What is the association of albuminuria with chronic kidney disease (CKD) regression?2), albuminuria level was directly associated with CKD progression and death, and inversely associated with sustained improvement of eGFR for 90 days or longer. Five-year probabilities of CKD regression were higher in people with lower urine albumin-creatinine ratios in a stepwise fashion.In this cohort study of 58 004 adults with newly diagnosed moderate to severe CKD  regression in adults with newly diagnosed CKD. People with chronic kidney disease (CKD) are risk-stratified for adverse events based on estimated glomerular filtration rate (eGFR) and albuminuria level. CKD has often a favorable course (CKD regression) regardless of eGFR. Determining whether lower albuminuria is associated with CKD regression may have implications on CKD management.To assess the 5-year probability of CKD regression across albuminuria categories accounting for the competing risks of CKD progression and death in people with newly diagnosed CKD and the association between albuminuria level and CKD regression.2 for >90 days), between April 1, 2008, and March 31, 2017, and albuminuria measures before cohort entry. Data analysis occurred in January to June 2022.This population-based cohort study used administrative and laboratory data from Alberta, Canada, for adults with incident moderate to severe CKD , and A3≥60 .Albuminuria categories were defined by albumin to creatinine ratios (ACRs): A1 , A2 , A3The main outcome was time to the earliest of CKD regression or progression , death, or censoring . Cumulative incidence functions were used to estimate absolute risks, and cause-specific Cox models were used to assess the association between albuminuria and CKD regression, accounting for age, sex, eGFR, comorbidities, and health services use indicators.<60 albuminuria (3%), and 5520 had A3≥60 albuminuria (10%). Five-year probability of regression was highest with A1 (22.6%), followed by A2 (16.5%), and A3<60 (11.6%) and lowest with A3≥60 (5.3%). Using A1 albuminuria as the reference group, the hazard of regression was highest for A2 , then A3<60 , and lowest for A3≥60 .Of 58 004 people with moderate to severe CKD , 35 360 had A1 albuminuria (61%), 15 597 had A2 albuminuria (27%), 1527 had A3In this cohort study of people with moderate to severe CKD, albuminuria levels were inversely associated with CKD regression. These findings extend the key prognostic role of albuminuria, offering novel opportunities to discuss both favorable and adverse outcomes in people with CKD and inform CKD management. Albuminuria level, a marker of kidney damage, and estimated glomerular filtration rate (eGFR), a marker of kidney function, are routinely used to assess the severity of CKD.3 Both eGFR and albuminuria have been informative in constructing risk-stratification strategies to tailor CKD management and guide appropriate resource allocation, including expedited referral of patients at higher risk of CKD progression.3The higher prevalence of chronic kidney disease (CKD) with global population aging5 the traditional framing of CKD as an unrelenting and progressive process persists. Viewing CKD trajectory as a 1-way path toward failure may lead to an overly pessimistic prognosis outlook for patients and health care practitioners, hindering opportunities to improve health, and result in suboptimal CKD management. Studies have found that patients are often referred to nephrology despite not meeting regional criteria,8 possibly reflecting the belief among primary care physicians that progressive disease is inevitable. Although eGFR alone may not reliably differentiate individuals whose CKD progresses from those in whom CKD remains stable or regresses,10 referral is usually triggered by reduced eGFR, even in the absence of albuminuria, while referral criteria for albuminuria vary across guidelines.12 Finally, discharge back to primary care following referral is uncommon, despite the uncertain benefit of long-term nephrology care for many patients.13 Determining whether the probability of regression varies by degree of albuminuria could offer guidance to optimize CKD management and allow for more comprehensive patient education regarding CKD prognosis.While recent evidence suggests that CKD regression  occurs as often as progression,We performed a population-based study of adults with incident moderate to severe CKD to evaluate the 5-year probabilities of CKD regression, CKD progression, and death across clinically relevant categories of albuminuria, considering the recommended referral threshold of albuminuria. We also studied the independent association between albuminuria and CKD regression accounting for several baseline characteristics.RECORD) guidelines.This cohort study was approved by the institutional review boards at the Universities of Alberta and Calgary with a waiver of participant consent because of the retrospective design and secondary use of routinely collected administrative data. This study is reported following the Reporting of Studies Conducted Using Observational Routinely-Collected Data , between April 1, 2008, and March 31, 2017. We did not include adults with G3a CKD whose very low 5-year risk of kidney failure has implications on CKD definition, referral policies, and patient care.15 We calculated eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, excluding the race coefficient, with serum creatinine values standardized to isotope dilution mass spectrometry–traceable methods.16 We used only outpatient eGFR measurements to minimize the inclusion of people with episodes of acute kidney injury. We used the mean value of eGFR when there were multiple measurements on the same day. To identify people with sustained reduction of eGFR, we screened each individual’s consecutive series of at least 2 eGFR measurements, where the first and last eGFR were separated by more than 90 days, the first and all possible intervening measurements within 90 days were 45 mL/min/1.73 m2 or less, and the last measure was 15 to 44 mL/min/1.73 m2. We selected the earliest series  where all eGFR measurements met the eGFR requirement for cohort entry , A2 , A3<60 , and A3≥60 . We used validated algorithms to identify comorbidities.18We identified adults (aged ≥18 years) with newly documented sustained reduction of eGFR to 15 to 44 mL/min/1.73 mRegression was defined as an increase in eGFR of 25% or more from baseline and sustained improvement of CKD stage, using 2 measures separated by more than 90 days , was included among the outcome of progression. We censored observations at study end  or emigration from province.We studied time to the first of CKD regression (primary outcome), CKD progression, or death. 19 for estimating the cumulative incidence functions of each competing event overall and across albuminuria categories. We further stratified these analyses by age and eGFR stage and summarized absolute risks at 5 years using bar-plots. We evaluated the associations between albuminuria and CKD regression using cause-specific Cox regression,20 accounting for age, sex, eGFR, comorbidities , and markers of access to health services . The association between albuminuria and CKD regression was estimated assuming absence and presence of effect modification by CKD severity (eGFR categories defined by 5-mL/min/1.73 m2 increments) and considering possible additional interactions . We used residual analyses to identify deviations from the linearity and proportionality assumption. During model building, we checked that results were consistent across study time.We used the Aalen-Johnson method21 We conducted analyses in January to June 2022. Statistical analyses were conducted using R software version 4.2.0 . P values were 2-sided, and statistical significance was set at P = .05.We checked consistency of results redefining CKD progression as incident chronic kidney replacement therapy only, instead of CKD progression or kidney replacement, and across subgroups defined by (1) diabetes status, (2) measured vs calculated ACR, (3) timing of albuminuria measurement , (4) outpatient eGFR documentation before the qualifying period; or (5) sustained vs nonsustained albuminuria. Since we expected few people with A1 albuminuria would have repeated measures, we included nonsustained A1 albuminuria as the reference category in Cox regression of the fifth subgroup analysis. We summarized the direct association between albuminuria and the cumulative incidence of CKD regression using Fine and Gray regression.We identified 65 509 adults with newly documented G3b or G4 CKD during the study period , and 5520 participants with A3≥60 albuminuria (10%) .In the final study cohort, 35 360 participants (61%) had A1 albuminuria, followed by 15 597 participants with A2 albuminuria (27%), 1527 participants with A3ia (10%) . People At 5 years from cohort entry, 14 545 participants (25%) had died, 10 299 participants (18%) had CKD regression, and 9266 participants (16%) had either progressed to stage G4 CKD (7211 participants [78%]) or G5-CKD . Less than 1% of the study participants who were censored or event-free at the study end date did not have a recorded outpatient eGFR during follow-up. The probability of regression was higher than the probability of progression in people with or without albuminuria data, with the group without albuminuria data showing higher mortality . The 5-year risk of death without kidney failure varied with a less evident trend across increased albuminuria category .The probability of regression at 5 years decreased with increasing degree of albuminuria, from 22.6% for A1 to 16.5% for A2, 11.6% for A3or A3≥60 . The ris<60 or A3≥60 had the lowest probability of regression, which remained stable across increasing age , followed by A3<60  and A2 . The pattern of association