to a similar extent as MS (OR 1.915 vs 1.907). Among the single LVH risk factors: hypertension, BMI and proteinuria significantly correlated with an increase in left ventricular mass. The search for modifiable factors influencing the development of LVH is important for reducing the risk of cardiovascular morbidity. Data from clinical trials indicate the possibility of LVH regression, e.g. in the case of effective antihypertensive treatment . Numerou disease . PotentiThe most important limitations of the study is the small size of the group and the case-control study design. Furthermore, the lack of healthy controls is an additional limitation of the study.5In children with chronic kidney disease LVH is associated with the cluster of multiple factors, among them the components of MS, hypertension, stage 5 CKD and growth deficit were the most significant.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Bioethical Committee of Jagiellonian University no. 122.6120.280.2015. Written informed consent to participate in this study was provided by the participants and their legal guardian/next of kinThe study was designed by MD and DD. AR performed echocardiography. Data was collected by MD. MD and AM contributed to analysis and interpretation of data, or both. All authors contributed to the article and approved the submitted version.


MBE was defined as neurological deterioration symptoms with imaging evidence of brain swelling. We employed a generalized estimating equation to compare the trend in longitudinal collected SIs and SId between patients with and without MBE. We used multivariate logistic regression to investigate the correlation between SIs, SId and outcomes. Results: Of the included 162 LHI patients, 28.4% (46/162) developed MBE and 25.3% (40/158) died within one month. SIs and SId increased over baseline in all patients, with a similar ascending profile during the first 12 h epoch and a more intensive increase in the MBE group during the second 12 h epoch (p < 0.05). During the overall 24 h, patients with greater SId variability had a significantly increased MBE risk after adjustment . Additionally, during the second 12 h epoch (13–24 h after symptom onset), patients developing MBE had a significantly higher SId level  and greater SId variability . Higher SId and greater SId variability within 24 h independently correlated with one-month death . Within the second 12 h epoch, higher SIs, higher SId and greater SId variability independently correlated with one-month death . No significant correlation was observed in the first 12 h epoch. Conclusions: Higher and more fluctuated heart-rate-to-blood-pressure ratios independently correlated with MBE development and one-month death in LHI patients, especially during the second 12 h (13–24 h) epoch after onset.Introduction: Large hemispheric infarction (LHI) can lead to fatal complications such as malignant brain edema (MBE). We aimed to investigate the correlation between heart-rate-to-blood-pressure ratios and MBE or one-month death after LHI. Methods: We prospectively included LHI patients from a registered cohort. Hourly heart-rate-to-blood-pressure ratios were recorded as a variation of the traditional shock index (SI), SI Stroke is the leading cause of death and disability worldwide ,2, and tThe autoregulation of cerebral blood flow is injured after stroke, increasing the dependence of cerebral blood supply on systemic blood pressure ,8. The fThe shock index (SI), calculated as the heart rate divided by systolic blood pressure, is a commonly used index in intensive care . Recent The natural history of brain edema can be categorized into cytotoxic and vasogenic edema. Cytotoxic edema is defined as cell swelling caused by intracellular fluid accumulation and is initially observed within hours after stroke onset and then declined within 1 day. Vasogenic edema is caused by extracellular fluid accumulation resulting through disruption of the blood–brain barrier and is usually developed within two to three days after onset and maintained for several days . TherefoIn this research, we aimed to explore the correlation between heart-rate-to-blood-pressure ratios and MBE, as well as one-month death after LHI. We enrolled patients with acute ischemic stroke consecutively admitted between January 2020 and December 2021 from our registry cohort database ,16. AcutWe collected demographic and clinical data including age, gender, body temperature, National Institute of Health stroke scale (NIHSS) and Glasgow Coma Scale (GCS) on admission, hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation and stenosis/occlusion of intra/extracerebral arteries; ischemic area (whether invisible hypodensity ≥ 1/2 territory of MCA), Trial of ORG 10,172 in Acute Stroke Treatment (TOAST) classification . Treatmes and SId for systolic and diastolic pressures, respectively. The equations for SIs and SId are derived by dividing heart rate by systolic or diastolic blood pressure. Hourly SIs and SId were recorded and calculated for mean, maximum, minimum, range (difference between maximum and minimum), standard deviation (SD) and coefficient of variation (CV) for the entire recording epoch (24 h) and during two 12 h epochs (1–12 h and 13–24 h after onset). For patients who developed MBE within 24 h of onset, the heart-rate-to-blood-pressure ratios