VRI was inversely but mildly correlated with age . Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I  and Registry-II  across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men (1.62 ± 0.56 vs. 1.54 ± 0.47,  Of the three layers of an artery, the intima or endothelial layer has gathered the most attention as it is a critical regulator of the overall hemodynamic function –3. It isFlow-mediated dilation (FMD) evaluates endothelial function at the conduit  artery level , 5, wherThe procedure for measuring microvascular function using DTM has been described previously in detail , 13–16. The DTM test registries included age, sex/gender, blood pressure, heart rate, and fingertip temperature recorded during DTM tests. The registries did not include other health-related information. All DTM tests were performed in outpatient clinical settings. The first VENDYS registry included 6,084 patients tested between 2011 and 2016, here referred to as Registry-I. The second registry included 1,021 patients tested between 2017 and the first half of 2018, here referred to as Registry-II. Overall, this study included a total of 7,105 patients. Data for both registries were collected from 49 outpatient clinics in the US.t-test. Comparisons of categorical data  were performed using Fisher's exact test. Pairwise correlations were performed using Pearson's correlation and regression analyses. Associations between VRI and multiple patient characteristics  were evaluated using bidirectional (forward and backward) multiple stepwise regression analyses. A p value of <0.05 was considered statistically significant. When performing statistical comparisons, tests with missing data were excluded from the comparison.Statistical analyses were performed using RStudio  and MATLAB . Descriptive statistics were expressed as the mean ± SD and categorical variables as percentages. VRI scores in men and women were compared using unpaired Student's Basic characteristics of patients and DTM tests for Registry-I and II are shown in p < 0.001), whereas VRI was nearly identical in men (1.51 ± 0.43) and women (1.52 ± 0.43) in Registry-II (The VRI distributions in both registries are shown in istry-II .p < 0.001). However, prevalence of poor VRI was not different between men and women . VRI was inversely and significantly correlated with age  (p < 0.001). However, the distribution of poor, intermediate, and good VRI values in the oldest age group was similar to that of the overall study population . 77% of men under 50 and 92% of women under 50 were classified as suboptimal. 87% of men over the age 50 and 79% of women over the age 50 were classified as suboptimal. VRI showed no correlations with systolic and diastolic blood pressure, pulse pressure, or heart rate. This was true for both men and women. As shown in The distribution of poor, intermediate, and good VRI in both registries is shown in < 0.001) . Poor VRTo our knowledge, this is the largest database to date on endothelial function measurement including 7,105 cases. The second largest is the data from the Framingham Heart Study with 7,031 FMD measurements . The mosReports of high residual risk in on-statin patients are well documented in the literature –28. AmonAnother interesting observation from the present study is the lack of correlations between endothelial function measured by DTM technique and arterial blood pressure. This finding is not unique to DTM. Studies with FMD and peripheral arterial tonometry (PAT) have shown similar findings , 47. TheAs reported in a community-based study of 5,000 individuals, traditional risk factors only accounted for 15% of FMD and 14% of PAT variability . This maThe strengths of our study include a large sample size and a mixed population of men and women, geographically dispersed, and coming from various outpatient clinics throughout the USA. Therefore, the registries can provide a real-world assessment of the problem at large. The main limitation of the present study is that neither Registry-I nor Registry-II contained detailed clinical information about patients' diagnostic or therapeutic status. Therefore, we cannot be certain as to whether these patients were maximally treated and what percentage of them reached the target treatment goals. However, it is generally expected that basic standards of care according to existing guidelines are provided by clinics that utilize cutting-edge technologies such as endothelial function testing devices. Furthermore, the near-target average blood pressure levels may suggest that these patients were treated based on current standards of care. Given reports of high residual risk in other studies, it is unlikely that our results represent an anomaly , 35.In conclusion, in this largest collection of peripheral microvascular function measurements in on-treatment patients, a high prevalence of suboptimal scores was found across both genders and all age groups. These findings suggest a possible high level of residual risk in this real-world data. More needs to be done to minimize residual risk, and further studies are warranted to validate the use of endothelial function testing, such as digital thermal monitoring, for detecting and monitoring residual risk.


Variabilities of low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were determined using the standard deviation of the respective parameter obtained from a mixed effects model to minimize regression dilution bias. The associations between lipid variability and renal outcomes including incident kidney disease, renal function decline defined as ≥ 30% reduction in estimated glomerular filtration rate since baseline, and end-stage renal disease (estimated glomerular filtration rate < 15 mL/min/1.73 m2) were evaluated by multivariable Cox regression. After a median follow-up of 66.5 months , 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Positive linear associations between low-density lipoprotein-cholesterol and total cholesterol to high-density lipoprotein-cholesterol ratio variabilities and the risk of all renal outcomes were demonstrated. However, no association between triglyceride variability and any outcome was found. Each mmol/L increase in low-density lipoprotein-cholesterol variability was associated with 20% (Hazard ratio 1.20 [95% CI 1.15–1.25]), 38% (Hazard ratio 1.37 [95% CI 1.30–1.45]), and 108% (Hazard ratio 2.08 [95% CI 1.74–2.50]) higher risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Similarly, each unit increase in total cholesterol to high-density lipoprotein-cholesterol ratio variability was associated with 35% (Hazard ratio 1.15 [95% CI 1.10–1.20]), 33% (Hazard ratio 1.33 [95% CI 1.26–1.40]), and 75% (Hazard ratio 1.75 [95% CI 1.46–2.09]) heightened risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Cholesterol variability may potentially be a useful predictor of kidney diseases in patients with type 2 diabetes mellitus. Attention should be drawn to cholesterol variability when managing diabetic patients and further research is warranted to investigate the modifiable risk factors for lipid variability.This study aimed to evaluate the associations between variability of lipid parameters and the risk of kidney disease in patients with type 2 diabetes mellitus. Low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were specifically addressed in this study. This retrospective cohort study included 105,552 patients aged 45–84 with type 2 diabetes mellitus and normal kidney function who were managed under Hong Kong public primary care clinics during 2008–2012. Those with kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m With increasing evidence showing associations between lipids and kidney diseases in diabetic populations2, optimal lipid level targets for diabetes management have been raised by various international guidelines, in efforts to prevent the escalating prevalence of kidney disease and related mortalities4. Though the evidence has shown effects of intra-individual lipid variabilities on cardiovascular diseases (CVD)8, its associations with kidney disease in the diabetic population remains briefly addressed in the literature.Kidney diseases are invariably associated with a myriad of significant morbidities and mortalities. In the United States, kidney disease and end stage renal disease (ESRD) cost 64 billion and 34 billion USD, respectively, thereby constituting a predominant worldwide public healthcare burden12, and the effects of respective lipid parameters have been inconsistent. An Italian study provided evidence for heightened risk in renal decline with increased variability in both low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C)10; though this was not replicated in another Taiwanese study, which solely demonstrated aggravating effects of HDL-C variability on diabetic nephropathy progression9. Additionally, although such studies have illuminated potential associations between renal disease and variabilities in lipid traits, most had relatively short follow-up periods, a limited small cohort, or included patients with baseline macroalbuminuria, with only two of the four studies evaluating kidney disease10. The inclusion of post-baseline measurements in the determination of cholesterol variability was also unclear12, and as a result potentially introducing informative censoring and immortal time bias14. Moreover, although two studies have focused on the detrimental effects of variability in LDL-C, HDL-C, total cholesterol (TC) and triglyceride (TG), the impacts of variability in TC to HDL-C ratio have rarely been analysed. Taking into consideration the clinical implications of TC to HDL-C ratio in CVD prediction models, which in turn contributes to the onset of renal dysfunction and kidney disease, it arguably provides a more overarching indication for the treatment of respective lipid traits16. Furthermore, of the four studies, only two demonstrated impact of lipid variabilities in diabetic populations, whilst the others addressed hypertensive or general populations. Here, the specificity to a diabetic population is important, given that diabetic patients displayed a higher risk of kidney disease and ESRD17, thus rendering their results inapplicable11. This calls for further