between albuminuria and regression did not change when we considered the effect modification by eGFR, although the association became stronger with lower eGFR (P for interaction <.001)  . Accordin <.001) .We found similar results when we redefined CKD progression as incident chronic kidney replacement therapy only instead of CKD progression or kidney replacement  were more likely to regress than die. These findings support the importance of albuminuria in delineating CKD outcomes and suggest that degree of albuminuria is not only a mutual risk factor of progression along with eGFR, but also a strong and unique indicator of CKD regression.In this population-based cohort study, we found a significant and inverse association between albuminuria and CKD regression in patients with incident moderate to severe CKD. First, increasing levels of albuminuria were associated with an incremental decrease in the probability of regression during follow-up, independent of eGFR and age. Compared with patients with A1 albuminuria, regression of CKD was less likely to occur in those with A2, A323 According to our findings, increasing albuminuria was also associated with significant decrease in the rates of CKD regression, independent of eGFR. Conversely, the association between eGFR levels and CKD regression is uncertain.9 While regression can occur at any degree of kidney function impairment, the probability of improvement may largely depend on the extent of kidney damage, as indicated by the degree of albuminuria.Many studies have demonstrated that increasing albuminuria, a reliable marker of kidney damage, is associated with higher rates of CKD progression or kidney failure.13 timing of referral and the decision to discharge back to primary care should consider both the absolute risk of CKD progression and the probability of CKD regression. While probabilities of regression and progression are comparable across CKD stages,5 albuminuria measures could help identify patients with more stable disease from those who are more or less likely to improve. In the setting of albuminuria that is within reference range to mild, further follow-up at the primary care level may be advised, since regression is common, especially in moderate G3b CKD. On the other hand, with higher albuminuria, regression becomes improbable and expedited referral for specialist care may be warranted. Although there is consensus that nephrology referral should occur once eGFR is less than 30 mL/min/1.73 m2 (stage G4 CKD), guidelines differ regarding referral recommendations based on ACR.12 We found that compared with people with G3b CKD with ACR less than 3 mg/mmol (54% of the cohort), those with G3b CKD and ACR of 30 to 59 mg/mmol CKD (2% of the cohort) had 44% to 60% lower hazard rates of regression. This small subset of patients with eGFR greater than 30 mL/min/1.73 m2 (stage G3b CKD) and ACR 30 to 59 mg/mmol may benefit from earlier nephrology referral, as recommended by some  guidelines.12 Although the probability of regression is reduced to a lesser extent in patients with stage G3b CKD and ACR of 3 to 29 mg/mmol (12%-29% lower hazard), their increased absolute risk of progression relative to those without albuminuria requires closer monitoring by their primary care physicians. Since patients with albuminuria that is mild or within reference range and G3b CKD comprise the largest proportion of the CKD population, these findings could result in a significant reduction of potentially inappropriate referrals, granting access to those most likely to benefit from consultation.Our study has health policy and clinical implications. Given the high demand for referral to specialist nephrology care relative to available resources,25 Compared with individuals with undiagnosed hypertension, people with a known diagnosis of hypertension report lower health-related quality of life, independent of symptoms.26 Studies also suggest that compared with optimism, pessimism in chronic disease is associated with reduced self-efficacy and poor adherence to recommended health behaviors.28 The unrelenting nature of chronic illness may evoke a sense of learned helplessness due to a perceived lack of control over the clinical outcome. Furthermore, patient education in CKD may slow progression and delay time to kidney replacement therapy.30 Our findings suggest that clinicians can empower their patients by providing a more optimistic outlook on disease prognosis, allowing patients and health care practitioners to better engage in shared decision-making and positively impact the psychosocial aspects of health.Finally, patients’ perception of a disease as a ceaseless and progressive process can have deleterious effects on mental health and clinical outcomes.31 Second, only 25% of people in our cohort had follow-up measures of proteinuria within the 3-year time frame preceding diagnosis of moderate to severe CKD. Repeated albuminuria measures were least common in those with A1 albuminuria (<1% of patients) despite more than one-third of this group being diagnosed with diabetes. Although higher mortality in people without albuminuria measurements may reflect selection bias , these findings suggest a need to address a possible lack of awareness regarding the importance of albuminuria in the screening and management of CKD.Although albuminuria is possibly one of the most important factors associated with CKD outcomes, it is not consistently measured in people with CKD. First, in our study, approximately 10% of people with sustained eGFR reduction consistent with moderate to severe CKD had not been tested for albuminuria within 3 years prior to diagnosis, despite a quarter of these people having confirmed diabetes. This pattern has not changed in the last decade, and of the individuals without preceding measures of albuminuria, only 13% had albuminuria measured in 3 months following CKD diagnosis. These findings are complementary to recent work examining quality of CKD management in Canada that found that only 18.4% of people had follow-up albuminuria measures within 6 months of CKD diagnosis.32 Although this may explain why regression is less likely with more severe albuminuria, we do not know what structural changes may occur in CKD regression. Clarification of the mechanistic basis of regression could identify potentially modifiable factors that could be targeted by interventions. Also, our study examined the association between baseline albuminuria and probability of regression and did not assess outcomes after regression or the impact of subsequent changes in albuminuria. Although pharmacologic reduction in albuminuria is known to slow the rate of disease progression,35 the impact of these interventions on CKD regression are unclear.33Our study has implications for future research. First, the pathologic relationship between albuminuria and CKD outcomes is not fully understood. Existing evidence suggests that persistent exposure to albumin at the level of the glomerulus leads to potentially irreversible fibrotic changes.4 and that CKD regression is the most common outcome in primary care settings.10 To our knowledge, the interplay between eGFR and albuminuria on the probability of regression has never been assessed using a large sample size of patients drawn from a population with universal access to health care. Also, we applied a chronicity criterion to define CKD following guideline recommendations.12 Finally, we evaluated albuminuria using clinically relevant categories allowing for application to clinical decision-making.This study is novel and has strengths. Previous studies have shown that CKD regression and death are more likely than CKD progression or kidney failure with advancing age,36 or kidney function recovery from an episode of acute kidney injury. Although we used 2 or more eGFR outpatient measures more than 90 days apart to define regression12 we cannot exclude that outcome misclassification might have occurred. Second, weight loss or malnutrition is an alternative explanation for increasing eGFR. Although some studies that evaluated group differences between regressors and nonregressors have not found a significant difference in body mass index or serum albumin levels,10 we could not include weight change as a potential confounder. Third, given its observational design, we could only account for measured confounders; thus, causal inference cannot be drawn from these data. More favorable outcomes in people with lower albuminuria may be due to individual characteristics, social determinants of health, or better access to care. Additionally, patient cohorts were formed using albuminuria categories that required the conversion of PCR and urine dipstick measures into ACR. Although this approach may have led to misclassification of some individuals, most study participants had direct measures of ACR, we used validated conversion methods, and albuminuria categories had a broad range; therefore, the impact of minor conversion errors was limited. Analyses restricted to participants with measured ACR, or sustained albuminuria were consistent with results of main analyses.Our study should be interpreted in the context of its potential limitations. First, it is possible that CKD regression, as we defined it, may have been influenced by regression-to-the-meanThis cohort study found that albuminuria was associated with CKD regression in patients with incident moderate to severe CKD. The degree of albuminuria could be used to inform referral practices by incorporating probability of CKD progression and regression. Furthermore, evaluating CKD with albuminuria could help clinicians and patients engage in a more comprehensive discussion that includes both adverse and favorable outcomes and positively impact the psychosocial aspects of health for people with CKD.


