Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has been associated with a greater risk of metabolic and cardiovascular comorbidities. The aim of this study is to assess cardiovascular risk by means of intima-media thickness (IMT), metabolic syndrome, and other potential biomarkers in patients with severe hidradenitis suppurativa who are candidates for biologic therapy and to explore potentially associated factors. A cross-sectional study was performed. Body mass index (BMI), carotid intima-media thickness (IMT), and blood tests, including glycemic and lipid profile, insulin, vitamin D, and inflammation markers were performed. Fifty patients were included in the study; the male/female ratio was 3:2. The mean age was 38 years, and the mean disease duration was 21.8 years. The mean carotid IMT was 651.39 μm. A positive association of IMT with disease duration, tobacco consumption, and HbA1c levels was observed. HbA1c correlated with the age of onset, hypertension, metabolic syndrome, and glucose levels. Vitamin D levels inversely correlated with the number of areas affected. In conclusion, patients with severe HS present a higher cardiovascular risk, but it is not distributed equally within the patients: Tobacco consumption, inadequate glycemic control, and disease duration could be useful clinical and biochemical markers to identify patients at higher risk. Cardiovascular diseases are a leading global cause of morbidity and mortality . DiffereOn the one hand, several studies address the issue that poor glycemic control is associated with HS ,14. MoreRecently, different chronic inflammatory diseases have been associated themselves with a higher cardiovascular risk: systemic lupus erythematosus , inflammHidradenitis suppurativa is a chronic inflammatory condition primarily affecting apocrine-gland-rich regions of the body such as the axillary and groin areas, presenting with painful nodules and abscesses that may coalesce and form fistulas where the pus may drain .Given the important implications of the factors associated with cardiovascular risk and the high burden of inflammation that is associated to severe hidradenitis suppurativa, the aim of this study is to assess cardiovascular risk by means of intima media thickness (IMT) and analyze other proatherosclerotic biomarkers in patients with severe hidradenitis suppurativa who are candidates to biologic therapy and to explore potentially associated clinical and biochemical factors.Design: A cross-sectional study was performed to assess IMT in patients suffering from severe HS who are candidates to biologic treatments, and to evaluate potential clinical and biomarkers factors associated.Patients: Patients included in the study are receiving health care in the Hidradenitis Suppurativa Clinic of the Virgen de las Nieves University Hospital. The patients are part of a prospective cohort in which socio-demographic, clinical, and analytic data are collected. This study was approved by the Institutional Review Board of the Hospital Universitario Virgen de las Nieves and is in accordance with the Declaration of Helsinki.Inclusion criteria: The inclusion criteria were as follows: (a) Patients with clinical diagnosis of HS; (b) Patients suffering from severe HS who are candidates to be treated with biologic drugs ; (c) InfExclusion criteria: The exclusion criteria were as follows: (a) Refusal from the patient or legal representative to participate in the study; (b) Patients suffering from HS who are not candidates to be treated with biologic drugs.The patients were assessed the day of the initiation of their biologic treatment before the first dose was administered. Main variables include variables related to the disease severity and variables related to cardiovascular risk assessment.Disease severity was assessed using disease activity indexes:The International HS severity scoring system (IHS4) was used to assess inflammatory activity. It was calculated using the following formula: (number of nodules × 1) + (number of abscesses × 2) + (number of fistulas × 4) .The Hurley classification was used to assess structural damage. It consists of 3 stages  .Number of body areas affected by HS lesions.To assess symptoms, the Numeric Rating System (NRS) was used for pain, itching and suppuration. Values range between 0 and 10 .Cardiovascular risk factors were evaluated by performing blood tests, clinical examination, and carotid artery ultrasonography:Carotid intima-media thickness (IMT): IMT was assessed in both carotid arteries of the patients by using ultrasonography. Left, right, and mean IMT was recorded. The procedure was performed as previously described in similar investigations : A complBlood biomarkers: Different measurements were performed in patients following an 8 h fasting period. Recorded blood parameters included: basal glucose, basal insulin, HOMA score, glycated hemoglobin, triglycerides, HDL and LDL cholesterol, transaminases, albumin, parathyrin, vitamin D, erythrocyte sedimentation rate (ESR), and C-Reactive Protein (CRP).Clinical data: Patients were explored to assess the Body Mass Index (BMI), the metabolic syndrome criteria (ATPIII criteria) , and tobSocio-demographic, biometric and clinical variables, including age, sex, comorbidities, and previous treatments for HS, were recorded by clinical interview, physical examination, and cutaneous ultrasonography through the use of a 7–15 MHz linear probe .t-test or Wilcoxon–Mann–Whitney test were used to compare between nominal and continuous data. To explore possible associated factors, simple linear regression was used for continuous variables. The β coefficient and SD were used to predict the log odds of the dependent variable. Significantly associated variables (p < 0.05) or those showing trends toward statistical significance (p < 0.20) were included in multivariate analysis. Multivariate logistic regression analyses were carried out to identify the factors associated with target variables. Statistical significance was considered if p values were less than 0.05. Statistical analyses were performed using JMP version 9.0.1 .Descriptive statistics were used to evaluate the characteristics of the sample. The Shapiro–Wilk test was used to assess the normality of the variables. Continuous variables are expressed as mean and standard deviation (SD). Qualitative variables are expressed as relative and absolute frequency distributions. The χ2 test or Fisher’s exact test, as appropriate, were used to compare