research to enable a clearer apprehension of the underlying relationship between cholesterol variability and the progression of kidney disease and mortality in diabetic population.The impact of lipid variability on kidney disease, specific to a diabetic population, has been insufficiently explored. Four studies to date have investigated the associations between lipid variability and progression of renal diseaseThis study aims to investigate the associations between the variabilities of respective lipid parameters, LDL-C, TC to HDL-C ratio and triglyceride, and the risk of kidney disease, renal function decline and ESRD in type 2 diabetes mellitus (T2DM) patients without kidney disease. This will enable a timely identification of those at risk, better predictions and earlier implementation of appropriate preventative measures.18. The data used in this study, including mortality data, was anonymous data from electronic health record database. Hence, no informed consent was required. All methods in this study were conducted in accordance with the relevant guidelines and regulations. Patients aged 45–84 with clinically diagnosed type 2 DM and managed in primary care were included in this study. The diagnosis of type 2 DM was determined by the International Classification of Primary Care-2 (ICPC-2) code of T90. Lipid variability was determined by three or more lipid readings, obtained from annual assessment during the 2-year period on or before baseline. The timeline of lipid measurements and outcome ascertainment in this study is illustrated in Supplementary Fig. 2 or urine albumin to creatinine ratio (ACR) ≥ 3 mg/mmol, or less than three lipid measurements were excluded from this study. The cut-off value for ACR corresponds to albuminuria category A2 or above as specified in the Kidney Disease: Improving Global Outcomes (KDIGO) guideline19.This retrospective cohort study was conducted between 1 January 2008 and 31 December 2012 with data obtained from the database of the Hong Kong Hospital Authority (HA). Managing over 43 public-sector hospitals, 49 specialist outpatient clinics and 73 primary care clinics, the HA attends over 90% of patients in Hong Kong with chronic diseases2 or new onset albuminuria, defined as ACR ≥ 3 mg/mmol; (2) renal function decline defined as ≥ 30% reduction in eGFR since baseline; (3) ESRD, coded as 585.5–585.6 in ICD-9-CM, or defined as eGFR < 15 mL/min/1.73 m2.The three outcomes included: (1) kidney disease, coded as 585.3–585.6 and 586.x in the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM), or defined as eGFR < 60 mL/min/1.73 mEthics approval for this study was granted by the Institutional Review Boards (IRB) of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Anonymous data was extracted from the database in Hong Kong Hospital Authority, and thus the informed consent from all study subjects is waived by the IRB of the Hong Kong Hospital Authority.20.Lipid levels were obtained from blood samples after an overnight fast in each subject, following standardised and universal blood-taking protocol across all clinics and hospitals in the HA. Cholesterol and triglyceride levels were determined using Roche diagnostics with automatic biochemical analyzer . Direct LDL-C levels were measured, unless TG levels exceed 4.0 mmol/L, in which LDL-C levels would subsequently be calculated by the Friedewald equationhttp://mcmc-jags.sourceforge.net/) and the R2jags package in R Version 3.6 (https://www.r-project.org/)22, Markov Chain Monte Carlo (MCMC), a method from the Bayesian framework, was used to construct the mixed effects model. In the output of MCMC, posterior mean of the random intercept and residual standard deviation was used for the respective estimation of usual lipid levels and lipid variability measurements, represented by the mean and standard deviation of lipid level corrected with regression dilution bias, respectively. Further information regarding the statistical theories and algorithms could be found in the 24.For each patient, mixed effects model was applied to estimate the usual lipid level and variability, in which the intra-individual variability was used as the random effect. In the mixed effects model, difference between lipid levels amongst individuals was considered to obtain more accurate lipid variability, in turn reducing the regression dilution bias in the result. Based on JAGS Version 4.3.0 , the use of anti-hypertensive drug , statins, and fibrates. All laboratory assays were conducted in accredited laboratories by the College of American Pathologists, the Hong Kong Accreditation Service, or the National Association of Testing Authorities, Australia.Baseline characteristics consisted of age, gender, duration of DM, smoking status, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), Haemoglobin A1c (HbA1c), eGFR28.The missing data for baseline characteristics was deduced from multiple imputation. With the chained equation method, each missing value was imputed based on all covariates and outcomes for five times, hence generating five different datasets, which was applied in the same analysis. The results were further pooled in accordance with Rubin’s rule29. The scaled Schoenfeld residuals against time for covariates was used to assess the proportional hazards assumption. To inspect the existence of multi-collinearity, variance inflation factor was calculated. For this study, the results showed the fulfilment of proportional hazards assumption amongst all models with no significant multi-collinearity. The analyses were also repeated with two variability measurements, the coefficient of variation (CV) and variability independent of mean (VIM) instead of standard deviation (SD), to ensure robustness. Restricted cubic splines with three knots in Cox models were drawn to check the nonlinear pattern between lipid variability and the risk of outcomes. Additionally, three sensitivity analyses were performed in this study. Firstly, a complete case analysis was conducted. Secondly, to avoid the reverse causality, subjects with follow-up period of less than 1 year were excluded. Thirdly, the 24-month patient inclusion period was extended to 36 months.The patients involved were divided into quintiles based on their lipid variabilities. Descriptive statistics for patient’s characteristics in each group were summarized. The incidence rate of kidney disease, renal function decline and ESRD were calculated for each group, with its 95% confidence interval (CI) based on Poisson distribution. Multivariable Cox proportional hazards regressions were adjusted to the patient’s characteristics and their usual lipids levels to evaluate the association between variability in lipids and the risk of an event. The CI of the hazard ratio was estimated using the floating absolute risk, without the requirement of reference group for reporting the standard error2), usual cholesterol level , baseline SBP , HbA1c (< 53 mmol/mol (< 7), ≥ 53 mmol/mol (≥ 7%)), eGFR , Charlson’s Index , use of anti-hypertensive drugs , use of anti-diabetic drugs , use of statins , and use of fibrates . To prevent multiple comparisons, the p-values were adjusted by Bonferroni correction.Patients were divided into subgroups to explore the different relationships between cholesterol variability and outcomes for variant baseline characteristics, including gender , age , smoking status , duration of DM , BMI .Two-tailed tests with p-value significance level of 0.05 were applied in this study. The statistical analysis was executed with Stata Version 15.1 , 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Table 2 and (ii) ACR ≥ 3 mg/mmol was shown in Supplementary Figs. Figure Further results of subgroup analyses are denoted in Fig. This is the first population-based study that demonstrated positive linear relationship between variabilities of LDL-C and TC to HDL-C ratio and the risk of kidney disease, renal function decline and ESRD in Chinese patients with T2DM. Nevertheless, triglyceride variability seemed to have an insignificant effect on any of the outcomes. Furthermore, patients of younger age were more susceptible to cholesterol variability in comparison to older patients, such that younger patients are at higher risk to kidney diseases despite same degree of variability in LDL-C and TC to HDL-C ratio in older patients. Therefore, cholesterol variability may be a potential indicator of diabetic nephropathy, and the importance of monitoring cholesterol variability in real-life practice should not be overlooked.9. This could be attributed to their relatively small sample size and inclusion of patients with baseline macroalbuminuria. Furthermore, this study ties in well with an Italian study conducted in 2017, wherein the variability in HDL-C and LDL-C indicated the decline in eGFR in diabetic population10. However, the median of patients’ baseline eGFR was significantly lower than that of our study population, and they did not stratify the severity of renal function decline. In this study, variability of TC to HDL-C ratio was assessed in lieu of HDL-C variability, as TC to HDL-C ratio has shown to be a better indicator of target organ damage when compared to other lipid parameters30. Additionally, TC to HDL-C ratio played an important role in predicting cardiovascular risk, which has been included in the QRISK cardiovascular disease risk algorithm, with atherosclerosis as one of the major causes of renal failure31. In terms of triglyceride level, this study did not find any significant association between TG variability and any of the outcomes, which parallels the findings in previous studies10. In short, this study demonstrated a positive correlation between all three outcomes and the variability in LDL-C and TC to HDL ratio, but further research is still warranted as there has only been limited studies documenting the effect of LDL-C and TC to HDL-C ratio variability on renal function decline in diabetic population and future work could reaffirm the validity of cholesterol as the indicator of diabetic nephropathy.The effect of lipid variability on renal function decline was first discussed in a Taiwanese study, in which only HDL-C variability was found to be associated with a higher