P < 0.05). Antibody acquisition rates were associated with body mass index  and the duration between transplantation and vaccination . The immunosuppressive drugs used were: prednisolone in all cases, tacrolimus in 89.0%, cyclosporine in 9.6%, and mofetil mycophenolate in 97.3%. None of the patients were excluded from receiving two doses of the vaccine due to adverse effects. The study indicated that vaccination-induced antibody acquisition rates against SARS-CoV-2 were extremely low in Japanese patients who underwent post-kidney transplantation. Thus, despite two doses of vaccination, it is necessary to closely monitor infection control in such patients.Immunocompromised patients, especially those who undergo kidney transplantation, have lower antibody levels following SARS-CoV-2 mRNA vaccination. The situation of transplant treatment, such as transplant source and immunosuppressive drugs, is different in Japan than that in other countries. Therefore, it is necessary to clarify whether antibody acquisition rates differ between Japan and other countries. This retrospective study included patients with post-kidney transplant who were attending at the Nagoya University Hospital. The anti-SARS-CoV-2 IgG antibody titers were measured between 3 weeks and 3 months after vaccination. Seventy-three patients (45 men and 28 women) were included. Of these, 23 (31.5%) showed antibody presence, and the rates of antibody acquisition were very low than those in the control group (100.0% vs. 31.5%,  It has been reported that immunocompromised patients, such as those with underlying diseases, are at a high risk for developing severe disease and need to be careful about infection2. The SARS-CoV-2 mRNA vaccines have shown high antibody acquisition rates in healthy individuals, indicating that they are useful in preventing infections and severe diseases4. However, immunocompromised patients, especially those after kidney transplantation, have low rates of antibody acquisition after SARS-CoV-2 mRNA vaccination than immunologically healthy individuals6. The antibody acquisition rates are higher with two doses of vaccination than with one dose in immunocompromised patients6, but they are still lower than those in healthy individuals.The COVID-19 pandemic that started in 2019 has killed many patients7.In case of kidney transplantation, many living-donor kidney transplantation and ABO-incompatible kidney transplantation have been performed to overcome the donor shortage issue7. Therefore, in addition to ethnic differences, the strength of immunosuppression in kidney transplants may also vary; thus, it is necessary to obtain Japan-specific data. In this study, we measured SARS-CoV-2 antibody titers in post-kidney transplant patients between 3 weeks and 3 months after vaccination to investigate the rates of antibody acquisition.The kidney transplant situation is different in Japan from that in other countries, as ABO-incompatible kidney transplants require blood purification procedures, such as plasma exchange and stronger immunosuppression than ABO-compatible transplants. Furthermore, due to a shortage of donors, kidney transplants are performed in some cases when weak positive donor-specific HLA antibodies (DSA) are considered acceptablen = 8) with chronic kidney disease (CKD) stage G3 or better, including transplant donors and patients with mild IgA nephropathy not requiring steroid therapy. The estimated glomerular filtration rate (eGFR) was calculated using the Japanese equation8. Data regarding patient background, past history, comorbidity, medication, and laboratory data were collected. The study was approved by the Institutional Review Board of the Nagoya University Hospital , and all participants provided written informed consent. All methods were conducted in compliance with the Declaration of Helsinki and the relevant guidelines.Post-kidney transplant recipients who attended Nagoya University Hospital between June and September 2021 were included in this study. Patients who underwent kidney transplantation at other hospitals, but were subsequently attended Nagoya University Hospital, were also included. At the time this study was conducted, two types of vaccines were used in Japan, namely BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). Whenever possible, we investigated which of them was used by obtaining the inoculation forms. Patients who failed to receive SARS-CoV-2 mRNA vaccine due to a history of anaphylaxis or allergy were excluded. Patients already on dialysis, post–SARS-CoV-2 infection, and those who failed to provide consent were also excluded. The control group comprised patients  was used as the analytical instrument. SARS-CoV-2 IgG II Quant Reagent Kit  was used for the SARS-CoV-2 IgG antibody assay. The antibody-positive cutoff was set as at least 50 AU/mL according to the previous reports2 test. Univariate and multivariate logistic regression analyses were used to evaluate the rates of antibody acquisition. Differences were considered statistically significant at P < 0.05. The R software  was used to perform all statistical analyses in this study11. We also used gglot2 package (https://ggplot2.tidyverse.org.) to draw violin plots12.Baseline characteristics are presented descriptively. They were tested using the Mann–Whitney U test and χInformed consent was obtained from all individual participants included in the study.3/μl  for white blood cells and 1.6 × 103/μl  for lymphocytes. The immunosuppressive drugs administered were prednisolone in all cases, tacrolimus in 89.0%, cyclosporine in 9.6%, and mofetil mycophenolate (MMF) in 97.3%. Twenty-three (31.5%) patients in the post-kidney transplant group tested positive for acquired antibodies that was a very low percentage than in control group  who received two doses of SARS-CoV-2 mRNA vaccine Fig. . The basFurther, we compared the characteristics in the antibody-acquired group with those in non-acquired group of patients who underwent post-kidney transplantation. The characteristics of the patients in each group are presented in Table Next, we performed a logistic regression analysis to examine the factors involved in antibody acquisition. Factors found significant in previous analysis Table  were conAdditionally, we attempted to confirm the type of vaccine  by obtaining details with an inoculation form, but failed to determine all of patients. In patients for whom the vaccine type was known, administration of mRNA-1273 vaccine (Moderna) correlated with a higher rate of antibody acquisition than BNT162b2 (Pfizer-BioNTech) .We measured antibody titers from 3 weeks to 3 months after two doses of vaccination, due to the timing of outpatient visits and vaccination. To investigate the possibility of antibody titer decline over time, we assessed for a correlation between the number of days from second vaccination to antibody titer measurement and the antibody titer values. Table The study demonstrated that the rate of antibody acquisition in post-kidney transplant patients was extremely low. Moreover, the study indicated that a significant proportion of post-kidney transplant patients may remain at risk for COVID-19 even after two doses of the mRNA vaccination. A lower BMI and shorter duration between transplantation and vaccination correlated with lower rate of antibody acquisition. Additionally, despite incomplete data, the analyses indicated that there may be differences in antibody acquisition rates depending on the vaccine type.13 are higher than those found in the present study. This may be due to the high intensity of immunosuppression in Japan, where many ABO-incompatible transplants are performed. However, the results of Fig. 14, and underweight people tend to have a weakened immunity. The BMI of patients in this study was not extremely low, but it could be lower than that in patients in other countries; therefore, the antibody acquisition rates may have been lower than those in other countries. The duration between transplantation and vaccination remains controversial. In the antibody-acquired group, the shortest duration between transplantation and vaccination was 16 months. We hypothesized that patients are less likely to acquire antibodies immediately after transplantation even if they are vaccinated; thus, extending the duration between transplantation and vaccination may have become a trend and contributed to bias. The antibody acquisition rate may drop considerably for approximately one year after transplantation, although it is difficult to confirm this based on the small sample size in the present study. However, it is ethically incorrect that patients who have undergone transplantation and are receiving strong immunosuppressive therapy be excluded from vaccination for one year. Furthermore, evidence suggests that people who received the third booster vaccine dose have higher antibody titers than those who received only the second dose, which is also true for organ transplant patients16. Therefore, it is preferable to administer the third dose for infection control, especially in patients with weakened immune systems, such as those immediately after transplantation. Additionally, patients receiving MMF as immunosuppressant have difficulty in acquiring antibodies6. In this study, we failed to examine the relationship between immunosuppressive drugs, especially with or without MMF administration, and antibody acquisition rates as a majority of the patients were administering MMF. However, there was no significant difference in MMF dose between the two groups. We observed a difference in eGFR between the antibody-acquired and non-acquired groups, although it was not significant. It has been reported that renal failure is associated with decreased immunity17. Therefore, patients undergoing strong immunosuppressive therapy for graft rejection or other reasons, and with impaired renal function should be especially careful.The rates of antibody acquisition in immunocompromised patients, such as those after organ transplantation, reported in previous studies19, and allergic reactions may be suppressed in immunosuppressed patients. None of the patients in the present study canceled the second vaccine dose due to allergic reactions. Thus, considering these factors, interventions to improve vaccine response, such as vaccine type, timing of vaccination, additional booster dose administration, and adjustment of immunosuppressive drugs, need to be further investigated in post-kidney transplant patients.In the present study, patients vaccinated with mRNA-1273 (Moderna) had a higher rate of antibody acquisition than those vaccinated with BNT162b2 (Pfizer-BioNTech). This may be attributed to differences in the amounts of chemicals contained in the products. Studies suggest that the frequency of side effects varies with the vaccine typeThe present study has a few limitations. First, it was a retrospective study. Second, the study had a limited number of participants and was conducted at a single center. Third, some of the participants failed to report the type of vaccine they had received. However, despite the limitation, it is extremely important to show the antibody acquisition rate after two doses of vaccinations in kidney transplant recipients because it provides basic information for clinical actions, such as infection control and the third vaccination.The antibody response to two doses of SARS-CoV-2 vaccine in Japanese kidney transplant recipients was lower than that in healthy subjects. Thus, post-kidney transplant patients may remain at risk of infection with only two doses of vaccination, and it is necessary to closely monitor infection control.Supplementary Information 1.Supplementary Information 2.