nominal variables, and Student’s p < 0.05). Moreover, IHS4 was inversely correlated with vitamin D levels (p = 0.04).Fifty patients with severe HS were included in the study. The male/female ratio was 3:2, and the mean age of the sample was 38 years old (SD 12.9). Family history of HS was present in 44% (22/50) of the patients; see Previously diagnosed prevalence of diabetes mellitus and dyslipidemia was 10% (5/50) for both entities; see Univariate analyses showed that increasing body mass index, metabolic syndrome criteria, and basal fasting glucose correlated with HbA1c levels. Moreover, high blood pressure and the age of onset showed trends toward statistical significance. No other factors were found to be related to HbA1c in univariant analyses. After multivariate analysis, age of onset, high blood pressure, metabolic syndrome, and basal glucose were correlated to HbA1c levels; see Vitamin D levels were inversely associated with the number of areas affected, IHS4 score, and Hurley stage in univariant analysis. No association was found with parathyrin levels. The multivariate analysis showed an inverse correlation between the number of areas affected and the vitamin D levels; see Mean IMT was 651.30 μm (SD 130.9). The potential predictors of IMT were explored in univariate analyses; see The results of our study show that the IMT is associated with cumulative inflammation and long-term glycemic control in patients with severe HS. We have also observed that HbA1c levels are linked to the presence of metabolic syndrome and that vitamin D levels inversely correlate with disease severity and extension. Patients with severe HS with active tobacco consumption, long disease duration, and metabolic comorbidities, especially abnormal glucose values or diabetes mellitus, may represent a subset of patients with particularly elevated cardiovascular risk.IMT is an useful tool to assess cardiovascular risk  as a marOn the other hand, the disease duration, as a marker of the cumulative burden of inflammation in HS, has correlated to IMT in our study. Previous reports ,43,44 agDespite its strengths, IMT might be inaccurate in some cases, given its operator-dependent nature , althougDiabetes mellitus and, specifically, high HbA1c levels have been linked to an increase in the cardiovascular risk ,53. In aAlthough still controversial, several studies have associated the low levels of vitamin D with cardiovascular risk ,18,19. MOn the other hand, as it has been recently described, HS, as a chronic inflammatory disease, is related to iron deficiency . Since iGiven that most biologic drugs used for HS act through the modulation of cytokines, their powerful anti-inflammatory effect could be related to the improvement of cardiovascular risk. This fact has been reported for other disorders where more studies have been performed. For example, it is known that biologic therapy in psoriasis patients leads to a decrease in the cardiovascular risk measured by the atherosclerosis plaque burden  or the dFuture studies based on the follow-up of the present cohort might be useful to assess whether biologic therapies are capable of modulating the cardiovascular risk and glycemic parameters of patients suffering from severe HS. Moreover, the differential analysis including different biologic therapies and targets might help dermatologists choose the most appropriate drug for patients with HS and significant cardiovascular risk.The main limitation of the present study is its cross-sectional nature, which makes it impossible to assess causality. Moreover, a higher number of patients could have been useful to find potential correlations between variables that have not been shown in the present analysis.Severe HS involves a great inflammatory burden and a higher cardiovascular risk. Cumulative inflammation and glycemic disorders could be useful to identify patients with significant cardiovascular risk and are potential targets to be improved in the treatment of this disease.


The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy. However, studies have shown varices recurrence especially after long-term follow-up. To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS. Thirty-six patients submitted to EGDS were followed for more than five years. They were divided into two groups, according to the portal pressure drop, more or less than 30%, and compared with the behavior of esophageal varices and the rate of bleeding recurrence. A significant reduction on the early and late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy. The drop in portal pressure did not significantly influence the variation of variceal calibers when comparing pre-operative and early or late post-operative diameters. The comparison between the portal pressure drop and the rebleeding rates was also not significant.  This obstruction, along with increased portal flow secondary to splenic vein drainage, represent the disease’s main physiopathologic mechanism. Increased portal flow is supported by the hyperdynamic systemic state, caused by increased cardiac output and by decreased peripheral vascular resistance. In these patients, the spleen acts as a large arterial-venous fistula, with blood flow being diverted from systemic to portal circulation,The rupture of esophageal varices and the consequent gastrointestinal hemorrhage is the main cause of the high mortality rate of this disease,,,,,,,,,,The treatment of choice for these patients, therefore, is surgery, and the most recommended procedure is esophagogastric devascularization and splenectomy (EGDS). The technique follows well-established standards and presents favorable results and safety in avoiding post-operative hepatic encephalopathy, a common complication of portal-systemic shunts. EGDS, on the other hand, present bleeding recurrence rates ranging from 6-29%15 showed that, in the long term, 57% of patients whose esophageal varices had been eliminated after EGDS with post-operative endoscopic treatment, presented with recurrence. Therefore, continuous endoscopic monitoring and treatment are recommended.Sakai et al. (1990)Studies combining esophagogastric devascularization and post-operative endoscopic therapy are scarce, and most use sclerotherapy as the endoscopic therapy, instead of elastic band ligation. On the other hand, studies that assess the progress of patients submitted to endoscopic elastic band ligation to treat esophageal varices involve mainly cirrhotic patients. Therefore, the efficacy of this