risk of diabetic nephropathy progression in patients with T2DM8, impair endothelial function and inhibit lipid efflux from plaques32, thus increasing the risk of atherosclerosis. Similarly, these factors may also provide plausible explanations for the associations between LDL-C variability and renal function decline. It has been widely speculated that an increase in lipoprotein levels causes CVD and kidney disease with similar mechanisms, through heightened lipid trapping and adherence of monocytes to endothelial cells, thereby resulting in the development of focal glomerulosclerosis33. A post-hoc analysis provided evidence for the correlation between variability in TC to HDL-C ratio and percent atheroma volume progression34, supporting the atherosclerotic hypothesis in causing renal dysfunction. Furthermore, lipid variability could be an epiphenomenon of other conditions and frailty that increases risk of kidney disease35. Lastly, some studies suggested non-adherence to statins as one of the possible reasons36, though medication compliance was not addressed in the current study and the effect of lipid variability remained significant after adjusting for the use of lipid-lowering agents.Current literature has almost exclusively focused on the correlation between lipid variability and increased cardiovascular risk, but research in renal dysfunction remains limited. It has been hypothesized that higher LDL-C variability could disrupt cholesterol-dependent plaque8, and further research is required to elucidate the exact underlying mechanism. Minor changes in levels of LDL-C, HDL-C and TC throughout menstrual cycles have also been observed37, providing potential explanations for the reduced susceptibility to renal dysfunction in females, with their innate exposure to greater fluctuating microenvironments.Patients of different age range and gender illustrated different outcomes. In this study, the effect of each unit increase in lipid variability on escalating kidney disease risk was more prominent in younger patients. This could be due to the fact that older patients are generally more vulnerable and have more comorbidities, hence masking the effect of lipid variability and in turn resulting in an age-specific difference. In addition, male patients demonstrated a higher risk in kidney disease when compared to females with the same unit increase in lipid variability, though previous studies provided evidence that females exhibit more variable LDL-C levels than malesWith the large sample size and appropriate study design, this cohort study yielded results of minimal bias, limiting all informative observation of lipid measurements, immortal time bias and regression dilution bias, thereby ensuring reliability and validity of results.However, although the study casts a new light on effects of lipid variability on kidney disease, it presents some apparent limitations. As a retrospective cohort study, the conclusion drawn suffers from the limitation of solely illustrating an associative relationship between lipid variability and kidney disease. This would require further investigation into the underlying mechanisms, in order to elucidate a causal relationship between the two. Nevertheless, multiple confounders were adjusted for in our analyses, and despite the possibility of residual confounding, the potentiality of reverse causation remains negligible with the exclusion of patients with baseline kidney disease. Besides, the results are in parallel with those acquired from the sensitivity analysis that only included patients with follow-up period of more than one year. Furthermore, serum urate level, which could be an independent risk factor for incident kidney disease, was not included in the current analysis. Additionally, although this study failed to take into consideration the various behavioural or habitual characteristics of patients, including levels of physical activity, dietary intake, and medication compliance; anthropometric and clinical parameters that were deemed relevant, such as BMI, HbA1c and blood pressure, have been included to account for patients’ disease severity and lifestyle. Lastly, with associations between cholesterol variability and elevated kidney disease risk ascribed to potential individual differences in diabetic patients of the cohort, the results therefore may not be extended to non-diabetic population.This population-based cohort study demonstrated a positive linear association between variability in LDL-C and TC to HDL-C ratio and kidney diseases in Chinese T2DM patients; shedding new light on the effects of cholesterol variability on kidney diseases, further reinforcing the validity of TC to HDL-C ratio as a clinical indicator of kidney diseases. These results not only confirmed the hypothesis that increased cholesterol variability aggravates the progression of kidney diseases, but also revealed a greater impact in younger, male patients. Such conclusions may reaffirm the validity of cholesterol variability as a useful predictor for kidney diseases outcomes in patients with T2DM, subsequently enabling diabetic patients to better envisage and prevent kidney diseases.Supplementary Information.


The purpose of this study was to evaluate the clinicopathological features of different degrees of extraglomerular renal vascular lesions (RVLs) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis and explore their clinical determinants. This is a retrospective study of 186 patients with ANCA-associated renal vasculitis diagnosed at the First Affiliated Hospital of Zhengzhou University from January 2014 to April 2019. The patients who met the inclusion criteria were divided into non-renal RVLs, mild RVLs, moderate RVLs, and severe RVLs. It was found that there were significant differences in serum creatinine (SCR), estimated glomerular filtration rate (eGFR), erythrocyte sedimentation rate (ESR), high-density lipoprotein (HDL), systolic blood pressure (SBP), the prevalence rate of hypertension, the proportion of normal glomeruli, and the proportion of sclerotic glomeruli and interstitial fibrosis integral. SCR and ESR are independent risk factors for RVLs. The participants were followed up for 1 year, and the progression to end-stage renal disease (ESRD) and death was defined as endpoint events. We found that the survival rate of patients without RVLs was significantly higher than that of patients with RVLs and that the RVLs were an independent risk factor for ESRD or death. Early intervention in the progression of RVLs can improve the prognosis. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of multisystem disorders characterized by necrotizing inflammation and destruction of small- and medium-sized blood vessels in conjunction with ANCA. The kidney is the most common organ involved in AAV, and more than 75% of patients with AAV have renal involvement and missed or delayed diagnosis may endanger the life of a patient –3. In 203) and/or proteinuria (>300 mg/day); (2) the detection of a positive ANCA by an antigen-specific immunoassay and/or indirect immunofluorescence; (3) the observation of more than 10 glomeruli in pathological sections, and (4) confirmation by renal biopsy of the presence of pauci-immune glomerulonephritis. The exclusion criteria were the following: (1) systemic diseases involving the kidneys, such as hepatitis B virus-associated glomerulonephritis, diabetic nephropathy, and systemic lupus erythematosus, and other primary glomerular diseases, such as membranous nephropathy and IgA nephropathy; (2) positive anti-glomerular basement membrane antibodies or renal pathological immunofluorescence showing a linear deposition of immunoglobulin or immunoglobulin deposition > 2+. The study was approved by the Committee of the First Affiliated Hospital of Zhengzhou University .This study retrospectively enrolled 186 patients with ANCA-associated renal vasculitis admitted to the First Affiliated Hospital of Zhengzhou University between January 2014 and April 2019. The inclusion criteria were: (1) the presence of hematuria , cardiovascular diseases, systolic blood pressure (SBP), diastolic blood pressure (DBP), leukocyte count (WBC), hemoglobin (HB), platelet count (PLT), serum creatinine (SCR), serum uric acid (UA), estimated glomerular filtration rate (eGFR), serum albumin (ALB), 24 h-proteinuria (24 h-TP), urine RBC count, total cholesterol (T-CHO), triglycerides (TGs), high-density lipoprotein (HDL), low-density lipoprotein (LDL), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), complement C3, complement C4, immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), myeloperoxidase antibody (anti-MPO), protease 3 antibody (anti-PR3), and the Birmingham Vasculitis Activity Score (BVAS). eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Hypertension refers to a blood pressure ≥ 140/90 mmHg . DM is dThe presence of fibrous, cellular, and cellular fibrous crescents, fibrous necrosis, destruction of Bowman's capsule, and global glomerulosclerosis of each glomerulus was recorded and calculated as the percentage of the total number of glomeruli. The presence of microangiopathic lesions was calculated as the percentage of the number of renal specimens in the four groups. Interstitial fibrosis and tubular atrophy were evaluated according to the extent of interstitial fibrosis with tubular atrophy in the cortex: 0 = no or trivial interstitial fibrosis (<5% of unscarred parenchyma), 1 = 6–25% of interstitial fibrosis, 2 = 26–50% of interstitial fibrosis, and 3 = more than 50% of interstitial fibrosis. Interstitial inflammation was evaluated according to the extent of inflammatory cells in the cortex: 0 = no or trivial interstitial inflammation (<10% of unscarred parenchyma), 1 = 10–25% of parenchyma was inflamed, 2 = 26–50% of parenchyma was inflamed, 3 = more than 50% of parenchyma was inflamed .Kidney biopsy specimens were examined by light microscopy, electron microscopy, and immunofluorescence. These specimens were then reviewed and scored by two independent and experienced pathologists who did not know the clinical indicators of the patients. If any disagreements arose during the evaluation, a third pathologist was consulted and reached a final