Cerebral small vessel disease (CSVD) plays an important role in cognitive impairment, stroke, disability, and death. Hypertension is the main risk factor for CSVD. The use of antihypertensive therapy has not resulted in the expected decrease in CSVD complications, which may be related to the underestimation of significance of daily blood pressure profile for blood–brain barrier (BBB) permeability. 53 patients with CSVD of varying severity  and 17 healthy volunteers underwent ambulatory blood pressure monitoring (ABPM) and MRI, including T1-weighted dynamic contrast-enhanced magnetic resonance imaging for assessing BBB permeability. Most of ABPM parameters in CSVD patients did not differ from controls, but were associated with the severity of white matter hyperintensity (WMH) and the total CSVD score. BBB permeability in normal-appearing white matter (NAWM) and grey matter (GM) was significantly higher in CSVD patients, and the severity of BBB permeability remained similar in patients with different stages of WMH. Among BBB permeability parameters, the area under the curve, corresponding to an increase in the contrast transit time in NAWM, had the greatest number of correlations with deviations of ABPM parameters. BBB permeability in CSVD is a universal mechanism of NAWM and GM damage associated with a slight increase in ABPM parameters. It is obvious that the treatment of hypertension in patients with not severe WMH should be more aggressive and carried out under the control of ABPM. In most cases, the severity of hypertension correlates with MRI markers of CSVD, such as white matter hyperintensity (WMH) and lacunae7. The leading mechanism of brain damage in patients with chronic hypertension is hypoperfusion secondary to arteriolosclerosis, which is characterized by the loss of smooth muscle cells, accumulation of fibrotic hyaline deposits, thickening of the blood vessel walls, and luminal narrowing9.Hypertension is the main risk factor for age-related CSVD11, but not the prevalence of cognitive impairment13. This can partly be explained by a lack of or a faint effect of antihypertensive therapy on the increased blood–brain barrier (BBB) permeability14, which, along with ischemia, is another significant mechanism of brain damage in hypertension17. BBB damage in patients with hypertension is considered to be the main mechanism for the initiation and progression of CSVD and the development of forms mixed with neurodegeneration17. In these cases, hypertension is both a factor in BBB damage18 and a consequence of the damage to the cerebral autonomic centres caused by the high BBB permeability19.Modern antihypertensive therapy, aimed primarily at preventing remodelling of small arteries and, accordingly, increasing blood flow, has led to a decrease in the incidence of stroke21. Further experiments on the spontaneously hypertensive rats and stroke‐prone spontaneously hypertensive rats have proven that the mechanism of BBB damage in CSVD is universal and can be observed in milder hypertension stages22. One of the possible explanations may be the effect of blood pressure variability on the high BBB permeability. This assumption is consistent with recent studies that have noted the importance of blood pressure variability in the development of CSVD, including in controlled hypertension according to outpatient measurements24.For a long time, BBB damage with high permeability has been considered mainly as a failure of cerebral autoregulation due to high blood pressure in acute and chronic hypertension26. Increased BBB permeability was found in normal-appearing white matter (NAWM) as compared to controls28; in WMH and adjacent NAWM, correlating with the severity of WMH, hypertension, age and leading to the delayed reduction in cognitive capacity25.In vivo study of the role of this mechanism in CSVD development has become possible with T1-weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), enabling a quantitative assessment of BBB permeability28, but antihypertensive therapy has insufficient effect on reduction of cognitive impairment13. Of particular interest is the clarification of the relationship between the features of hypertension, which is well controlled by outpatient measurements, and BBB permeability in patients with CSVD and cognitive impairment. The study aims to evaluate the relation between daily blood pressure profile and BBB permeability in patients with CSVD and cognitive impairment.Thus, hypertension and increased BBB permeability are of great importance in the development of CSVD29. Patients with low WMH burden  were included in the study if they had hypertension stage 2 or 3 and/or ≥ 1 lacuna.The study included patients aged 46–70 years with cognitive and other neurological complaints, such as gait and balance problems, mood disorders or residual symptoms after stroke, brain changes on MRI corresponded to CSVD 31; (2) patients with small subcortical infarcts/lacunes < 3 months after an acute cerebrovascular event; (3) CSVD due to other independent causes ; (4) a different cause of stroke and concomitant brain pathology other than CSVD; (5) > 50% atherosclerotic stenosis of the extra- or intracranial arteries; (6) serious medical condition—cardiac (ejection fraction < 50%), endocrine , renal (chronic kidney disease with glomerular filtration rate < 30 ml/min), etc.; (7) contraindications for MRI.Exclusion criteria: (1) cognitive impairment due to probable Alzheimer's disease according to the U.S. National Institute on Aging criteria32.The control group consisted of volunteers with no clinical or MRI evidence of vascular and degenerative brain pathology, no hypertension in the medical history and during Ambulatory Blood Pressure Monitoring (ABPM), and matched for age and gender. Controls with hypertension according to ABPM were excluded from the study, in accordance with the European Society of Hypertension recommendations: awake blood pressure was ≥ 135/85 mmHg and/or asleep blood pressure was ≥ 120/70 mmHg, or if blood pressure increased by more than 24% over time during exertionIn total 53 patients  and 17 healthy volunteers  were enrolled in the study.33, hypercholesterolemia, obesity, diabetes mellitus and smoking were assessed in the patients and controls.Traditional vascular risk factors, such as hypertensionThe study was approved by the Local Ethics Committee of the Research Centre of Neurology № №2–4/16 dated 17.02.2016 and performed in accordance with the principles of the Declaration of Helsinki. All subjects signed an informed consent form for participation in the study., Moscow) based on oscillometric method. Patients underwent ABPM during hospitalization with blood pressure measurement every 30 min during the day (8:00 am to 10:00 pm) and every 60 min during the night (10:00 pm to 8:00 am). The ABPM device inflatable cuff was placed on the non-dominant upper limb. In all cases, at least 70% of the measurements were suitable for analysis. We calculated mean 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP); mean, standard deviation and maximal values of awake and asleep SBP and DBP; and blood pressure load parameters as the percentage of readings in a given period , which exceeded the normal levels for awake and asleep SBP and DBP32.All participants underwent ABPM with an automated device ; sagittal 3D T2 FLAIR ; sagittal 3D T1-weighed imaging ; diffusion MRI (DWI) using axial spin-echo echo-planar imaging sequence with two b-values—0, 1000 s/mm2 ; axial susceptibility weighted imaging sequence (SWI) with magnitude and phase images reconstruction .Imaging was carried out in a Siemens MAGNETOM Verio 3 T scanner  with a standard 12-channel matrix head coil. To evaluate STRIVE criteria35.Two neuroradiologists evaluated MR images in a standardized manner, blinded to clinical information. No STRIVE criteria were found in volunteers from control group. There were no acute or recent small lacunar infarcts based on DWI analysis in patients with CSVD. MRI presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0–4 representing all CSVD features combined36 was used to quantify T2 FLAIR white matter hyperintensities (WMH) (score 0–3) as well as semi-automatic WMH segmentation using LST toolbox (http://www.applied-statistics.de/lst.htm) for SPM12 (http://www.fil.ion.ucl.ac.uk/spm) with further manual correction using ITK-SNAP viewer (http://itksnap.org). The obtained data were saved as a binary mask, which was taken into consideration when the NAWM mask was subsequently created to calculate BBB permeability.The Fazekas ScaleDCE-MRI was performed for BBB leak assessment. After two T1-weighted volumetric interpolated breath-hold examination (T1-VIBE) acquisitions (flip angles 2 and 15) for pre-contrast T1-mapping, we injected gadodiamide  0.2 mL/kg  at a rate of 3 mL/s intravenously via injection pump and then performed continuous serial acquisitions of 100 volumes of T1-VIBE images for 15 min 33 s. The scanning parameters were: TR − 8.6 ms, TE − 4 ms, field of view − 250 mm, matrix − 256 × 230 px, flip angle − 15°, and slice thickness − 3.6 mm.37. The hematocrit, contrast agent dose and relaxivity of the contrast agent were set individually for each patient. The Patlak pharmacokinetic model was used to assess the low BBB permeability in CSVD resulting in Ktrans (volume transfer coefficient), Vp  maps, and AUC (area under the curve—corresponding to increased contrast transit time in the brain) maps . This included automatic correction of motion artefacts, correction of pre- and post-contrast data in the dynamic series, concentration of contrast agent in the brain tissue calculation using relative signal change and T1 mapping. Individual vascular input functions were derived semi-automatically from the superior sagittal sinushttp://www.fil.ion.ucl.ac.uk/spm). This included the following steps: coregistration of each subject’s permeability parameter maps and the T1-weighted images; segmenting the T1-weighted images into grey matter and white matter, followed by the correction of obtained images using WMH masks based on a MatLab script (https://matlab.ru/), resulting in the binary images of the corrected grey and white matter. Permeability parameters were calculated in ITK-SNAP (http://itksnap.org) separately for grey matter (GM), NAWM and WMH by superimposing the relevant masks over the individual permeability maps , which do not visually differ, therefore, an analysis of the data of a patient with CSVD stage 2 according to Fazekas Scale is given as an example.Once permeability parameter maps were obtained, further data processing was performed in SPM12  and R 3.4.3  software. Data are presented as n (%) for categorical variables or as mean ± standard deviation (SD) or median [interquartile range (IQR)] for quantitative data. Differences between groups were determined using χ2, independent samples t-test or Mann–Whitney test, univariate analysis of variance or Kruskal–Wallis test with Bonferroni correction, where appropriate. In all cases, two-way statistical criteria were used. The null hypothesis was rejected if CSVD and the control groups were matched for age and gender, and consisted predominantly of women Table . VasculaMost of the patients in the main group (84.8%) had hypertension of varying severity and were taking one or more antihypertensive drugs.The main disease symptoms were cognitive impairment, gait disturbances unrelated to post-stroke hemiparesis, and MRI changes including WMH, lacunae, microbleeds and dilated perivascular spaces Table .Table 2CDifferences in mean asleep DBP, and asleep SBP and DBP load were found