technique in the post-operative treatment of esophageal varices and the rate of bleeding recurrence in patients with schistosomiasis who were submitted to EGDS remains an unanswered question.The aim of this study was to assess the long-term impact on the behavior of esophageal varices and their hemorrhagic recurrence in the post-operative endoscopic treatment of patients who presented with schistosomiasis and were submitted to EGDS, in two Brazilian university hospitals.This study was approved by the Ethics Committees of both the Clinics Hospital of the University of São Paulo, and the Clinics Hospital of the Federal University of Goiás, Brazil. It was retrospective investigating 176 patients who presented with portal hypertension due to hepatosplenic schistosomiasis with prior bleeding from esophageal variceal rupture, and who were submitted to esophagogastric devascularization and splenectomy at the University of São Paulo School of Medicine, and at the Goiás Federal University School of Medicine. From that group, 59 had been subjected to a protocol to measure the intra-operative portal pressure before and immediately after the surgery, with the goal of evaluating the impact in portal pressure due to the procedure. Of them, 36 had complete medical records, and were monitored for more than five years after the surgery. The inclusion criteria were: over 18 years old; had had a previous episode of upper gastrointestinal bleeding due to esophageal variceal rupture and submitted to EGDS with monitoring of the intra-operative portal pressure; had been diagnosed with mansonic schistosomiasis based on epidemiology and clinical evidence, and confirmed by histopathologic examination with a biopsy during the surgery; had post-operative monitoring  for more than five years.The exclusion criteria were: chronic alcoholism or positive tests for hepatitis B or C; clinical or laboratory evidence of hepatocellular insufficiency, or histopathologic evidence of other hepatopathies; and portal vein thrombosis.The pre- and post-operative endoscopic evaluations, and the operative technique with the portal pressure evaluation have been previously describedThe endoscopic data for the caliber of esophageal varices of 21 patients in the early post-operative period (the first 30 days) were evaluated and compared with the respective calibers in the late post-operative period (greater than five years).,,,Patients were divided into two groups, according to the portal pressure drop, in more or less than 30%.The threshold value of 30% was chosen because it was the average indicated by studies that measured the portal pressure before and after EGDS or splenectomyThe following evaluations were done based on analyzed data: variceal calibers in the pre-operative compared to early and late post-operative periods; drop of portal pressure and the behavior of the varices in the early and late post-operative period; and drop of portal pressure and the rate of post-operative bleeding recurrence.The Kolmogorov test was used to analyze the caliber of the varices in the pre-operative, early post-operative, and late post-operative periods. The exact Fisher test was used to compare the drop in portal pressure with bleeding recurrence. All analyses considered a significance level of 5%.Average patients age was 35 years (22-49), 52.7% were male and 47.3% female.All 36 patients had pre-operative esophageal varices of medium or large caliber. Eighteen (50%) had grade IV varices; 16 (44.4%) grade III, and two (5.4%) grade II.Regarding the evaluation of the drop in portal pressure 21 (58.3%) drop less than 30%, while (41.7%) greater than 30%.When the calibers of pre-operative varices were compared with those of the 21 patients for whom early post-operative data was available, a significant reduction in diameter was observed p<0.001, .When variceal calibers in the pre-operative period were compared with those in the late post-operative period, a significant reduction in diameter was found p<0.001, .Of the 21 patients who were evaluated in the early post-operative period and monitored in the post-operative period, 13 (61.9%) showed an increase in the number of varices during the monitoring.No statistically significant difference was found when the variation in drop of portal pressure (above and below 30%) was analyzed against the variation of variceal caliber, in a comparison between pre- and early post-operative data. The same result was not found when comparing the caliber of the varices in the pre- and late post-operative periods.When comparing the portal pressure drop (above and below 30%), in the group with a drop lower than 30%, 16 (76.2%) did not present bleeding recurrence, while five (23.8%) did.In the group with a drop higher than 30%, 14 (93.3%) did not present bleeding recurrence, while one (6.7%) did. The comparison between the two groups of portal pressure drop and their relations to the rates of bleeding recurrence was not significant p=0.20, .This study found a significant reduction in the caliber of the varices evaluated endoscopically in the early post- in comparison with the pre-operative period; in other words, the surgical treatment per se had a positive influence in reducing the diameter of esophageal varices. However, the intra-operative variation in drop of portal pressure (greater than 30%) did not have a significant influence on the diameter of esophageal varices in the immediate post-operative period (no influence of endoscopic therapy).The reduction in caliber of the esophageal varices was not significant when comparing the pre- and post-operative (early and late) periods in relation to the drop in portal pressure (above and below 30%), in absolute values. This supports the impression that the interruption of the circuit between the portal system and other venous systems, rather than the drop in portal pressure during surgery, is responsible for the positive results of EGDS. Although this significant reduction in variceal caliber in the early post-operative period was followed by a stabilization or reduction of variceal caliber in long term monitoring, a considerable number of patients showed increased variceal calibers during post-operative monitoring.It is possible that, with time, the changes caused by the surgery gradually lose their effect; in this regard, we were able to observe that the increase in variceal caliber during endoscopic monitoring was independent of the drop in post-operative portal pressure. Another finding that supports