consensus. RVLs in this study referred to extraglomerular vascular lesions, including arterial fibrotic intimal thickening and arteriolar hyaline, whose scores were evaluated based on the definition described in the Oxford classification, with some modifications . The rul2 test was performed to compare categorical variables between the groups. A binary logistic regression analysis model was used to analyze the factors influencing RVLs in patients with ANCA-associated renal vasculitis. The results were expressed as the ratio (OR) and 95% confidence interval (CI). Survival curves were plotted using the Kaplan-Meier (K-M) method, and differences in survival curves were compared by a Log-rank test. Univariate and multivariate COX regression models were used to identify the predictors of end-stage renal disease (ESRD) or death. The results were expressed as hazard ratio (HR) (with 95% CI). p < 0.05 was considered statistically significant. SPSS statistical software version 26.0 (SPSS 26.0) was used for statistical analysis.Continuous variables that conformed to a normal distribution were expressed as mean ± SD, and those that were not normally distributed were expressed as median with interquartile range (IQR). Categorical variables were expressed as frequency and percentage. Comparisons of continuous variables among the four groups were determined by one-way ANOVA or Kruskal-Wallis H test. An χOne hundred eighty-six patients with ANCA-associated renal vasculitis were enrolled in this study. According to different degrees of vascular disease, they were divided into four groups: 23 cases (12.36%) in the non-RVL group, 72 cases (38.71%) in the mild RVL group, 65 cases (34.95%) in the moderate RVLs group, and 26 cases (13.98%) in the severe RVL group. Pathological manifestations of the RVLs are shown in P < 0.05). The SBP of patients with severe lesions was significantly higher than that of patients with mild and moderate RVLs and without RVLs (P < 0.05). The SCR and ESR of the patients with severe, moderate, and mild lesions were significantly higher than those of the patients without RVLs (P < 0.05), and eGFR was lower (P < 0.05).Of the 186 patients, 95 were men and 91 were women (16–82 years old). There were 84 (45.16%) with hypertension, 16 (8.6%) with DM, and 23 (12.37%) with cardiovascular diseases. The prevalence of hypertension was significantly higher in patients with severe vascular lesions than in patients without RVLs and with mild RVLs . The proportion of global glomerulosclerosis of the patients with severe RVLs was significantly higher than that of the patients with mild RVLs and without RVLs (P < 0.05) (P < 0.05)  . The ren < 0.05) . In addi2 = 33.307, P = 0.001) and goodness of fit tests , suggested that the binary logistic regression model was suitable for this study. The results showed that SCR and ESR had a significant positive correlation on RVLs in patients with AAV-related renal vasculitis   .P = 0.002), urine RBC counts , BVAS , and RVLs  were independent risk factors for ESRD or death in patients with ANCA-related renal vasculitis  had RVLs. It suggested that RVLs were common pathological characteristics in the renal biopsies of patients with ANCA-associated renal vasculitis. Among the patients with RVLs in this study, 72 cases (38.71%) of mild RVLs, 65 cases (34.95%) of moderate RVLs, and 26 cases (13.98%) of severe RVLs were included.+T cells via dendritic cells, resulting in ANCA production. ANCA induces the over-activation of neutrophils, leading to the production of abnormal cytokines, accompanied by the release of reactive oxygen species and lytic enzymes and further formation of NET, which damages vascular endothelial cells. NETs are not only involved in ANCA-mediated vascular injury but also in the production of ANCA itself. Therefore, a vicious cycle of NET formation and ANCA production is thought to be involved in the pathogenesis of AAV  are an important means of defense against pathogen invasion . Persists of AAV . MoreoveThe SCR of patients with severe, moderate, and mild RVLs was significantly higher than that of patients without RVLs, and eGFR was lower. The results of the regression analysis showed that SCR was an independent risk factor for RVLs. It was probably that the AAV disease activity, rapid progression, and prolongation of the duration of AAV, autoimmune abnormality, inflammation, oxidative stress, hemodynamic changes, mechanical stretch, and other factors led to endothelial dysfunction, thus resulting in arterial intimal thickening, arteriolar hyaline, and thrombosis. The above processes interacted with each other, exacerbating the development of renal dysfunction, and renal function loss is accompanied by the intimal hyperplasia of renal arterioles .via a mechanism of increasing oxidative stress that could lead to the accumulation of advanced glycation end products. Levels of these oxidation products increase as the glomerular filtration rate declines, which might lead to arterial intimal thickening and directly increased vascular permeability .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.


The aim of the study was to develop a method for diagnosing pre-nosological changes in the electrophysiological state of the myocardium in patients with somatoform dysfunction of the autonomic nervous system (SDANS) and risk factors for cardiovascular diseases using the ECG dispersion mapping method.The study involved 109 male patients, 58 of them with SDANS, and 51 were healthy subjects. The patients with SDANS had the following risk factors for cardiovascular diseases, in decreasing order: stress (71% of cases), low physical activity (59%), smoking (57%), overweight and obesity (43%), anxiety (41%), low consumption of vegetables and fruit (36%), lack of extra aerobic physical activity (36%), excessive alcohol consumption (34%), depression (26%), total cholesterol ≥5 mmol/L (23%), and heart rate ≥80 (9% of the cases). All the subjects underwent clinical examination, laboratory investigation, ECG, ECG dispersion mapping, heart rate variability monitoring.Using the method of ECG dispersion mapping allowed a way for diagnosing pre-nosological changes in the electrophysiological state of the myocardium in male patients with SDANS, the basis of the pathogenesis of which is formed by the tension of the regulatory systems. Correlation between the total score according to the developed method, the RRNN value after 4 min of staying in orthostasis, and the “Myocardium” integral index has been proved. The diagnostic sensitivity of the proposed method with a threshold score of 8 was 80%, specificity — 70.8%.The developed method for assessing pre-nosological changes in the electrophysiological state of the myocardium which includes cardiovascular risk factors with a reclassifying potential, proves the development of pre-nosological changes in patients with SDANS in response to daily physical strain. The changes are associated with the tension of the electrophysiological state of the myocardium, an increased activity of the sympathetic division of the ANS being one of its pathogenetic mechanisms. The development of new methods for the diagnosis of cardiovascular diseases (CVD) continues to be an urgent problem , 2. CurrThe aim of the study was to develop a method for diagnosing pre-nosological changes in the electrophysiological state of the myocardium (EPSM) using the ECG dispersion mapping method in patients with somatoform dysfunction of the autonomic nervous system and risk factors for cardiovascular diseases.The work was carried out at the Voronezh State Medical University named after N.N. Burdenko at the Department of Polyclinic Therapy and General Medical Practice. A total of 109 male patients were examined, including 58 subjects with SDANS aged 22.9±1.6 years (the main group) and 51 healthy men aged 22.8±2.0 years (the control group).The diagnosis of SDANS was based on the criteria of neurocirculatory asthenia proposed by V.I. Makolkin and S.A. Abakumov (1996). The CVD risk factors were analyzed in conformity with the “Cardiovascular Prevention 2017” National Guidelines developed by the Committee of Experts of the Russian Cardiological Society and Russian National Society for Cardiovascular Prevention and Rehabilitation. The study of the functional reserves was based on the R.M. Baevsky’s classification (2003), according to which there are four main states of the regulatory systems: physiological norm, pre-nosological, premorbid states, and disruption of adaptation mechanisms with disease development.EСG dispersion mapping was used as a method of pre-nosological diagnosis. The EPSM was studied by the values of the “Myocardium” integral index. The values of the integral index ≤14% at rest and ≤17% after the physical stress test were interpreted as normal. The values equal to 15–19% represented the borderline state associated with the EPSM tension . The values of the integral index of 20–25% and >25% showed a premorbid state associated with the EPSM overstrain and depletion of the reserves of the myocardial functioning with signs of the disease, respectively [All the subjects involved in the study underwent two functional tests: a physical stress test and an active orthoclinostatic test (AOCT). The day before the functional tests, strong tea, coffee, and alcohol were excluded. The physical stress test consisted of the baseline examination within 60 s at rest and then 2 and 4 min after physical exertion respectively at examination points T1, T2, T3, and T4. The AOCT was performed according to the following algorithm: initial examination in a lying position (T5); in an upright position (T6); 2 min (T7) and 4 min (T8) after staying in orthostasis; in a horizontal position (T9); 2 min (T10) and 4 min (T11) after the transition to the horizontal position.The statistical data processing was carried out using the Statistica software package for Windows and IBM SPSS Statistics 20.0. The p=0.05 value was taken as the threshold level of statistical significance. The Shapiro–Wilk test was used to verify the normality of the analyzed data and the equality of the variances of the feature distributions in the compared groups. In the case of the distribution of the studied features