when ABPM results were compared between subjects with CSVD and those in the control group Table .Table 3AABPM results showed a good response to antihypertensive therapy in the main group. Most of ABPM parameters in the study  did not show intergroup differences corresponding to doctors’ and patients’ opinion that hypertension was well controlled as measured on the outpatient basis.Although, there were found the relations of ABPM results with neuroimaging markers of CSVD Table .Table 4RIncreased SBP and DBP values had significant relations with WMH load, based on Fazekas Scale score, and correlations with WMH volume and total CSVD score.Relationships between the standard deviation of blood pressure, which correspond to the indices of variability, and neuroimaging markers of CSVD were not found either by comparative or correlation analysis, therefore these data are not included in the table.To clarify the link between daily blood pressure fluctuations and BBB permeability, the last one was assessed using DCE-MRI in patients and controls Fig. .Figure 2According to DCE-MRI, all the study parameters of BBB permeability in NAWM and GM, except for Ktrans in NAWM, were significantly higher in patients with CSVD than in controls.BBB permeability decreased as WMH Fazekas score increased, with significant differences in Vp and AUC in WMH Table .Table 5DDifferences in the BBB permeability parameters in GM and NAWM depending on the WMH Fazekas score were not found.Statistically significant correlations were seen between AUC in GM and NAWM, Vp in NAWM and the parameters of 24-h and awake SBP and DBP Table .Table 6CIncreased BBB permeability, as assessed by AUC, was correlated with mean awake DBP, maximal awake SBP and DBP, awake SBP load (%) in GM, as well as with mean awake DBP and asleep SBP, maximal awake and asleep SBP and DBP, awake SBP load (%) in the NAWM.AUC, which characterizes the contrast delay in the brain, had the highest sensitivity out of BBB permeability parameters.No significant correlations were found between ABPM results and BBB permeability parameters in WMH, so these data are not provided.40.This study sought to clarify the relation between treated hypertension characteristics, assessed by ABPM, and BBB permeability, assessed by DCE-MRI, in patients with CSVD. Most of ABPM parameters in the study did not show intergroup differences, which confirms a good response to antihypertensive therapy in the main group. However, comparison of ABPM results with the severity of WMH based on Fazekas Score and its volume, as well as with total CSVD score, showed direct and significant relations. These data indicate the presence of certain mechanisms related to the abnormal ABPM parameters in patients compared with controls. Since a significant proportion of the studied patients had mild hypertension, as well as mild clinical and MRI signs of the disease, we could assume that BBB damage and its high permeability played a significant role in CSVD development. This hypothesis is based on the study results that indicate the special role of endothelial dysfunction with high BBB permeability as a mechanism of early CSVD41. There were no significant differences in BBB permeability in GM and NAWM between patients with WMH of varying severity. It should be noted that the results of previous studies regarding the significance of BBB permeability in the development of early or late CSVD are contradictory41. A reasonable explanation for our data may be that an increase in BBB permeability is possible with a relatively intact endothelium of small vessels in GM and NAWM in CSVD, corresponding the data about the universal mechanism of BBB damage in patients with CSVD and hypertension of varying severity22. On the other hand, the obtained data on a decrease in BBB permeability in the WMH may represent the conditions that characterize late-stage CSVD such as progressive endothelial death, impaired autoregulation due to small vessel remodelling, wall thickening and lumen narrowing, reduced microvascular perfusion28. This explanation is also supported by the fact that none of the abnormal ABPM parameters had relations with increased BBB permeability in the WMH. This result matches the different responses to elevated blood pressure in normotensive and hypertensive rats in following experiment. The hypertensive rats had higher permeability to sucrose which was absorbed more slowly by the brain, and the authors attributed this to changes in blood flow in hypertension42. AUC, which characterizes the contrast delay in the brain, had the highest sensitivity out of BBB permeability parameters. In our study, AUC in GM and NAWM had the most of relations with ABPM parameters. Although the latter in patients with CSVD did not differ from ones of the control group, we cannot exclude preceding rises in blood pressure that exceeds the upper threshold of cerebral autoregulation with an increase in BBB permeability21. It can be assumed that the use of antihypertensive therapy may change the upper threshold of cerebral autoregulation and the conditions for its disruption. This statement is indirectly supported by the fact that a greater reduction in blood pressure in elderly people with hypertension is associated with increased cerebral blood flow, corresponding to a shift in the autoregulation curve43. On the whole, these data support the necessity for more aggressive treatment of hypertension in patients with CSVD45. The risk of cardiovascular complications is decreased when blood pressure is reduced more aggressively, so the guidelines were rationally revised to the target SBP < 120 mmHg46. A recent randomized trial also supported this finding, as cerebral perfusion did not decrease in patients with severe CSVD when blood pressure was aggressively reduced, unlike in healthy controls47.According to DCE-MRI, all the study parameters of BBB permeability in GM and NAWM, except for Ktrans in NAWM, were significantly higher in patients with CSVD compared to controls that is consistent with the previous studies49.The obtained data on the universal nature of increased BBB permeability in the NAWM and GM in patients with CSVD indicate an ongoing pathological process in the small arteries, which leads to endothelial damage in relatively well-preserved small vessels. The connection between BBB permeability in NAWM and GM and elevated ABPM parameters indicated the importance of autoregulation dysfunction in promoting this mechanism. It is possible that the underestimation of the pathological mechanism of brain damage due to increased BBB permeability can partly explain the significance of hypertension in middle age for the development of cognitive impairment in the elderly50 or high salt sensitivity, which have been found to independently correlate with CSVD51.The lack of significant differences in ABPM results related to BBB permeability between patients and controls allow us to hypothesize the presence of additional factors of endothelial damage and increased BBB permeability alongside hypertension. These factors may be chronic inflammationThe results of the study point out the necessity for more aggressive treatment of hypertension and repeat usage of ABPM as well as requirement for searching and affecting factors that potentiate the role of hypertension in CSVD development. It is obvious that further studies are needed on the effect of antihypertensive therapy on BBB permeability and its ability to protect the brain from damage in patients with CSVD.


The anterograde collaterals were associated with higher relative cerebral blood volume  and a higher rate of deep cerebral microbleeds , whereas retrograde collaterals were associated with higher systolic and diastolic blood pressure (p = 0.031 and 0.020), smaller initial infarction volume , and a higher rate of lobar cerebral microbleeds . Both anterograde and retrograde collaterals may play a critical role in maintaining cerebral perfusion and can have an impact on patient clinical outcomes. Further studies are warranted to verify these findings and to investigate effective treatments.The hemodynamic changes of acute small subcortical infarction (SSI) are not well understood. We evaluate the hemodynamic changes and collaterals in acute SSI using perfusion magnetic resonance imaging (MRI). A total of 103 patients with acute SSI in penetrating artery territories were recruited and underwent MRI within 24 h of stroke onset. Using 4D dynamic perfusion MRI, they were divided into three patterns: 25 (24%) with normal perfusion, 31 (30%) with compensated perfusion, and 47 (46%) with hypoperfusion. The development of anterograde or retrograde collaterals was also evaluated. Patients with hypoperfusion pattern had the highest rate of early neurological deterioration (32%, The online version contains supplementary material available at 10.1007/s12975-021-00953-x. Clinically evident recent small subcortical infarctions (SSI), commonly called lacunar infarcts, account for around one quarter of all cases of ischemic stroke and are also one of the neuroimaging features of small vessel disease (SVD) . Recent In the past, lacunar infarction was thought to be caused by the occlusion of a terminal penetrating artery, without collateral circulation and the occurrence of penumbra , 7. HoweForster et al. first observed anterograde and retrograde collaterals in acute lacunar infarction using 4D dynamic susceptibility contrast (DSC) MR perfusion . RudilosIn the present study, we aimed to evaluate the perfusion and collateral flow patterns in patients with acute SSI, and to evaluate their clinical significance.The current study was retrospective and all patients were recruited from previous prospective studies that used MRI to predict END at Chang Gung Memorial Hospital . All exaWe recorded patient data, including age, sex, and a medical history of hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, atrial fibrillation, and prior cerebrovascular disease. Systolic and diastolic blood pressure values, cell counts, blood biochemistry and coagulation profiles, as determined on the patient’s admission, were also recorded. Neurological deficits were evaluated prospectively using the National Institutes of Health Stroke Scale (NIHSS) scores. END was defined as an elevation of ≥ 2 points on the NIHSS within 72 h of stroke onset. Clinical outcomes at 3 months were evaluated using the modified Rankin scale (mRS).MRI was performed using a 3 Tesla Siemens Verio MRI system  with a 16-channel head coil. A standard protocol was used for all patients including (1) axial T1-magnetization prepared rapid gradient echo (MPRAGE) images, (2) axial T2-weighted turbo spin-echo (TSE) images, (3) axial diffusion-weighted images (DWI), (4) axial fluid-attenuated inversion recovery (FLAIR) images, (5) T2*-weighted gradient echo images, (6) 3D time-of-flight MR angiography, and (7) dynamic susceptibility contrast perfusion weighted images.The imaging sequences and parameters were as follows: DWI , axial T2-weighted TSE images , FLAIR sequence , T2*-weighted gradient echo , and MPRAGE images . The MR angiography used 3D time of flight (TR/TE = 21/3.6 ms and 0.6 mm thickness) covering the extracranial carotid artery and the circle of Willis. The dynamic susceptibility contrast perfusion weighted imaging scans were acquired using a gradient echo echo-planar imaging sequence  with an intravenous bolus injection of gadolinium contrast agent (0.2 mmol/kg) at the fifth dynamic [MIStar  was used to generate the perfusion imaging for each patient. The automatic arterial input function (AIF) was used and then