this theory is that, when the bleeding recurrence rates were compared in the two patient groups with intra-operative portal pressure drops lower or greater than 30%, the difference was also not significant.It is important to point out that in post-operative endoscopic monitoring, interventions on the varices were made whenever necessary, either through sclerotherapy or, more recently, through elastic band ligation. The recurrence or progression in variceal caliber evidenced the important role of post-operative endoscopic therapy. Reinforcing this concept, Makdissi et al. 15 demonstrated, in long term monitoring after EGDS, that in 56.6% of patients whose varices had been eliminated by surgery associated to endoscopic treatment, the varices recurred or increased in diameter during monitoring. On the other hand, when was assessed the caliber of the varices in the early post-operative period in comparison with the late one, was not found a significant difference; this seems to occur in the majority of patients due to the endoscopic therapy.The effectiveness of EGDS associated with endoscopic therapy does not seem to be replicated by the use of either treatment on its own, as shown by Strauss et al. 25 when comparing surgery alone and surgery associated to endoscopic treatment for schistosomiasis-associated portal hypertension. The authors showed that, in patients subjected to EGDS alone (not complemented by other therapies), after an average monitoring period of six years, 28% of patients presented with varices of equal or larger caliber in comparison to the early post-operative period.Lacet et al. 14 showed that, with an average monitoring period of six years, although a significant reduction in variceal caliber was observed in both, patients subjected to endoscopic therapy alone and the ones to endoscopy and EGDS, 8% of those patients with endoscopic therapy alone had a recurrence of large caliber varices.The assessment of the hemodynamic  impact of EGDS has been the object of research at both centers of this research since the 1990s. Most of the papers on the subject evaluated only the immediate results of surgery, without investigating the long-term impact of these interventions. The late results of associating EGDS with endoscopic treatment, regarding the caliber of esophageal varices and bleeding recurrence, are still scarcely studied15,23,24.EGDS with endoscopic therapy has shown low rates of bleeding recurrence, between 5.1% and 15.7%9,14,15,21,22.In this work, the rate of bleeding recurrence by rupture of esophageal varices was 16.6%, the highest among all studies that performed similar analyses; however, this research present the longest post-operative period. The higher percentage of patients with bleeding recurrence supports the statement of Ferreira et al9. that the bleeding recurrence rate increases with longer post-operative follow-up. This study had a few limitations, such as a less than ideal sample size.That is because the number of patients with schistosomiasis has dropped significantly both in São Paulo and Goiás,due to a decrease in the occurrence, morbidity, and mortality of schistosomiasis in our country16,17.Another limitation is the fact that this is a retrospective study, which decreases its conclusive value; however, it has provided the chance to evaluate a very long monitoring period, which would not be possible in a prospective study.Despite these inherent limitations, this study had the advantage of analyzing the drop in intra-operative portal pressure, a rare reported data (only four studies address this data for EGDS patients), correlating this drop to the behavior of esophageal varices and bleeding recurrence over a long post-operative period (10 years). Another benefit of this study is comparing therapeutic results in a cohort of patients in which was assessed the immediate influence of surgical treatment , as well as the short-term (prior to the influence of endoscopic therapy) and long term impacts of the procedure, in individuals that were not influenced by any other diseases or disorders, as observed in cirrhotic patients. The limited size of the sample does not allow us to infer what type of treatment - whether surgery with endoscopic therapy or endoscopic therapy alone - would be the best approach for these patients. Further studies are necessary to understand the role of surgery in the long-term control of esophageal varices in schistosomiasis patients.The drop in portal pressure did not significantly influence the variation of variceal calibers when comparing pre-operative and early or late post-operative diameters. The comparison between the portal pressure drop and the rebleeding rates was also not significant.


Pharmaceutical counseling (PC) interventions have been shown to improve adherence to controller medication and asthma control. However, the real-life impact of these PC interventions in difficult-to-control asthma patients remains unclear. We aimed to assess the effectiveness of PC interventions in real life using nationwide claims data.Demographics and drugs use of patients who received ICS in 2017 with or without pharmaceutical counseling were retrieved from a Belgian claims database. Asthma-related drug use from 1 year before first ICS dispensing in 2017 (reference period) was compared with 1 year after. Outcomes were usage of inhaled corticosteroids (ICS) in defined daily doses (DDD), proportion of users of short-acting beta-agonist (SABA), antibiotics, oral corticosteroids (OCS), asthma biologicals and controller-to-total (CTT) ratio.n = 1350). ICS usage increased significantly in the year after PC intervention compared with the reference period . A nominal decrease was observed in the proportion of SABA (48.0 to 46.2%) and antibiotics (54.5 to 52.7%) after PC intervention compared with the reference period. CTT ratio significantly increased from 0.671 to 0.749 (p < 0.05). The proportion of biological users was nominally lower in the intervention group compared with a control group  in the post-intervention time period (0.22% versus 0.30%).The study population consisted of difficult-to-control asthma patients aged 5–40 years with at least the first interview within 90 days after first ICS dispensing (This first nationwide study among difficult-to-control asthma patients suggests that community pharmacist counseling is effective in real life to improve controller adherence and asthma control.The online version contains supplementary material available