collected after MBE development were excluded for analysis in order to ensure the appropriate sequential order of studied parameters and outcome.We collected repeated time-stamped blood pressure and heart rate of all included patients within the first 24 h post-onset. Blood pressure and heart rate were measured simultaneously by noninvasive monitoring devices and were recorded by trained nurses hourly (±30 min) after admission. The relationship between heart rate and diastolic blood pressure can be represented as a variation of the traditional shock index, wherein heart-rate-to-blood-pressure ratios are assigned as SIThe primary outcome was MBE, defined as midline shift ≥ 5 mm with a deteriorated status of consciousness or anisocoria, or indications for decompressive craniectomy. All images were independently viewed by two researchers (X.S and W.G) who were blinded to clinical data. A final decision was made by a senior neurologist (M.L) if two researchers could not reach a consensus. Presence of mild degree of hemorrhagic transformation was permitted, since it was not considered to result in mass effect . Secondat-test or Mann–Whitney U test for continuous variables as appropriate. We employed the generalized estimating equation (GEE) to compare the trend in longitudinal collected SIs and SId measurement values between patients with and without MBE, as well as between patients who survived and those who died within one month. This method allowed us to account for the correlation between the repeated measurements over time, improving the accuracy of our parameter estimates and providing scientific rigor to our analysis. We used multivariable logistic regression to analyze independent correlation between SIs or SId parameters and outcomes. SD and CV values of SIs and SId were entered into the regression model as log-transformed values due to the skewness distribution of data, while other SIs and SId parameters were entered as ten-fold values (per 0.1-unit increase). We preselected the adjusted covariates with clinical significance for MBE , and one-month death/three-month poor outcome . Cumulative risk of one-month death was estimated with Kaplan–Meier curves and compared by log-rank test. We further conducted a restricted cubic spline regression model to assess the non-linear dose effect of SIs or SId parameters on outcomes with four knots  [s or SId that best predicted MBE and one-month death based on receiver operating characteristic curves and the Youden index. All statistical analyses were performed by SPSS , STATA 16.0 , and GraphPad Prism . A two-sided p < 0.05 was considered statistically significant.All data were reported as mean ± standard deviation (SD), median  or count (percentage). Inter-group differences were compared by χ2 test or Fisher’s exact test for categorical variables, and Student’s entiles) . We deteDuring the study period, 175 LHI patients were preliminarily screened. A total of 13 patients were excluded: 3 patients developed bilateral ischemia; 1 patient was diagnosed with recurrent stroke at this visit; 6 patients developed parenchymal hemorrhage type 2 before imaging evaluation for MBE; 3 patients were with absence of blood pressure and heart rate measurements . We finaWe included 2138 sets of time-stamped blood pressure and heart rate measurements in total. For up to 24 h after onset, 14 ± 6 sets of blood pressure and heart rate were recorded per patient, 6 ± 3 and 8 ± 3 for the first and second 12 h epoch, respectively. Missing data were mainly due to pre-hospital referral and transferring for thrombectomy or follow-up imaging.s and SId in LHI patients with and without MBE are shown in s and SId increased in the early phase  for both the MBE group and non-MBE group, then reached a plateau for the remainder of the monitoring epoch in the non-MBE group. In contrast, SIs and SId continued to rise at a lower rate in the MBE group, beginning at approximately 13 h after onset. During the second 12 h epoch (13–24 h after symptom onset), in patients with MBE, SIs and SId were higher than that in patients without MBE . We did not find differences in SIs and SId during the entire 24 h recording period or during the first 12 h epoch between patients with and without MBE . The temporal evolutions of SIs an SId were similar in patients who died or had survived at one month  than those without MBE. Patients with MBE had a greater SId variability during the entire 24 h recording epoch , and higher SId level  with greater variability  during second 12 h recording epoch (13–24 h after onset). The clinical features and heart-rate-to-blood-pressure ratio parameters in patients with and without MBE were compared in d level was observed in the MBE group , though no significant correlation was observed after adjustment. In contrast, a higher maximum SId value , wider SId range  and greater SId variability  during the overall 24 h recording epoch significantly correlated with MBE development after adjustment. In d level  independently correlated with an increased risk of MBE after adjustment. Additionally, 13–24 h after onset, a higher maximum SId value , wider SId range  and greater SId variability  independently correlated with an increased risk of MBE. No SId parameters in the first 12 h epoch presented significant correlation with MBE after adjustment. No significant