in accordance with the normal law, the mean value (M) was taken as the most typical indicator for the sample, and the standard deviation (σ) was taken as a measure of dispersion. The median and interquartile range were used as a measure of the central tendency and a measure of dispersion in the event that the studied features did not obey the normal law. The correlation between the quantitative normally distributed data was investigated with the Pearson’s method, the relationship between the quantitative abnormally distributed data was measured using Spearman’s correlation (R). Logistic regression was used for the theoretical verification of the developed method and determination of the threshold score. The ROC analysis was used to assess the predictive power of the method and analysis for sensitivity and specificity.Among the CVD risk factors in men with SDANS, psychosocial stress, low physical activity, smoking, overweight and obesity were the leaders . In healThe male patients with SDANS reported the following complaints: stabbing pain in the heart — 48 (82%); respiratory disorders manifesting themselves in a feeling of having a lack of air or lack of breath sensation — 46 (80%). Pulse and blood pressure lability occurring spontaneously or inadequately to physical activity, complaints of palpitation or pulsation in the precordial area or in the neck vessels, vegetative-vascular symptoms , low physical performance, increased fatigue and weakness occurred in 31 (54%), 27 (47%), 23 (39%), and 32 (55%) patients, respectively. The analysis of some clinical parameters in the patients with SDANS and healthy subjects, the “Myocardium” integral index values, the average duration of R–R intervals (RRNN) during the physical stress test and AOCT showed no statistically significant differences between the groups .To develop a method for diagnosing pre-nosological changes in the EPSM in patients with SDANS, the severity of the studied CVD risk factors was ranged from 0 to 3 points. If the office heart rate in a patient with SDANS was 50–59 per minute, it was scored 0 and suggested high cardiovascular fitness of the vascular system. When the office heart rate fluctuated between 60–69, 70–79, or was ≥80 per minute, 1, 2, or 3 points were given, respectively. In this case, the fitness of the cardiovascular system in the subjects was determined as good, satisfactory, and unsatisfactory. 2 points were given and a high level of stress was suggested if the stress level according to the questionnaire by L.G. Reeder et al. (1969) was 1–2. If the stress level was 2.01–3.0 or 3.01–4.0, 1 or 0 points were given and medium and low stress levels were suggested, respectively. The total response on the anxiety subscale  of 0–5, 6–9, ≥10 was given 0, 1, or 2 points, respectively, which characterized the absence of anxiety, subclinical or clinically pronounced anxiety. On the HADS depression subscale, the total response of 0–5, 6–9, ≥10 was interpreted as 0, 1, and 2 points, respectively, suggesting no depression, subclinical or clinically significant depression. If a patient with SDANS smoked ≥1 cigarette per day, 2 points were given, <1 cigarette per day — 1, with a negative smoking status — 0 points.The physical activity level according to R.A. Potemkina (2012) was determined by a positive answer to questions 1–4, 5–6, and 7–8, with the assignment of 2, 1, and 0 points, respectively. If the patient answered “yes” to questions 1–4, it suggested low activity, questions 5–6 — moderate activity, 7–8 — intense physical activity. The values of body mass index (BMI) of 18.5–24.9, 25.0–29.9, and ≥30, respectively, were assigned 0, 1, and 2 points: 0 points suggested normal BMI, 1 — overweight, 2 — obesity.If the office BP was ≤129/84 mm Hg, it was given 0 points, if the SBP was 130–139 mm Hg and DBP was 85–89 mm Hg, it was given 1 point, interpreted as normal and high blood pressure, respectively. If SBP and DBP ≥140/90 mm Hg, it was given 2 points.The daily alcohol consumption of <2 servings in the patients with SDANS was assigned 0 points, 2 and >2 servings were evaluated as 1 and 2 points, respectively.We studied the past history of extra aerobic physical activity during childhood and/or adolescence. If the history was positive, it was given 0 points, it being negative — 1 point.Negative and positive family history of IHD or CVD in the first-degree relatives (men <55 years old and women <65 years old) was interpreted as 0 and 1 points, respectively.If the subject ate ≥5 servings of vegetables and fruit per day, excluding potatoes, 0 points were given, if <5 servings, 1 point was given .The value of RRNN after 4 min of orthostasis (T8) and the value of the “Myocardium” integral index after physical exertion (T2) were selected as the reference points in the development of the method which was based on the literature data , 7. AccoWe had to prove the statistical significance of the correlation between the total score for all the CVD risk factors and the RRNN value after 4 min in orthostasis (T8), between RRNN value in T8 and the “Myocardium” integral index after PE (T2) and, finally, between the “Myocardium” integral index in T2 and the total score for CVD risk factors. As a result, according to our method, we established a statistically significant inverse moderate  correlation between the total score for all CVD risk factors and RRNN in T8. This proves that the greater the total score, the lower the RRNN value in T8, i.e. the higher the activity of the sympathetic part of the ANS, is. Having obtained a moderate correlation between RRNN in T8 and the “Myocardium” integral index in T2 , we demonstrated that the higher the activity of the sympathetic part of the ANS, the greater the value of the “Myocardium” integral index after PE (T2) is. And, finally, our method proves the presence of a direct moderate correlation between the total score for CVD risk factors and the “Myocardium” integral index in T2  in the patients with SDANS. This, in its turn, proved that the higher the total score, the higher the value of the “Myocardium” integral index after PE is.Thus, the total score for CVD risk factors of more than 8 in men suffering from SDANS corresponds to the “Myocardium” integral index value after PE of ≥18% and shows the tension of the regulatory systems with the development of pre-nosological conditions.The theoretical verification of the method was carried out using binary logistic regression. The dependent variable in the patients with SDANS was the presence of pre-nosological changes in the EPSM, and the only predictor was the total score calculated with the use of the developed and studied method see .The regression equation looks as follows:x is the value of the total score for CVD risk factors in a patient with SDANS.where ρ is the theoretical probability of pre-nosological changes in the EPSM in patients with SDANS according to the developed method; 2 coefficient of determination is 0.269; Nagelkerke’s R2 is 0.447; –2Log likelihood ratio is 35.178; χ2=18.146; p<0.001; the level of statistical significance of the regression coefficients is p<0.05.This regression model predicts the risk of developing pre-nosological changes in the EPSM in patients with SDANS with an accuracy of 89.7%. The Cox and Snell’s R2 was 0.330; Nagelkerke’s R2 was 0.549; –2Log likelihood ratio was 30.109; χ2=23.216; p<0.05; the level of statistical significance of the regression coefficients was p>0.05.The prediction accuracy in the patients with SDANS with independent inclusion of predictors in the regression model was the same as in the model based on the total score and amounted to 89.7%. However, the coefficients of determination were slightly greater: Cox and Snell’s RTherefore, the exact model was determined by the total score according to our method, serving the only integral categorized predictor. The theoretical probability of the presence of pre-nosological changes in the EPSM for each patient was calculated using the above regression equation.In the same way, we calculated the mean probability values for each patient with SDANS and determined the range of theoretical probability values at which the pre-nosological changes in the EPSM were practically not detected in the sample. The range of the theoretical probability values from 0.0061 to 0.2095 characterized the interval at which pre-nosological changes in EPSM in the sample were not practically detected. On the graph , it was Further, the threshold score, its diagnostic sensitivity, and specificity were determined by the ROC analysis method for the patients with SDANS. Using the ROC analysis of the sensitivity and specificity indicators and plotting the characteristic curve , we reveThroughout the entire study of SDANS, the researchers were interested in the relationship between mental and somatic disorders, and the CVS symptoms occurring in the patients were studied most closely. In our study, using ECG dispersion mapping as a new method of preclinical diagnosis, we studied the pathogenesis of SDANS in male patients with CVD risk factors. It was established that having the total score of more than 8 for CVD risk factors according to this method, patients with SDANS develop pre-nosological conditions in response to daily physical strain associated with the tension of the EPSM. One of the pathogenetic mechanisms of pre-nosological conditions is an increase in the activity of the sympathetic division of the ANS , 6. ConsThe limited set of risk factors is a drawback of the modern scales used to assess cardiovascular risks , 2, 8. OThus, a patient with somatoform dysfunction of the autonomic nervous system continues to be a difficult patient for the clinician. The interdisciplinary approach is needed in the management of these patients with close interaction between the primary care physician who is most often seen by the patient, the cardiologist, and the mental health professional who must interact on the basis of the biopsychosocial model of the integration of somatic, therapeutic factors and psychosocial determinants.The method developed on the basis of ECG dispersion mapping will improve the efficiency of preventive interventions in patients with borderline mental disorders.