at 10.1186/s12913-022-07518-0. Asthma is a prevalent chronic airway disease, often starting during childhood and affecting individuals of all ages . Its worPharmacists may improve patient outcomes through pharmaceutical counseling (PC), which involves an interaction between pharmacist and patient with the objective to improve medication use by teaching them about disease and drug application . A pre-dThe overall aim of this study was to evaluate whether PC interventions improve adherence to chronic inhaler therapy among difficult-to-control asthma patients using real-world, nationwide data. We hypothesized that PC interventions improve ICS adherence and improved adherence results in a better asthma control.The source was the BelPhar database, which collects monthly reimbursement claims and patients’ demographics from all community pharmacies affiliated with the Association of Pharmacists Belgium . At national level, the registered data represents around 85% of all Belgian community pharmacies and corresponds to approximately 78% of all national reimbursed community pharmaceutical dispenses. The database from these community pharmacies open to the general public contains information on dispensed and reimbursed medicines, magisterial preparations, and various fees for community pharmacist services . In Belgium, respiratory medicines listed in Additional Table The source population contained all patients aged 5+ in the BelPharData with at least one ICS dispensing in the period 1/1/2017–31/12/2017, with the date of first dispensing in 2017 defining the reference date. The asthma-related drug use ) with patients who received also a follow-up interview . In both groups, we compared the drug use of the year after first ICS dispensing in 2017 with the drug use the year before. Also, in both groups the first interview happened within 90 days after ICS dispensing.Recruitment of the patients was possible if a PC intervention was 1) prescribed by a physician, 2) suggested by the pharmacist or, 3) at request of the patient .The change in drug use from 1 year before to 1 year after the PC intervention was analyzed. Asthma-relevant drug use was the main outcome of interest, reported as drug usage for ICS and proportion of drug users for the other asthma medications. Drug usage for ICS was defined as the proportion of total Defined Daily Dose (DDD) of ICS and the number of patients receiving ICS. Proportion of drug users was defined as the number of patients receiving an asthma-related drug of interest divided by the total number of ICS patients. For SABA, antibiotics and OCS, the proportion drug users from 1 year before first ICS dispensing in 2017 (reference period) was compared with 1 year after. The ratio of controller-to-total (CTT) asthma medications, an overall proxy for adherence and asthma control, was derived from the reported drug use . The CTTP value < 0.05 was considered significant. Data analyses were performed using SAS 9.4 . Figures were made using Microsoft Excel 16.45.Confidence intervals for the group means were computed by the assumed mean method. Confidence intervals for the difference between two proportions were calculated using the Newcombe method . P valuen = 1350). Among those, 83% (n = 1119) received only the first interview and 17% (n = 231) received also a follow-up interview.The BelPharData-based source population included 922,943 patients having an ICS dispensing recorded in 2017. Of this source population, 288,069 (31%) were chronic ICS users, of whom 56,582 (20%) were aged 5 to 40 years. Among these 5-to-40-year-old asthma patients on chronic ICS therapy, about half (54%) were women and 6% received at least one pharmaceutical counselling interview. Furthermore, 49% were SABA users, 51% were antibiotic users and 8% OCS users. The average ICS adherence was 36%, based on their DDD coverage in 2017. The study population consisted of difficult-to-control asthma patients identified by the pharmacist in this group of chronic ICS users aged 5–40 years, having their first interview within 90 days after the reference date (p < 0.05).The primary analysis showed a significant increase of 43.3 DDD/patient in ICS usage with 125.9 DDD/patient  in the year following the PC intervention compared with a usage of of 82.6 DDD/patient (95% CI 82.0–83.2) the year before  of 39.3 DDD/patient  showed a significant gain of even greater magnitude in ICS usage of 62.1 DDD/patient.A sensitivity analysis on the number of interventions showed a similar, significant increase in ICS usage in patients who received only the first interview n = 119; 83% p > 0.05) lower proportion of SABA users  lower proportion of antibiotic users compared with the reference period. Regarding the OCS use, there was a 1.1%  higher proportion of OCS users, going from 9.0% in the year before to 10.1% the year after the intervention.Difficult-to-control 5–40-year-old asthma patients who received a PC intervention in 2017 experienced a reduction in reliever use. The proportion of SABA users decreased from 48.0% in the year before the intervention to 46.2% in the year after the intervention, leading to a 1.8%  lower absolute proportion of biological use in the study population receiving at least the first interview compared with a similar, chronic ICS user group never receiving this PC intervention.The proportion of biological users was 0.22% when analyzing biological use in the year after the reference date among difficult-to-control 5–40-year-old asthma patients who had a PC intervention. In chronic ICS patients aged 5–40 years who never had an intervention (control group) on the other hand, the proportion of biological use was 0.30%. This indicates a 0.08% (95% CI -0.36,0.23%; The results of this real-world observational study indicate that PC intervention improves adherence to ICS controller therapy and asthma control in difficult-to-control asthma patients.Our findings of an improved adherence to ICS and higher CTT ratio after PC intervention when using real-life data, is supporting earlier trial results on community pharmacy interventions , 21, 22.The findings that PC interventions improved medication adherence and asthma control highlight the increasingly important role of the pharmacist in improving patients’ adherence in the healthcare system. Indeed, they may be considered as guardians of adherence in patients with chronic conditions. Their role in adherence support may be fulfilled with or without novel technologies, such as telemedicine , and hasRegarding reliever use, the number of SABA users was found to be reduced in the pharmacist intervention group compared to their own reference period. These real-life observations are also in line with RCTs observing a decline in reliever medication use in the intervention arm , 23. ThiAs the severity of asthma increases, the patient may need OCS therapy more often to adequately manage the disease and associated exacerbations , 32. TheMoreover, the total percentage of biological users among the studied difficult-to-treat asthma patients was low during the entire follow-up period. This can partially be explained by the fact that omalizumab was the only reimbursed biological available on the Belgian market until the end of 2016. This means that it was being implemented in common pulmonary practice in 2017. The low observed use of these add-on drugs is also in line with their proven efficacy within a very specific target group of very severe asthma, the high costs and under-studied long-term side effects in a young to adult population . AnotherEven though the changes we observed were rather small, they might be of greater clinical importance than the numbers reveal. First, a small decrease in antibiotic use may contribute to a reduction in antibiotic resistance. Furthermore, every reduction in SABA use, reflecting better asthma control, might lead to a reduction in exacerbations, hospitalisations and so a lowering of healthcare expenses and potentially deaths. Although an apparently small absolute decline of 0.08% was observed in the proportion of biological users in cases compared with controls, avoiding unnecessary and potential ineffective initiation of biologicals may reduce substantial drug costs . This isThe pharmaceutical care intervention in Belgium may have benefited from a dense network of pharmacies per inhabitants compared to other countries, adequate training and a renumerated service . MoreoveAnother strength of this research is the large number of patients using ICS therapy registered in the database. This provided a recent and general picture of the current asthma burden on a national, Belgian level. In addition, the database contains extensive information that offered the opportunity to observe various factors related to disease control. This included objective medication data, such as the use of reliever medication, medications treating exacerbations and add-on drugs. Additionally, using the BelPharData had the great advantage of observing a large amount of PC interventions and patient data in the general population. This database also created the opportunities to perform longitudinal analyses of unidentified asthma patients and their corresponding drug profile. The well-considered study design made it possible to perform an intra-patient comparison, taking their own period of time before the PC intervention as reference, and to compare between patients receiving and not receiving the pharmacist intervention, to account for possible time-trend bias.An important limitation of this study was the difficulty to clearly identify asthma patients, especially for a control group, since a medical diagnosis of a physician is not being shared with the community pharmacist in the Belgian healthcare system. The control patients used for the analysis of biologicals never received an intervention, meaning that there was no pharmacist assessment as to whether these ICS users were actually patients with asthma. These probably different patient groups make comparative research challenging. Another limitation is ICS usage as a measure of adherence. We assumed that an increase in ICS usage reflected improved adherence through the PC intervention, but theoretically it could also be due to the need for a higher ICS dose in uncontrolled disease. Moreover, the observed differences in proportion of users of asthma-related drugs were rather small. This may be caused by a lower number of patients in the study population by limiting the definition to only difficult-to-control asthma patients among chronic ICS users aged 5–40 years. Another result of defining our study population this way is that patients not diagnosed, recognized or treated as having asthma, are not captured through our definition. In addition, there was no control over the quality of the way the intervention was carried out, since this was a real-life observation. Although, participating pharmacists were offered training, there is undoubtedly a difference in the way pharmacists conduct the counseling interviews and how much time and effort they had invest in it. Nevertheless, the study results suggest that an intervention generally contributes to an average improvement in the asthma patients’ health. Since we had only data from independent pharmacies, our results cannot be generalized to chain pharmacies. Further research is needed to investigate possible differences between rural and urban pharmacies. Finally, there are some limitations on using CTT ratio as a measure for adherence and asthma control. First, a short-acting beta-agonist might be used before exercising, which reflects a good health and disease control. This will overestimate the use of reliever medication taken for poor asthma control and so underestimate the CTT and asthma control. Second, there will be asthma patients on low dose ICS combined with the LABA formoterol as ‘maintenance and rescue therapy’. This would mean that the ICS and LABA do not always reflect good asthma control, since they could also be used as relievers, but would sometimes have been misclassified as controllers when calculating a CTT ratio. Since 2019, GINA guidelines recommend all individuals with asthma receiving ICS-containing controller treatment for mild asthma, to receive as-needed low dose ICS combined with the LABA formoterol . HoweverFuture studies could evaluate whether PC intervention also improves therapy adherence and disease control of middle-aged and older adults with asthma and/or COPD. Sharing medical diagnosis might help community pharmacists to identify these patients.In summary, the results of this real-world observational study indicate that PC intervention improves adherence to ICS controller therapy and asthma control in difficult-to-treat asthma patients. This study suggests that community pharmacist counseling benefits the management of patients’ asthma on a national level and supports a follow-up interview, especially in all difficult-to-control asthma patients.Additional file 1.