adjusted manually if the quality of the automatic AIF was not satisfactory. Standard singular value decomposition was used to generate quantitative cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps.The topographic location of the acute infarction was first identified on DWIs. With reference to the location of the acute infarction, the location of the perfusion delay was identified visually using the MTT maps. A region of interest (ROI) was placed covering the hypoperfused area on the MTT maps whenever a well-defined hypoperfused area was identified. Alternatively, a ROI was placed on the acute infarction in the DWI maps and it was then shifted into the perfusion maps. The relative MTT (rMTT) ratio was calculated as the ratio of the ROI value of the lesion side to the contralateral normal hemisphere. The ROIs were shifted to the CBV and CBF maps to calculate the relative CBV (rCBV) and relative CBF (rCBF) ratios, respectively.All of the images were evaluated by two experienced stroke neurologists, both of whom were blinded to the clinical information. Any results with discrepancies were reviewed again by both neurologists until a consensus was reached.The DSC perfusion imaging was obtained from perfusion-weighted raw images in each frame to demonstrate the sequential visualization of blood flow in a 1.5-s interval, from the baseline prebolus image to the late venous phase. The perfusion defect on the DSC perfusion imaging was traced with reference to the topographical location of the perfusion defect in the MTT maps or the acute infarction in the DWI maps.The flow patterns were classified as normal perfusion, compensated perfusion, or hypoperfusion Fig. . PatientEvaluation of the development of anterograde or retrograde collaterals was performed for all patients first. Anterograde collateral flow was defined as when the filling contrast appeared inside. However, it was classified as retrograde collateral flow if the contrast filled from outside to inside in continuous images Fig. . PatientNeuroimaging features of SVD and their topographic distribution were analyzed, including white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVSs), and lacunes . WMHs wet test and one-way analysis of variance respectively. Mann–Whitney U test and Kruskal–Wallis test were used respectively to compare means of 2 and 3 groups of variables not normally distributed. Categorical data was analyzed using Fisher’s exact test or Pearson’s chi-square test, when appropriate. If significant differences were found between the three perfusion patterns by Kruskal–Wallis test or Pearson’s chi-square test, multiple comparisons between three groups were conducted and the significance values had been adjusted by the Bonferroni correction. Inter-rater reliability between two raters for the rating of neuroimaging markers was judged by Cohen’s kappa values.Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) statistical software . The Kolmogorov–Smirnov test was used to examine the normalization of continuous variables. Continuous variables with normal distribution were presented as mean ± standard deviation . Means of 2 and 3 normally distributed continuous variables were compared by independent samples Student’s A total of 385 patients with suspected stroke who underwent MRI studies within 24 h of symptom onset were evaluated in the current study. A total of 34 patients were unable to finish their MRI scan and 67 did not show any diffusion restriction lesions in their DWIs. Of the remaining 284 patients, 131 had acute SSS with an axial diameter ≤ 20 mm. There were 11 patients with relevant artery stenosis > 50% and 17 patients with perfusion imaging unsuitable for analysis, who were excluded. A total of 103 patients were recruited into the present study, with a median age of 71 (61–77) years and a median NIHSS score of 4 (3–6) on arrival. The median duration from stroke onset to MRI was 16.7(10.5–22.4) hours and 21 (20%) patients had brainstem strokes. There were 100 (97%) patients who presented with classical lacunar syndromes, including 29 (28%) with pure motor, 21 (20%) with sensorimotor, 24 (23%) with ataxic hemiparesis, 21 (20%) with dysarthria-clumsy hand, and 5 (5%) with pure sensory lacunar syndromes. There were 6 (6%) patients with coexistent atrial fibrillation, while 22 patients (21%) had END. The baseline characteristics, imaging findings, and outcomes as well as their association with perfusion defects, are shown in Table p < 0.001) and rCBV , and the lowest rate of anterograde and retrograde collaterals . Despite low rCBF (0.76) and prolonged rMTT (1.72) in the compensated perfusion patients, the rCBV (0.92) was relatively normal. In 21 patients with brainstem stroke, compensated perfusion patterns were observed notably less (9.5%) than in patients with normal perfusion (42.9%) or hypoperfusion (47.6%) patterns. Among all SVD features, there were no difference between three perfusion patterns. However, patients with hypoperfusion pattern had higher rate of BAD than those with normal perfusion. For baseline characteristics and imaging findings with p values < 0.05 in Table On the basis of the perfusion patterns, there were 25 (24%) patients with normal perfusion, 31 (30%) with compensated perfusion, and 47 (46%) with hypoperfusion. There was no significant difference between perfusion patterns for stroke risk factors, vital signs, and laboratory data. However, none of the patients with a normal perfusion pattern had END and they had the smallest initial and final infarction volumes (Table p = 0.024) and more prolonged rMTT . Anterograde collaterals were significantly associated with a shorter onset-MRI duration  and a higher rate of deep CMBs . Infarction at the brainstem was not associated with anterograde collaterals . Patients with retrograde collaterals were associated with higher systolic blood pressure , higher diastolic blood pressure , smaller initial infarction volume , and a higher rate of lobar CMBs . However, there was no difference for rCBF, rCBV, and rMTT between patients with and without retrograde collaterals.In the 78 patients without normal perfusion, 30 patients had anterograde collaterals, 57 patients had retrograde collaterals, and 24 patients had both (Table p = 0.020), higher mRS at 3 months , higher rate of mRS ≧ 3 at 3 months , higher rate of BAD , and higher rate of retrograde collaterals .The analysis of CMBs with correlation to the baseline characteristics and imaging findings was shown in the supplemental Table The current study demonstrates that there are different hemodynamic compromise and microvascular collaterals in acute SSI. Anterograde and retrograde collaterals may play a critical role in maintaining cerebral perfusion, while perfusion compromise was closely associated with the development of END and final infarct size.Acute SSI is caused by the occlusion of penetrating arteries, which have been long regarded as independent vessels with less interterritorial anastomoses , 22. HowIn acute large steno-occlusive stroke, both anterograde and retrograde collateral perfusion may account for target territory perfusion and complex intercorrelations may exist between them that determine clinical outcomes and treatment responses. Analysis of the Warfarin–Aspirin Symptomatic Intracranial Disease trial data revealed that good retrograde collaterals were a protective factor against ipsilateral recurrent stroke in patients with severe (70–99%) intracranial atherosclerotic stenosis (ICAS), but a risk factor for recurrent stroke in those with moderate (50–69%) ICAS . These fLike steno-occlusive disease, our study suggests that anterograde collaterals may play a crucial role in maintaining adequate microvascular perfusion after acute SSI, given that patients with hypoperfusion had lower rates of anterograde collaterals. Anterograde collaterals may come directly from partially occlusive arteries or indirectly from anastomosis of the proximal penetrating arteries. However, there are fewer proximal anastomosis from basilar arteries and MCA , so the Patients with retrograde collaterals were associated with a smaller initial infarct volume, suggesting a protective effect or an existence of penumbra by the retrograde collaterals. As time passed, the followed infarct volume increased because of no recanalization. However, the perfusion parameters were not different between patients with or without retrograde collaterals. One reason is that the anterograde collaterals play the major role in maintaining the tissue perfusion. Another reason, which we think is more likely to be true, is the methodological limitation that the margin of retrograde collaterals is hard to delineate in such a small perfusion defect and the applied ROI did not include the peripheral area with less severely impaired perfusion so that perfusion parameters did not show the difference.A previous study by Rudilosso et al. reported that systolic blood pressure was higher in patients with sustained hypoperfusion and we also noticed a trend of higher systolic blood pressure in patients with hypoperfusion or in patients without anterograde collaterals. In contrast, retrograde collaterals were associated with higher systolic and diastolic blood pressure. Patients without anterograde collaterals also had a higher percentage of hypertension. Several previous studies revealed that hypertension increases shear stress, endothelial dysfunction, and large artery stiffness that transmits pulsatile flow to the cerebral microcirculation . HyperteThe topographic distribution of SVD imaging markers has been reported to be associated to different pathologies of SVD . CerebraInfarction at the brainstem was less associated with compensated perfusion and anterograde collaterals. These findings may be explained by less autoregulation or fewer proximal anastomosis of the penetrating arteries from the basilar artery . BAD wasThere were several limitations to the present study. First, we excluded patients receiving thrombolytic therapy or thrombectomy so that the timing of MRI was beyond the time window of hyperacute stroke. The measurement in our study may not represent the hemodynamic status in hyperacute stage after SSI. In addition, a single measurement of perfusion status may not fully delineate the dynamic changes. Patients with transient symptoms but with SSI were not enrolled and this may have caused the effects of collateral flow to be underestimated. Because of the restricted spatial resolution of perfusion MRI and the susceptibility of bone artifacts, especially in the posterior fossa, tiny perfusion defects and collaterals may have been missed due to these methodological limitations. Moreover, the number of patients included in the study was relatively small. Despite these limitations, our study still provides valuable information that improves current understanding of the hemodynamic status and collateral flow in acute SSI.In conclusion, this study revealed that there are different microvascular collaterals in acute SSI that determine the variable perfusion compromise and have an impact on clinical outcomes. Both anterograde and retrograde collaterals may play a critical role in maintaining cerebral perfusion. These findings support the penumbral hypothesis for microvascular vascularity in acute SSI and potential pharmacotherapy for recanalization. Further studies are warranted to verify these findings and to investigate effective treatments for the prevention of END and to improve clinical outcomes.Supplementary file1 (DOCX 35 KB)Below is the link to the electronic supplementary material.