correlation between SIs parameters with MBE were observed.The same effect direction with a stronger correlation was observed during the second 12 h epoch (13–24 h after onset). During this epoch, a higher SId level and MBE were in a non-linear dose–effect manner (d level of 1.11 bpm/mmHg during the second 12 h epoch after onset (13–24 h after onset) as able to discriminate between patients with and without MBE. The area under the receiver operating characteristic curve was 0.61 bpm/mmHg, sensitivity was 78%, and specificity was 47%.According to restricted cubic spline regression, during the second 12 h epoch after onset, the correlation between the mean SIt manner . The Youp < 0.05, s  and SId  levels were observed in patients who died within one-month  independently correlated with one-month death after adjustment. Moreover, a higher maximum SId value , wider SId range  and greater SId variability  during overall 24 h independently correlated with increased risk of MBE. In s or SId parameters in the first 12 h epoch presented a significant correlation with one-month death. During the second 12 h epoch, a higher SIs level  independently correlated with one-month death. Meanwhile, a higher SId level , a higher maximum SId value , a wider SId range  and greater SId variability  during this epoch independently correlated with one-month death. The cumulative incidences of one-month death were significantly higher among patients with higher SIs or SId levels during the 13–24 h epoch  and 0.64 bpm/mmHg , respectively. No SI h epoch . The Yous or SId parameters was observed between patients with and without a three-month poor functional outcome .No difference in SIs and SId), as well as their impact on MBE and one-month death. We are also the first to investigate this correlation among specific, fatal stroke subtypes as LHI patients, using a registry cohort database. In this study, SIs and SId increased over baseline in all patients, with similar profiles during the first 12 h epoch and a more intensive increase in patients with MBE or one-month death during the second 12 h epoch. Higher and more fluctuated heart-rate-to-blood-pressure ratios independently correlated with increased risk of MBE and one-month death in LHI patients, especially during the second 12 h (13–24 h) epoch after onset.To our knowledge, this study is the first to examine the temporal evolution of heart-rate-to-blood-pressure ratios . BRS is an index that quantifies the extent of baroreflex modulation of the heart rate in response to changes in blood pressure . Previous is reported to be of prognostic importance for infection, which may influence stroke outcomes [s or SId for MBE and one-month death. However, due to a limited sample size, we regret that we were unable to perform a sensitivity analysis on patients without in-hospital infections. Therefore, further research involving larger sample sizes is needed to explore this issue further.Elevated SIoutcomes . Patientoutcomes ,40 and uoutcomes . LHI patoutcomes . This phoutcomes . In thisoutcomes . It is ad with greater variability was observed during the overall 24 h recording epoch and second 12 h epoch (13–24 h after onset), but not the first 12 h epoch, which suggested that SId may affect outcomes by mainly interfering vasogenic edema 13–24 h after onset. We investigated the association between the heart-rate-to-blood-pressure ratio parameters and the natural history of MBE progression by dividing the overall 24 h recording epoch into two 12 h epochs. The progression of MBE can be separated into two stages: cytotoxic edema and vasogenic edema. The initial stage of cytotoxic edema occurs within the first few hours and declines within one day, which aligns temporally with the first 12 h epoch. The second stage of vasogenic edema develops within one to three days and is maintained for several days , which cs and SId are two simple indices derived from two readily available recordings during monitoring. It can be measured in emergencies or in the ICU without training from a neurologist, with usefulness in a clinical setting. Thirdly, we conducted serial measurements of HR and BP, revealing the temporal and variability pattern of the ratios. Our study has some limitations. Firstly, the population is relatively small due to the low incidence of LHI. Secondly, the ratios were collected less within the first 12 h epoch after onset due to the hospitalization delay of patients. Thirdly, our study lacked more hemodynamic parameters, such as PaCO2 and beat-to-beat data, which could have provided further insights into the underlying mechanisms. In order to validate our results, further studies are required across multiple centers, with a larger sample size. However, the limitations of this study do not obscure its strengths. Firstly, we focused on LHI, which is the very subtype of ischemic stroke with the worst outcome. We provided some specific evidence for intensive care in this population. Secondly, SId) independently correlated with increased risk of MBE and one-month death in LHI patients, especially during the second 12 h (13–24 h) epoch after onset. A higher heart rate-to-systolic blood pressure ratio (SIs) 13–24 h after onset was independently correlated with one-month death in LHI patients.A higher and more fluctuated heart-rate-to-diastolic-blood-pressure ratio (SI