Antihypertensive medications and higher dialysate calcium were negatively associated with the relative decrease in SBP (p < 0.05 for both). Age had a quadratic relationship with SBP trends (p < 0.05). Pre-HD volume status measured by extracellular to total body water ratio was not associated with SBP variation (p = 0.216). Peridialytic SBP trends represent a continuum with serum Na variation being a major determinant while volume status has negligible influence. Middle-aged and overweight patients are particularly prone to SBP decline. Tailoring Na and calcium dialysate concentrations could influence haemodynamic stability during HD and improve patient experience and outcomes.Intradialytic hypotension (IDH) and peridialytic blood pressure (BP) trends are associated with morbidity and mortality in haemodialysis (HD) patients. We aimed to characterise the respective influence of volume status and small solutes variation on peridialytic systolic BP (SBP) trends during HD. We retrospectively analysed the relative peridialytic SBP decrease in 647 prevalent outpatients attending for their mid-week session with corresponding pre- and post-HD bioelectrical impedance analysis. Mean SBP decreased by 10.5 ± 23.6 mmHg. Factors positively associated with the relative decrease in SBP were: serum sodium (Na) decrease, body mass index, serum albumin, dialysis vintage, ultrafiltration rate and urea Kt/V ( During a HD session, the systolic blood pressure (SBP) is expected to fall by 10 to 15 mmHg, mainly during the first hour of treatment2. While the definition of intradialytic hypotension (IDH) varies between studies and clinical guideline committees, it is the most commonly reported complication of outpatient HD treatments affecting up to 50% of ambulatory sessions and is associated with an increased risk of both patient morbidity and mortality4. Peridialytic blood pressure (BP) trends are also associated with cardiovascular and all-cause mortality5.More than 2 million patients with chronic kidney disease are treated with intermittent haemodialysis (HD) worldwide6. As such, patients with greater extracellular water (ECW) were reported to be at reduced risk of IDH7. On the other hand, intradialytic variation of small solutes could influence plasma refilling and patients starting HD with higher calculated osmolarity were reported to have greater falls in SBP8. Dialysate sodium (Na) manipulation and the fall of urea have also been associated with intradialytic hemodynamic stability10.The underlying pathophysiology of BP regulation during HD is complex and multifactorial. During most HD sessions, fluid is removed from the vascular compartment by ultrafiltration (UF) to restore volume homeostasis. A decline in intravascular volume is expected to occur when the UF rate (UFR) exceeds the plasma refilling rate and UFR is thus regarded as an important determinant of IDHAlthough several individual factors have been reported to contribute to SBP changes during HD, their respective contributions and potential interplay in determining SBP trends have not been characterized. As clinical implications are potentially important, we aimed to describe the relationship between volume status, small solute variation and peridialytic SBP trends in a large HD outpatient cohort.We retrospectively reviewed the medical records of prevalent HD outpatients who attended for their mid-week HD session and had corresponding pre- and post-HD bioelectrical impedance analysis and laboratory evaluation as part of their routine follow-up. Patients were screened from two dialysis centres under the care of a single university hospital  between January 2014 and December 2016. Patients were dialyzed with ultrapure quality water using Fresenius 5008  or BBraun Dialogue +  machines with high-flux polysulfone dialyzers  anticoagulated with low molecular weight heparin . All dialysates contained magnesium 0.5 mEq/L, bicarbonate 28 mmol/L, acetate 3.0 mmol/L and glucose 5.5 mmol/L. Sodium dialysate concentration was at the discretion of the clinical care team, with a centre policy of using a dialysate sodium 136–138 mmol/L. Exclusion criteria were: (1) < 18 years-old, (2) limb amputation, or paralysis (3) presence of cardiac pacemaker or implantable defibrillator, and (4) recent urgent hospital admission. Patient co-morbidities and relevant medical history were obtained from computerized hospital medical records. Patients did not receive intravenous iron or erythropoietin-stimulating agents during the considered sessions.0.5)11. Bioelectrical impedance analysis was performed prior to and 20–30 min after the HD session using multifrequency segmental InBody 720 Body Composition Analysis , following a standardized protocol12.BP was measured in a standardized manner both immediately prior to and after the HD session in the non-fistula arm while in the sitting position with cuff size chosen according to patient’s arm size. BP was measured using the automated HD integrated monitors. Devices were regularly calibrated. Mean arterial pressure (MAP) was calculated as 1/3 * SBP + 2/3 * diastolic BP (DBP). SBP decrease was expressed in mmHg and defined as: pre-HD SBP–post-HD SBP. The decrease in SBP index was expressed as a percentage and defined as: (pre-HD SBP–post-HD SBP) / pre-HD SBP. DBP and MAP decrease as well as decrease in DBP and MAP index were defined similarly. Pre- and post-HD blood samples were measured using a standard multi-channel biochemical analyser  with an indirect ion-selective electrode technique for Na. Serum albumin was determined by the bromocresol green method. Total serum calcium was measured and ionized calcium calculated using the Mateu-de Antonio equation, derived from patients with kidney failure  < 35% or > 50%, serum Na < 100 mmol/L or > 160 mmol/L, potassium < 1 mmol/L or > 10 mmol/L, urea > 100 mmol/L and glucose > 60 mmol/L.Continuous variables are expressed as mean ± standard deviation (SD) or median (interquartile range) according to distribution and categorical variables as number and relative frequencies. Normality of distribution was assessed graphically. In univariate analysis, patients were grouped into three categories based on the decrease in SBP: (1) hypotensive ≥ 20 mmHg (2) stable < 20 mmHg and > -− 10mmHg (3) hypertensive ≤ -− 10 mmHg. Patient’s characteristics were compared between groups using one-way ANOVA or Kruskal–Wallis and Chi2 for continuous and categorical variables respectively.Multivariate linear regression with SBP decrease index as the dependent variable was used to build three distinct models adjusted for different covariates. In model 1, considered variables were: pre-HD ECW/TBW, Na decrease, potassium decrease, urea decrease, pre-HD glucose, age, gender, ethnicity (Caucasian vs non-Caucasian), body mass index (BMI), diabetes, antihypertensive medication, coronary artery disease and congestive heart failure. Model 2 was adjusted for the same variables as model 1 with the addition of: serum albumin, access type (arteriovenous fistula vs catheter) and dialysis vintage. Model 3 was adjusted for the same variables as model 2 with the addition of: dialysate calcium, dialysate temperature, UFR, session duration and sessional urea Kt/V. A final multivariate model was specified where variables that were not significant in model 3 were excluded using a stepwise backward procedure. Owing to a quadratic relationship with the decrease in SBP index, the square of age was considered in addition to age in every model.p-value < 0.05 was considered significant in every analysis. Statistical analyses were conducted using STATA version 15 .As data could be collected on several occasions for every patient, multi-level mixed effect analysis was implemented for every regression model. For each model, linearity of relationship, normality of residuals and homoscedasticity of residuals were assessed graphically. Data were considered to be missing completely at random and therefore patients with any missing value were excluded from the multivariate analyses. Continuous variables were standardized to a mean of 0 and a SD of 1 in every model. A two-sided https://www.hra.nhs.uk), and registered with the UCL Department of Nephrology Royal Free Hospital. All patient data was anonymized.Our retrospective audit was checked with, and complied with the United Kingdom (UK) National Health Service Health Research Authority guidelines for clinical audit and service development . Other considered characteristics were similar between groups.Mean SBP decreased by 10.5 ± 23.6 mmHg, corresponding to a mean decrease in SBP index of 6.0 ± 16.1%. Mean DBP decreased by 3.2 ± 13.3 mmHg, corresponding to a mean decrease in DBP index of 2.3 ± 19.3%. Finally, mean MAP decreased by 5.6 ± 14.4 mmHg, corresponding to a mean decrease in MAP index of 4.7 ± 14.9%. Overall, 395 (61.0%) patients were men and median age was 66 (52–76). Patient demographic and clinical characteristics are described according to categories of SBP decrease in Table p < 0.05 for all). Other considered characteristics were similar between groups.Mean pre- and post-HD ECW/TBW were 40.0 ± 1.4% and 39.3 ± 1.6% respectively. Patient laboratory and bioelectrical impedance analysis characteristics are described according to categories of SBP decrease in Table As 39 patients had missing values on considered covariates, 608 patients and 1′186 HD sessions were included in multivariate analysis. Median number of HD session per patient was 2 (1–2) with minimum and maximum values of 1 and 7 sessions respectively.p = 0.008) (Table p = 0.005). This association however did not remain significant in multivariate models. In the final multivariate model, factors positively associated with a decrease in SBP index were: Serum Na decrease, BMI, serum albumin, dialysis vintage, UFR and Kt/V  (Table p < 0.05 for both). Based on standardized β coefficients, relative effect sizes of significant continuous variables in descending order were as follows: UFR, BMI, serum albumin, dialysis vintage, Kt/V, serum Na decrease and dialysate calcium. For every 1 SD (3.2 mmol/l) decrease in serum Na, there was a 1.19% decrease in SBP index    Table . This asl) Table . Factorsy 1 SD 3. mmol/l dp = 0.019) (Supplementary Table p = 0.414). Skeletal muscle mass index and body fat mass index, instead of BMI, were considered in the final multivariate model. Results were similar and the decrease in serum Na remained positively associated with the decrease in SBP index . Body fat mass index , but not skeletal muscle mass index , was positively associated with the decrease in SBP index. The final multivariate model was also adjusted for the administration of intradialytic IV fluid. Results were similar and the decrease in serum Na remained positively associated with the decrease in SBP index (p = 0.004) (Supplementary Table p = 0.237). Serum Na decrease was positively associated with the decrease in MAP index . Age had a significant quadratic relationship with the decrease in DBP and MAP index (p < 0.001 and p = 0.001 respectively).Absolute SBP decrease, instead of relative decrease in SBP index, was considered as the dependent variable in the final multivariate