The present findings showed that cinacalcet could be a novel therapeutic tool for suppression of kidney enlargement in hemodialysis patients with ADPKD.A massively enlarged kidney can impact quality of life of autosomal dominant polycystic kidney disease (ADPKD) patients. A recent in vitro study demonstrated that an allosteric modulator of the calcium sensing receptor decreases adenosine-3′,5′-cyclic monophosphate, an important factor for kidney enlargement in ADPKD. Therefore, the present study was performed to determine whether cinacalcet, a calcium sensing receptor agonist, suppresses kidney enlargement in hemodialysis patients with ADPKD. Alteration of total kidney volume together with clinical parameters was retrospectively examined in 12 hemodialysis patients with ADPKD treated at a single institution in Japan. In the non-cinacalcet group with longer hemodialysis duration (n = 5), total kidney volume had an annual increase of 4.19 ± 1.71% during an overall period of 877 ± 494 days. In contrast, the annual rate of increase in total kidney volume in the cinacalcet group (n = 7) was significantly suppressed after cinacalcet treatment, from 3.26 ± 2.87% during a period of 734 ± 352 days before the start of cinacalcet to − 4.71 ± 6.42% during 918 ± 524 days after initiation of treatment ( As kidney function deteriorates, total kidney volume (TKV) generally decreases in most patients with various types of CKD. In contrast, TKV in ADPKD patients usually continues to increase, even after initiation of dialysis therapy, because normal renal parenchyma is replaced by numerous cysts4. At the initiation of KRT, a cyst-filled kidney can weigh as much as 9–13 kg5, then as the cysts grow, ADPKD patients suffer from assorted uncomfortable complications, such as kidney pain, back pain, palpable kidneys, nephrolithiasis, urinary tract infection, gross hematuria, and gastrointestinal symptoms6. Of those, gastrointestinal symptoms, such as appetite loss and nausea, are clinically important, because an enlarged kidney associated with ADPKD has been reported to be a risk factor for malnutrition7, a strong predictor of mortality and morbidity in patients receiving dialysis9. Occasionally, kidneys that are massively enlarged require volume reduction intervention to relieve symptoms and improve quality of life4. Several methods, including needle aspiration and sclerosing of enlarged kidney cysts, fenestration of the cysts, a nephrectomy, and transcatheter arterial embolization (TAE), are available and have been found to be effective, though such intervention is generally accompanied by clinical complications, including bleeding, severe pain, and fever4. Thus, an effective safe therapy that suppresses progression of kidney enlargement in KRT patients with ADPKD needs to be developed.Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of chronic kidney disease (CKD) and the fourth leading cause of kidney failure in patients who underwent kidney replacement therapy (KRT) worldwide14. In ADPKD patients, treatment with tolvaptan, a vasopressin V2 receptor antagonist, has been reported to suppress cAMP levels in the kidney, and also inhibit cell proliferation and kidney enlargement in a dose-dependent manner16. Furthermore, its efficacy to prevent enlargement of the kidneys and kidney function deterioration has been established by the results of two different pivotal clinical trials18. However, tolvaptan cannot be administrated to patients with kidney failure, because its efficacy and safety in such cases has not been proven. A previous in vivo study demonstrated that injection of parathyroid hormone (PTH) or long-acting PTH analog administration in mice led to an increase in cAMP levels in blood as well as in the kidneys19. Vitamin D receptor agonists (VDRA) could have the possibility to reduce increase in TKV. Although VDRAs have been available for patients with kidney failure for a long period, no reports regarding their efficacy to prevent enlargement of the kidneys in patients with ADPKD have been presented. Targeting somatostatin receptors with long-acting somatostatin analogues such as octreotide has also been shown to reduce cAMP accumulation and disease progression in experimental models of ADPKD20. However, that has yet to be shown in hemodialysis ADPKD patients. In consideration of the central role of cAMP in the pathogenesis of ADPKD progression, strategies to lower the level of cAMP in cystic tissues of ADPKD patients with kidney failure are necessary.Previously reported in vitro and in vivo studies have noted that calcium signaling dysregulation, represented by an elevated adenosine-3′,5′-cyclic monophosphate (cAMP) level, is a pivotal promoter of kidney-cyst cell proliferation and luminal fluid secretion21, increased intracellular calcium and reduced cAMP levels22. The findings of the previous study22 suggested a potential therapeutic effect of cinacalcet to suppress kidney enlargement in ADPKD patients with hemodialysis. Hence, the present retrospective observational study was conducted to determine the effects of cinacalcet hydrochloride on kidney volume changes in hemodialysis ADPKD patients with secondary hyperparathyroidism.A recent in vitro study of human conditionally immortalized proximal tubular epithelial cells carrying the PKD1 mutation demonstrated that selective calcium sensing receptor (CaSR) activation by NPS-R568, a first-generation calcimimetic compoundp = 0.429)  examination after initiation of hemodialysis was 68.4 ± 8.6 years. Serum intact PTH was 195 ± 153 pg/mL, which was significantly higher in the cinacalcet group as compared to the non-cinacalcet group (p = 0.030).A flow chart showing selection of the study participants is presented in Fig. 9) Table . In the p = 0.755). However, following the start of cinacalcet treatment, the annual change in TKV rate in the cinacalcet group was − 4.71 ± 6.42% during a period of 918 ± 524 days (range 346–1700 days) , the annual change in TKV rate was significantly decreased in the cinacalcet group after starting cinacalcet treatment as compared to that in the cinacalcet group before treatment started (p = 0.047). Although both the follow-up period and hemodialysis duration were not significantly different between the cinacalcet group after starting cinacalcet treatment and non-cinacalcet group, the annual change in TKV rate was significantly lower in