Inflammation increases the risk of thrombosis in coronary artery disease (CAD) patients and affects the antiplatelet efficacy of clopidogrel. C1q interacts with platelets to activate platelets and induce thrombosis by participating in and regulating the inflammatory response. Whether C1q affects adenosine diphosphate (ADP)-induced platelet reactivity during clopidogrel therapy was unclear and our study aimed to explore the issue.ADP) > 47 mm plus ADP-induced platelet aggregation (ADPi) < 50%.We enrolled 1,334 CAD patients receiving clopidogrel therapy and evaluated the association between C1q level and high residual platelet reactivity (HRPR) using logistic regression and restricted cubic spline (RCS). HRPR was defined as ADP-induced maximum amplitude . RCS depicted the nonlinear relationship between C1q and HRPR risk (p for non-linear < 0.05).A total of 516 patients (38.7%) performed HRPR. The frequency of HRPR increases with the increase in C1q level . The result of multivariate logistic regression demonstrated elevated C1q as an independent predictor for HRPR (2The current research is the first to explore the association of C1q and ADP-induced platelet reactivity and to demonstrate elevated C1q as an independent risk factor for HRPR in CAD patients during clopidogrel therapy. As the leading cause of death worldwide, cardiovascular diseases represent more than 40% of all deaths among Chinese . CAD, usClopidogrel, one of the earlier P2Y12 inhibitor agents to be applied , is stilComplement component C1q is the recognition molecule of the classical activation pathway, which plays a critical role in defending against invading pathogens, maintenance of immunologic tolerance, and modulation of inflammatory responses . Serum lA cross-sectional study was carried out to explore the association between C1q and ADP-induced HRPR during clopidogrel therapy. Study data were derived from a prospectively collected database, which was created in the Twelfth Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University. We consecutively recruited 1,404 SCAD patients undergoing elective PCI prospectively and evaluated their platelet function using thromboelastography (TEG) from January 2019 to December 2019. All the subjects were Chinese Han population of northern China. All participants were required to receive a loading dose (300 mg) of clopidogrel at least 12 h before PCI or receive a maintenance dose  for at least 5 days before PCI. The following were the exclusion criteria (1) age <18 years old, (2) an abnormal baseline platelet count of <50 × 109/L, or >400 × 109/L, (3) taking other drugs known to affect platelet function, (4) intolerant to DAPT therapy consisting of aspirin and clopidogrel idelines , or thoshttp://ckdepi.org/equations/gfr-calculator/) to get an estimated glomerular filtration rate (eGFR) based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We used a biochemical analyzer to test serum C1q based on the operation process and quality control criteria suggested by the instrument’s instruction .All of the patients included in our study were examined in the same way. The peripheral venous blood sample was drawn after at least 8 h of fasting. Laboratory data included routine blood indicators , lipid profiles , glycemic parameters [glycosylated hemoglobin A1c (HbA1c) and fasting blood glucose (FBG)], uric acid (UA), creatinine (CR), albumin (ALB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), high-sensitivity C-reactive protein (hs-CRP), and complement C1q, which were obtained from the Department of Laboratory Medicine of Beijing Anzhen Hospital based on standard procedure. We used an online tool (thrombin) by the TEG System. Then, the equipment adds 340 μl of heparinized blood into a cup with activator F and reptilase to measure the maximum amplitude of fibrin cross-linked clot without platelet (MAfibrin). Finally, the equipment adds 340 μl of heparinized blood to a cup coated with nonheparinase in the presence of the activator F and ADP (2 μmol) to generate a whole blood cross-linked clot with activated platelet and measure its max strength (MAADP). MAADP reflects the peak intensity of clot developed by ADP in a heparinized whole blood sample, which represents the aggregation capacity of platelet and fibrin induced by ADP. The aggregation capacity of platelet and fibrin induced by thrombin and the aggregation capacity of only fibrin induced by activator F is evaluated by the maximum amplitude of thrombin-induced clot strength (MAthrombin) and of fibrin clot strength (MAfbrin), respectively. The efficacy of clopidogrel in inhibiting ADP-induced platelet aggregation was assessed using ADPi, which was calculated as We used the LEPU TEG System  to assess ADP-induced platelet aggregation, the detection principle of which was described in detail in previous literature , 23. Samte < 50% , 25.We presented continuously normally or non-normally distributed variables by the mean and standard deviation (SD) or by the median and interquartile range (IQR), and presented categorical variables by number and percentage. Normality distribution was assessed using graphical methods and the Shapiro–Wilk test. To compare differences between groups with low and high responses to clopidogrel, p-values were determined using the Student’s t-test or Mann–Whitney test for continuous normally or non-normally distributed variables and using the chi-square test for categorical variables. C1q level was divided into quartiles, and we detected baseline characteristics’ differences among patients with different quartiles of C1q using analysis of variance, Kruskal–Wallis test, or chi-square test when appropriate. Chi-square test, Student’s t-test, and Mann–Whitney test were used to multiply assess differences in ADP-induced platelet aggregation between the reference group (the lowest quartile of C1q) and each higher level using a Bonferroni-corrected significance level of p = 0.05/3. We calculated the odds ratio (OR) and 95% confidence interval (CI) for HRPR in each C1q quartile using univariate logistic regression analysis. In order to evaluate the effect of C1q on a continuous scale, we additionally constructed models including continuous C1q. Furthermore, we included a series of confounders that were picked based on clinical judgment, previous literature, and statistical significance, in multivariable regression models while correcting for confounders (1) Model 1: adjusted for age and sex ; (2) Model 2: adjusted for variables included in Model 1 and smoking status (current smoker), and medical history of diabetes and hypertension; (3) Model 3: adjusted for variables included in Model 2 and laboratory data including PLT, WBC, Hb, LDL-C, HDL-C, eGFR, and hs-CRP]. To reduce the risk of distorted model, we additionally calculated the variance inflation factor (VIF) for each covariate to test data multicollinearity. All models met our criteria of nonmulticollinearity with VIF less than 5  and R (v. 4.0.5).After screening according to inclusion and exclusion criteria, a total of 1,334 participants were consecutively recruited in this study, of whom 516 patients (38.7%) had low response to clopidogrel. All covariate data of interest are complete. Baseline characteristics are presented using stratification based on low and high ADP-induced platelet aggregation in ADP, while correlating negatively with age and ADPi.A total of 1,334 participants were split into four quartiles based on C1q: Q1 . ADP and decreased ADPi with the increase of C1q level . Additionally, patients with higher C1q level were more likely to perform HRPR . MAADP and frequency of HRPR in each higher C1q quartile significantly increase compared to the reference group , but the significant difference in ADPi is present only between the lowest and the highest quartile of C1q (p = 0.011).C1q quartile was set as an ordered categorical variable, which was included in a univariate logistic regression model. The results show that higher C1q level significantly increases risk of HRPR during clopidogrel therapy compared with the lowest quartile . We constructed three additional multivariate logistic regression models (as described previously) to adjust for confounding variables. As We constructed restrictive cubic spline models to flexibly visualize the relationship between the risk of HRPR during clopidogrel therapy and serum C1q on a continuous scale with or without correcting for covariates. In We reported the following novel findings based on the present cross-sectional study. Serum level of C1q is correlated with ADP-induced platelet aggregation assessed by TEG parameters in CAD patients receiving clopidogrel therapy and elevated C1q was proved to be an independent risk factor for HRPR induced by ADP during clopidogrel treatment. Besides these, there exist weak but significant associations between C1q and several HRPR-related factors detected in current and previous studies. Previous studies had demonstrated that the occurrence of HRPR significantly increases the risk of thrombotic and ischemic events in CAD patients , 27, whiAntiplatelet therapy represents the cornerstone of secondary prevention for avoiding coronary artery thrombosis in patients with CAD. Although novel potent P2Y12 receptor antagonists including prasugrel and ticagrelor had already been widely applied in clinical practice, clopidogrel is still indispensable in many clinical scenarios due to its advantages in lower bleeding risk, lower economic burden, and better medication adherence . As a prADP represents the peak clot strength in citrated or heparinized whole blood samples with the addition of moderate ADP , Beijing Municipal Administration of Hospitals’ Mission plan (SML20180601), Capital’s Funds for Health Improvement and Research (CFH 2020-2-2063), and Beijing Municipal Natural Science Foundation (7202041).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.