model. Results were similar and serum Na decrease remained positively associated with SBP decrease  effectively showed differential effects on SBP trends16. Although not previously described, we report an association between elevated serum albumin and peridialytic decrease in SBP. Hypoalbuminemia in HD patients may be due to reduced synthesis and increased catabolism, both potentially driven by an inflammatory response36. However, it has also been suggested that lower albumin levels result from extracellular dilution in volume overloaded HD patients37. Thus, our results would support that higher albumin concentrations are associated with intravascular volume contraction, so increasing the risk of IDH. Finally, we observed that a lower dialysate calcium concentration was associated with peridialytic SBP decline. This result supports several earlier smaller studies which have reported greater falls in SBP with lower calcium dialysates, in particular in combination with low magnesium dialysates40. Concerns that using higher dialysate calcium concentrations may promote a positive calcium balance have led to an increase use of lower calcium containing dialysates41. As such, we noted that patients with higher pre-HD serum calcium were prescribed lower calcium dialysate concentration resulting in a lower dialysate to serum calcium gradient ultimately favouring peridialytic BP decline.Age was considered a risk factor of IDH in some studies42. Post-HD glucose was not analysed as it is not routinely measured at our institution. However, pre-HD glucose showed no association with our main outcome and was among the first discarded variables during the backward stepwise procedure. Thus, as all patients were dialyzed against a standard 5.5 mmol/L glucose dialysate, we have no reason to believe that post-HD glucose would have been associated with our outcome. Even so, our main conclusions would likely not have been affected by such an adjustment.As with any observational study, causal inference is inherently limited and confounding by indication has to be considered. However, as most included variables were not readily modifiable and several potential confounders were included, our conclusions should not be significantly altered. Intradialytic BP measurements were not available in our study. Our goal was however slightly different as we considered dialytic SBP regulation as a continuous phenomenon rather than focusing on an arbitrary definition of IDH. As such, the observed linearity of the relationship between SBP variation and its clinical determinants highlighted the fact that quantitative, and not qualitative, differences physiologically determined hemodynamic stability during HD. Likewise, ambulatory interdialytic BP measurements were not considered in our study. While interdialytic BP values are of greater prognostic significance regarding end-organ damage and cardiovascular outcomes, they do not reflect the impact of dialysis itself on hemodynamic regulationIn this observational study, we present novel insights into the hemodynamic regulation during HD by describing clinical determinants of peridialytic BP patterns in a large HD outpatient population. We found that serum Na variation is a major determinant of SBP regulation during HD while volume status at the start of the treatment only plays a negligible role when accounting for relevant clinical variables. While younger as well as older patients tended to maintain their BP throughout treatment, middle-aged and overweight individuals were prone to peridialytic BP decline. Elevated serum calcium also favoured hypotension by clinicians choosing lower dialysate calcium, so decreasing dialysate to serum calcium gradient. In light of these findings, peridialytic BP trends should be perceived as part of a quantitative spectrum determined by certain modifiable physiological variables. Tailoring Na and calcium dialysate prescription could potentially influence hemodynamic stability during HD regardless of volume status and improve patient experience and outcomes.Supplementary Information


Measurement of cerebral oximetry by near-infrared spectroscopy provides continuous and non-invasive information about the oxygen saturation of haemoglobin in the central nervous system. This is especially important in the case of patients with traumatic brain injuries. Monitoring of cerebral oximetry in these patients could allow for the diagnosis of inadequate cerebral oxygenation caused by disturbances in cerebral blood flow. It could enable identification of episodes of hypoxia and cerebral ischemia. Continuous bedside measurement could facilitate the rapid diagnosis of intracranial bleeding or cerebrovascular autoregulation disorders and accelerate the implementation of treatment. However, it should be remembered that the method of monitoring cerebral oximetry by means of near-infrared spectroscopy also has its numerous limitations, resulting mainly from its physical properties. This paper summarizes the usefulness of monitoring cerebral oximetry by near-infrared spectroscopy in patients with traumatic brain injury, taking into account the advantages and the disadvantages of this technique. Traumatic brain injuries (TBIs) are some of the main causes of mortality in patients injured as a result of traffic accidents, falls from a height, battery, or firearm assault. TBIs are classified in various ways. Depending on the severity of the injury, they are divided into mild, moderate, and severe injuries. Depending on the mechanism of injury, they are classified into focal injuries and primary diffuse brain injuries. They can be isolated or part of a multi-organ trauma. TBI leads to primary brain injury.Treatment of patients with TBI is primarily focused on preventing secondary brain injury. For many years, the standard of care for patients with TBI has been the monitoring of intracranial pressure (ICP) and cerebral perfusion pressure (CPP), estimated as the difference between ICP and mean arterial pressure (MAP) . ContinuFor almost 30 years now, a method of non-invasive monitoring of cerebral oximetry using near-infrared spectroscopy (NIRS) has been available. This technique was initially used in neonatal intensive care  and cardCerebral oximetry measurements are performed using near-infrared spectroscopy (NIRS). It is a continuous, non-invasive method that enables monitoring of regional cerebral oxygen saturation. Normal NIRS readings represent a balance between oxygen supply and consumption in peripheral tissues.The technique was first described by Jobsis in 1977 . Under pCerebral oximetry measurements are cheap and easy to take. Special sensors are applied to the scalp which allow one to obtain measurements mainly from the external parts of the brain. For practical reasons, the sensors are commonly attached to the scalp overlying the frontal lobe, but measurements can be made from above any brain lobe. Each probe has a near-infrared light generator (diode or laser) and a proximal and distal light detector. Mixed arterial and venous blood in the brain and external tissues is measured. The arterial to venous blood ratio in the brain is 15:85 . Hemogloc), its extinction coefficient (α), distance traveled by light in tissues (d), and the ratio of the incident light intensity (I0) to the intensity of transmitted light (I) is determined by the Beer-Lambert equation [The light transmitted through biological tissues is reflected, absorbed and scattered. Light reflection is determined by the angle between the light beam and the tissue surface. The absorption of light by tissues, causing the attenuation of light, depends on the chromophores—oxyhemoglobin, deoxyhaemoglobin and cytochrome oxidase. NIRS uses the different absorption properties of oxyhemoglobin, deoxyhaemoglobin and cytochrome oxidase to quantify their concentrations in tissues . The relequation ,8:(1)A=lMost photons in tissues are scattered, so the path traveled by photons can be much longer than the direct distance between the optodes. Most of the total attenuation of an infrared light beam is due to scattering, and only a small portion is absorbed. That is why the differential pathlength factor (DPF) and factor G, which depends on light losses other than attenuation, need to be added to the above equation ,9:(2)A=lNIRS measurements in adults can be performed with the emitter and detectors placed on the same side of the head, providing “regional” information on brain oxygenation as only a small volume of brain tissue between the optodes is examined. In this method, the light travels along an arc with a tissue penetration depth of approximately half the distance between the emitter and the detectors. It is recommended that the distance between the optodes be not less than 2.5 to 3 cm, because the shorter the distance between the optodes, the more strongly the extracerebral tissues attenuate the light [The first NIRS devices used two or three wavelengths and were mainly trend monitors. Nowadays, a four-wavelength generation of NIRS monitors are available, which provide reliable real-time regional cerebral oxygen saturation readings. NIRS devices can use three different detection modes: continuous wave (CW), frequency domain (FD), and time domain (TD). CW monitors are the most popular and the simplest devices. They measure the attenuation of incident light. FD monitors use high-frequency modulation to measure the phase and intensity of the signals generated. This technique allows a more quantitative assessment of the optical properties of tissues. TD monitors measure the time of flight of photons and are the most expensive of all NIRS devices .Adequate cerebral oxygenation is essential in treating patients with TBI. There exist invasive measurement methods, such as the measurement of jugular bulb oxygen saturation (SjvO2) or the measurement of brain tissue oxygen pressure (PbtO2). However, cerebral oximeters using NIRS are more and more frequently employed to obtain non-invasive measurements of cerebral oxygenation.In a study by Esnault et al., cerebral oximetry (rScO2) values obtained by NIRS were compared with the results of an invasive measurement of brain tissue oxygen pressure. A PbtO2 probe was inserted into the frontal lobe of the cerebral hemisphere with more severe tissue injury/damage. The rScO2 sensor, on the other hand, was placed on the skin in the frontal area ipsilateral to the PbtO2 probe. The authors found no correlation between the readings obtained with NIRS and the tissue oxygen pressure probe. Cerebral oximetry allowed one to identify only about 15% of the ischemic episodes detected by the PbtO2 measurement. When one of the subjects developed brain death, NIRS continued to show normal rScO2 values, while PbtO2 dropped to 0 mmHg. Esnault et al. concluded that rScO2 measurement could not be used interchangeably with PbtO2 as a monitor of cerebral oxygenation in patients with TBI .The correlation between rScO2 and PbtO2 in TBI patients was also investigated by Leal-Noval et al. In their study, involving 56 patients, a weak correlation was observed between rScO2 and PbtO2 measurements. Moreover, rScO2 was shown to have poor accuracy in detecting