Considering that some studies have suggested that imatinib (IM) plasma trough levels . The correlation between IM Cmin at different time stages and clinicopathological characteristics was assessed.In 204 patients with intermediate- or high-risk GIST who were taking IM, IM CP = 0.049 and 0.01, respectively). In Group E, IM Cmin correlated with sex (P = 0.049) and age (P = 0.029) and negatively correlated with body weight, height, and body surface area . In Groups F and G, IM Cmin was significantly higher in non-gastric operation patients than in patients with gastrectomy  and was significantly higher in patients with the primary sites of others than in the stomach . In addition, IM Cmin was much higher in patients with mutation sites other than KIT exon 11 in Group F (P = 0.011).Statistically significant differences were observed between Groups A, C, and D (min during the long-term treatment of patients with intermediate- or high-risk GIST. IM Cmin was the highest for the first 3 months and then declined, and long-term administration of IM showed a relatively stable plasma trough level. The IM Cmin correlated with different clinical characteristics at different durations of medication. This meant that future “trough level–clinicopathological characteristics” analyses should be time-point-specific. We also need to formulate time-specific medication monitoring plans in clinical practice to study disease progression caused by the occurrence of drug resistance.This is the first study of IM C Before the year 2000, there was no known effective therapy for gastrointestinal stromal tumors (GISTs). GIST treatment was developed on the basis of the finding that most GISTs have mutations in KIT and platelet-derived growth factor receptor-alpha (PDGFRA). These findings led to the development of effective systemic therapies in the form of small molecule tyrosine kinase inhibitors (TKIs), of which the prototype is imatinib (IM). It is a small molecule that inhibits intracellular autophosphorylation of tyrosine kinase receptors involved in GIST pathogenesis. After a decade of therapeutic use, IM is proven to be a highly effective targeted agent for the treatment of patients with advanced GIST, with a median overall survival of only approximately 19 months to approximately 5 years  were included in this study. The inclusion criteria were as follows: (1) pathologically confirmed GIST; (2) according to the guidelines and expert consensus , 8, patiFor quantifying IM plasma concentration, blood sampling was conducted at 24 ± 3 h following the previous dose of IM in patients with GIST. Patient data were grouped according to the duration of medication with IM . Methods for blood sample processing and storage, as well as IM quantitative analysis, have been previously described (min) after different durations of IM medication.The patients regularly visited the same surgeon every 3–6 months. The clinical characteristics of all patients with GIST were recorded. These clinical characteristics included age, sex, gene mutation site, risk level, primary tumor site, CD34/CD117/DOG-1 (positive or negative), surgical procedures, stable disease or progression, liver metastasis, ki67, and the maximum diameter of the tumor. Body weight was measured at the time of blood sampling, and the body surface area was calculated. A retrospective analysis was conducted to assess the relative factors affecting IM plasma trough concentration ; continuous variables that did not conform to normal distribution were analyzed using the Spearman rank correlation. The IM plasma trough concentrations were measured in 230 patients with GIST. Twenty-one patients were excluded for dexamethasone, omeprazole, ranitidine, metformin, simvastatin, losartan, rifampicin, lamivudine, or levothyroxine. Five patients with serious comorbidities or in whom oral administration was restricted because of significant gastrointestinal bleeding or obstruction were excluded. Finally, 204 patients were included in the study. The details are provided in min of each group were 1390.13 ± 553.80, 1292.94 ± 441.95, 1156.53 ± 450.24, 1040.01 ± 301.70, 1270.64 ± 513.19, 1213.21 ± 446.54, and 1291.97 ± 440.04 ng/ml, respectively. There were statistically significant differences between Groups A, C, and D  (P = 0.617)  , but the= 0.617) .min were performed retrospectively. Within the medication duration of 12 months, IM Cmin was significantly higher in female patients than in male patients  vs. 1,150.7 ± 359.74 ng/ml (n = 39), P = 0.049)  and negatively correlated with body weight, height, and body surface area   . IM Cminctively) .min was significantly higher in patients with the primary site of the small intestine  and other sites (other operations) than the stomach (gastrectomy)  and 1,457.02 ± 410.39 ng/ml (n = 8) vs. 1,087.23 ± 452.74 ng/ml (n = 44), P = 0.029)  or other sites (other operations) than the stomach (gastrectomy)  vs. 1,162.59 ± 327.67 ng/ml (n = 25), P = 0.027)  . When th= 0.027) .min was much higher in patients with mutation sites other than KIT exon 11 mutation during the medication duration of 12<–≤36 months  vs. 1,126.56 ± 421.75 ng/ml (n = 52), P = 0.02)  .min during long-term treatment in patients with adjuvant therapy for GIST. We have shown here that during the first year, IM Cmin was highest for the first 3 months and then declined. There were no significant differences in the Cmin of IM among patients who took the drug for 1 year, 1 to 3 years, and more than 3 years. We also analyzed the relationships between the clinicopathological characteristics of the patients and IM Cmin at different time points. Within the first year of treatment, IM Cmin correlated with age, sex, body weight, height, and body surface area. When the medication duration was 12–36 months, IM Cmin correlated with the primary site of GIST, surgical procedures, and gene mutations. When the medication duration was over 36 months, IM Cmin was significantly higher in patients with primary sites other than the stomach and the corresponding surgical procedures.This is the first study that focuses on the changes in IM Cmin threshold of 760 ng/ml associated with prolonged progression-free survival (For advanced GIST, although IM treatment has proven efficacy, disease progression ultimately occurs because of drug resistance. An altered expression of these transporters may lead to increased clearance of the drug and lower plasma concentrations of IM over time. In a retrospective study, Demetri et al. reported that a significantly shorter time to progression was observed in patients, which showed 1-month IM trough levels below 1,100 ng/ml after 1 month of medication . In realmin in populations with intermediate- or high-risk GIST for a long time. This is the first step in determining the Cmin threshold value and therapeutic drug monitoring for IM in GIST after complete excision. In this study, during the first year of IM, the plasma trough level was highest for the first 3 months and then declined. During long-term treatment, the IM Cmin did not decrease significantly but remained stable or slightly increased after 3 years, but the difference was not statistically significant. This result was consistent with those reported by Eechoute et al. and Yoo et al. in patients with advanced GIST (To the best of our knowledge, no similar study has been conducted on IM adjuvant therapy. But this is a crucial parameter to monitor IM Cced GIST , 11.min included white blood cell count, age, body weight, body surface area, and previous gastrectomy (min in the Chinese population (min were found for different durations of medication, we were surprised to notice that IM Cmin correlated with different clinical characteristics for different durations of medication.Exposure to IM during treatment may be influenced by various factors. Pharmacokinetic studies in patients with chronic myeloid leukemia and GIST have found that variables that were significantly influenced or associated with IM Ctrectomy –14. Our pulation . Howevermin within 1 year of taking medicine. IM Cmin was higher in females than in males. Some researchers believe that this difference may be attributed to differences in body weight between sexes (min (min.Sex, age, body weight, height, and body surface area were the factors influencing IM Cen sexes . In addixes (min . Whethermin was significantly lower both in patients with gastrectomies and in the primary site of the stomach. Although wedge gastric resection was the main type of operation in our study, low IM Cmin was also associated with gastrectomy. Because IM tablets dissolved easily and rapidly at pH 5.5 or less (When the medication duration was over 12 months, IM C or less , the redmin was found to be much higher in patients with mutation sites other than KIT exon 11 mutation during the medication duration of 12–36 months. KIT exon 11 mutation is the most significant benefit of GIST adjuvant therapy (In addition, after excluding patients with wild-type GIST, IM C therapy , 18, butmin, but this study does not clarify all of them. Finally, this is a retrospective study, and there is a possibility that selection bias could influence the outcomes, even though strict screening of the enrolled patients was carried out. In future research, we hope to further expand the sample size, undertake a multicenter study, and focus on patient survival.This study has several limitations. First, only 204 patients were included; the results of this study need to be verified by using a larger sample size. Second, there are several other factors influencing IM Cmin was the highest for the first 3 months and then declined, and the long-term administration of IM showed a relatively stable Cmin. The IM Cmin correlated with different clinical characteristics at different durations of medication. Our results remind us again that “trough level–clinicopathological characteristics” analyses should be time-point-specific in the future. Prospective studies with larger sample sizes are required to verify the results of this study. There is still a long way to go in adjusting the dosage of IM according to IM Cmin and the influencing factors. However, in clinical practice, according to the rules found in this study, we can develop targeted drug monitoring plans for special populations to prevent disease recurrence caused by a low IM Cmin.IM plasma trough levels during long-term treatment of patients with intermediate- or high-risk GIST showed that IM C