moderate cerebral hypoxia , which iEntirely different observations have been reported by Brawanski et al. Over 90% of their rScO2 readings from the frontal area and PbtO2 measurements from the white matter of the frontal lobe showed a significant correlation. An analysis of their data indicated that the PbrO2 and the rScO2 signals contained similar information despite the fact that they were obtained using completely different technologies . A signiIn a study comparing two types of NIRS monitors—NIRO 200, which measures the cerebral tissue oxygenation index (TOI), and INVOS 5100, which monitors rScO2, jugular bulb oxygen saturation (SjvO2) and central venous saturation (ScvO2) were also measured. Thirty one pediatric patients with congenital heart defects were examined. A significant correlation was demonstrated between the rScO2 and SjvO2 measurements, and an even higher correlation between rScO2 and ScvO2. Similarly, a high correlation between readings was observed for TOI .Monitoring of cerebral oximetry using NIRS in septic shock patients allowed investigation of the relationship between rScO2 and ScvO2. rScO2 and ScvO2 values increased with the progressing stabilization of the patients’ condition and the decrease in lactic acidosis. The study demonstrated that there was a significant negative correlation between lactic acid levels and rScO2 values. On the other hand, a significant positive correlation between rScO2 and ScvO2 readings was observed at 8, 24, 48, and 72 h after admission to the ICU .Many authors believe that cerebral oximetry monitoring using NIRS is an unreliable technique for monitoring oxygen metabolism in the brain tissue compared to measurements of brain tissue oxygen pressure. However, it should be noted that rScO2 and PbtO2 measure different parameters using different techniques. Moreover, PbtO2 is not acknowledged as a gold standard for monitoring oxygen metabolism in the brain. PbtO2 measurements are representative of a small area of tissue in the immediate vicinity of the probe. On the other hand, monitoring of rScO2 could prove very useful in patients in whom an invasive technique cannot or should not be used for various reasons. Both of these parameters could be monitored simultaneously to obtain a more complete picture of changes in cerebral oxygen metabolism . Of noteAutoregulation of cerebral blood flow (CBF) is one of the most important mechanisms for maintaining intracranial homeostasis. It keeps CBF at a constant level in the face of changing cerebral perfusion pressure (CPP). This prevents disturbances in CBF during significant changes in arterial blood pressure. Autoregulation is extremely important in TBI patients in the context of the development of secondary injuries. As a result of impaired autoregulation, the balance between the cerebral metabolic rate of oxygen (CMRO2), cerebral blood volume (CBV) and CBF can be disturbed. This may lead to ischemic or hyperemic brain lesions, hypoxia or increased intracranial pressure. There is ample scientific evidence that abnormal autoregulation of CBF is associated with poorer treatment outcomes in patients with TBI ,20. MoniCurrently, different methods are available for assessing CBF autoregulation. The most widely used invasive techniques include measurement of intracranial pressure (ICP) and direct measurement of oxygen content in the brain tissue . Among non-invasive methods, transcranial Doppler (TCD) ultrasonography, which measures CBF velocity , and NIRThe values of cerebral oximetry are mainly influenced by CBF, cerebral metabolic rate of oxygen and arterial blood oxygen content. Owing to the fact that the factors affecting oxygen metabolism are relatively stable over short periods of time, NIRS can be used in place of invasive methods of bedside monitoring of changes in CBF ,25.Depending on the manufacturer and the technology used, NIRS devices generate various measurements, such as regional cerebral oxygen saturation (rScO2), cerebral blood flow index (rCBFi), tissue oxygenation index (TOI), and relative total tissue hemoglobin concentration (rTHb) .Analyses of cerebrovascular autoregulation include computing correlations of CBF or CBV with CPP using mathematical models  . Brady eMonitoring of CBF autoregulation using NIRS has also been studied in patients with sepsis. NIRS readings were consistent with measurements of changes in autoregulation performed using TCD . SimilarCurrently, the market offers a CBF monitoring device called c-FLOW Ornim Medical LTD device, which uses low-power ultrasound and near-infrared laser light to continuously monitor blood flow in tissue microcirculation. It tracks CBF trends, continuously measures blood pressure, and correlates the measurements to provide a real-time autoregulation index. This allows to identify the limits of cerebrovascular autoregulation and detect impairments in autoregulation .In a study of non-invasive CBF measurement using NIRS and indocyanine green, Gora et al. obtained CBF values that were low compared to those obtained with conventional positron emission tomography (PET) . SimilarIn contrast to these observations are the results of a study by Keller et al., in which measurements obtained by NIRS and indocyanine green were consistent with those obtained by MRI . Also inIn patients with TBI, monitoring of ICP is extremely important in preventing secondary injuries. An increase in ICP is associated with a decrease in CPP, and thus a decline in CBF, which can lead, among others, to a secondary ischemic phenomenon. Moreover, elevated ICP values in patients with TBI are associated with a higher risk of death .Typically, ICP is measured invasively using a probe placed inside the brain. However, attempts are being made at using NIRS cerebral oximetry measurements as a non-invasive ICP monitor.Kampfl et al. used NIRS to monitor cerebral oximetry in two groups of patients with TBI—with ICP higher or lower than 25 mmHg. They observed significantly lower values of rScO2 in patients with increased ICP compared to the group of patients with ICP below 25 mmHg. Moreover, no differences were observed between CPP, TCD or blood gas values between these two groups. It seems that cerebral oximetry monitoring using NIRS may be of help in detecting CBF abnormalities in patients with elevated ICP .Similar observations were made by Dias et al. in a study of the characteristics of plateau waves of intracranial pressure. They observed that an increase in ICP was associated with the detection of brain hypoxia by NIRS .By contrast, Zuluaga et al. observed different trends in rScO2 in a pediatric population depending on the underlying disease causing intracranial hypertension. rScO2 decreased with increasing ICP in children with brain tumors and hydrocephalus, but increased when ICP was caused by intracranial hemorrhage. The authors clearly demonstrated that changes in rScO2 were not significantly related to CPP or ICP. Accordingly, NIRS does not seem to be an appropriate method for monitoring and predicting changes in ICP .It should be noted that in all the studies reviewed here, authors observed changes in cerebral oximetry readings in response to an increase in ICP, thus confirming the usefulness of NIRS in detecting hypoxic episodes. However, these studies do not confirm that NIRS allows to directly diagnose changes in ICP. Nonetheless, it seems that monitoring of rScO2 in patients with TBI may be used as an auxiliary method to signal a possible increase in ICP and the need to initiate more invasive monitoring.A newer method of monitoring CBF that uses infrared light is diffuse correlation spectroscopy (DCS), which is based on the use of the intensity fluctuations of near-infrared light.In a study carried out on neonatal piglets with closed head injury simulating TBI, CBF was monitored with DCS and cerebral blood oxygenation using NIRS. A significant correlation of the results obtained with the DCS with the values obtained with the fluorescent microsphere technique was demonstrated. Measurements made with DCS correlated with the values of arterial oxygen saturation, mean arterial pressure and heart rate. DCS was also sensitive to changing physiological conditions such as cardiac arrest .Baker et al. monitored CBF and oxidative metabolism in brain-injured adults. In the research, they used both invasive methods such as ICP monitor or cerebral microdialysis, as well as non-invasive measurement of NIRS and DCS. Conducted observations confirmed the usefulness of non-invasive methods in monitoring patients with brain injury. There were no significant correlations between the absolute values of the parameters measured with invasive and non-invasive methods. However, the NIRS and DCS measurements allowed the detection of disproportions between cerebral perfusion and oxygen metabolism during specific clinical events, which were also observed by invasive methods. The possibility of longitudinal assessment of cerebral autoregulation, based on non-invasive measurements, has also been demonstrated .Due to the use of hybrid monitors, using both the NIRS and DCS techniques, it is also possible to estimate CMRO2 . The comAlthough monitoring of cerebral oximetry using NIRS has been refined over the years, it still has some limitations.An unquestionable disadvantage of this monitoring technique is the multitude of devices available on the market, which differ in the technical aspects of making measurements, and therefore cannot be used interchangeably .The results obtained with the use of NIRS are influenced by extracerebral blood flow, cerebrospinal fluid, thickness of skull bones, and myelin sheaths . InterfeThe range of normal cerebral oximetry values is also still being discussed. The most commonly used lower and upper limits are 60% and 75%, respectively, with deviations from these baseline values as high as 10%. These limits are individually variable and depend on comorbidities .In patients with TBI, there are also other issues. These patients very often have multiple wounds or postoperative sutures on the scalp, as well as subcutaneous hematomas accompanied by swelling of the soft tissues. These lesions make it impossible to properly attach NIRS electrodes, or cause disturbances in signal reception and falsify readings.The influence of the presence of hematomas and brain edema on the absorption and scattering of near-infrared light in TBI patients has also been debated .Importantly, there have been reports of measuring devices registering normal cerebral oximetry values in patients with confirmed absence of cerebral perfusion . These rCerebral oximetry monitoring using NIRS is increasingly employed in the therapy of TBI patients, not only to register cerebral oximetry. The greatest advantage of this method is that it enables continuous and non-invasive measurement of rScO2. Despite technical imperfections, cerebral oximetry measurements can be an important complement to other parameters monitored, providing a more holistic picture of intracranial pathologies. However, attention should be paid to the still present technical imperfections of the method, which significantly affect the obtained, often inconclusive results.