the cinacalcet group after starting cinacalcet treatment as compared to that in the non-cinacalcet group (p = 0.030)  in the cinacalcet and non-cinacalcet groups are shown in Tables p = 0.032). Cinacalcet treatment also tended to cause a decrease in serum calcium and phosphate from the baseline to the end of the observation period . Serum albumin, body mass index, and body weight were not significantly different between the baseline and final follow-up examination, suggesting that the nutritional status in those patients did not appreciably change during the follow-up period.Table The present study was conducted to investigate the effects of cinacalcet on progressive kidney enlargement in hemodialysis patients affected by ADPKD and with secondary hyperparathyroidism. Our findings demonstrated that cinacalcet treatment significantly suppressed an increase in TKV in the examined patients.25. However, in maintenance hemodialysis patients with ADPKD with a longer hemodialysis duration, TKV usually continues to increase, because kidney blood flow is well preserved in the enlarged kidney arteries with preserved peripheral branches4. In the present study, TKV showed a tendency to gradually decrease in ADPKD patients within 3 years after initiation of hemodialysis, after which a gradual increase was seen  orthologous animal model, inhibited cyst growth and renal fibrosis progression, and significantly reduced kidney weights in the later stage of NPHP31. In another study, NPS-R568 was administrated to heterozygote Cy/+ rats, an animal model of ADPKD, from 20 to 38 weeks of age, and kidney and cyst volumes were shown to be significantly lower as compared to rats without NPS-R568 treatment that received calcium32. In contrast, a study that used PCK rats, a model of autosomal recessive polycystic kidney disease, from 10 to 16 weeks of age, and also Pkd2/WS25− mice, a mild phenotype of ADPKD, found no detectable effects of NPS-R568 on cystogenesis33. The discrepancy of reported effects of NPS-568 may be possibly due to different stages of PKD and kidney function. In the study that used PCK rats and Pkd2/WS25− mice, the animals were younger and the stages of kidney dysfunction were milder. In contrast, the animals used in experiments of NPHP mice and Cy/+ rats were older, and also showed enlarged kidneys and advanced kidney failure. Notably, administration of NPS-R568 to Cy/+ rats aged from 20 to 34 weeks did not change kidney or cyst volumes, as compared to those without treatment or with calcium treatment used as a placebo32. Those previous results along with the present findings suggest that the effects of CaSR agonist might be limited to later or advanced stages of ADPKD, particularly in affected patients with kidney failure. The efficacy of tolvaptan to prevent enlargement of the kidneys and kidney function deterioration in pre-dialysis ADPKD patients has been established18. In contrast, tolvaptan is contraindicated for ADPKD patients with kidney failure. For CKD stage 1–4 ADPKD patients, following treatment with tolvaptan, administration of cinacalcet for CKD stage 5D might be a rational strategy to suppress kidney enlargement.Several in vivo studies have been conducted in which NPS-R568 was administrated in animal models of PKD. NPS-R568 administration in 34. One possible mechanism by which cinacalcet suppressed kidney enlargement in the present cohort is by lowering the level of PTH in serum, which leads to reduced tubular activation of PTH1R and cAMP production in kidney cyst cells. Since PTH increases both serum and kidney cAMP levels, we examined the relationship between change in PTH level and TKV in the present ADPKD patients. However, even though the cinacalcet group showed significantly higher serum PTH levels as compared to the non-cinacalcet group, the annual rate of TKV increase was similar between them before cinacalcet treatment. Six of the 16 patients in the non-cinacalcet group were treated with intravenous VDRA and TKV was increased at a similar rate. Therefore, it is considered that cinacalcet has a beneficial effect to suppress kidney enlargement, independent of the level of PTH in serum.PTH is positively coupled to generation of cAMP via the action of PTH receptor 1 (PTH1R)4. Although TAE is an effective procedure, complications such as severe pain within 5 days and fever greater than 38 °C persisting for up to eight days can occur within the first week after treatment4. As compared to interventions to reduce TKV, CaSR agonist are safer, though one of the present patients discontinued cinacalcet due to nausea. A recent meta-analysis of related trials reported risk ratios related to cinacalcet treatment as compared to a placebo in hemodialysis patients of 8.37 for hypocalcemia, 2.10 for nausea, and 2.01 for vomiting35. Although hypocalcemia is the main adverse event associated with cinacalcet treatment, it is relatively easily controlled with use of a VDRA and/or calcium-containing phosphate binders.Intervention to reduce TKV can cause complications36. Therefore, the results obtained from this study conducted in Japan might not be applicable to other ethnicities. Third, this was performed as a retrospective observational study, possibly limiting conclusions to be made from the findings. Fourth, the method used for measuring TKV in the present study was simple37, though more precise qualitative assessment of TKV is available. Furthermore, the CT findings obtained could not be analyzed with newer advanced systems, as those were not available. A fifth limitation is that total liver volume could not be evaluated. In some of the present cases, there were no apparent changes after cinacalcet treatment  scores, such as the mental component and role/social component summaries41. Whether cinacalcet has a beneficial effect on those outcomes should be investigated in future study. Lastly, in the cinacalcet group, although the annual rate of increase in htTKV before cinacalcet treatment was significantly suppressed after cinacalcet treatment, the difference in the slopes of htTKV changes between the periods before and after cinacalcet treatment did not reach a statistically significance. It may be because the timing of CTs, duration of cinacalcet treatment, and htTVK in each patient were very varied, and also because the number of patients was small. Future well-designed prospective longitudinal or randomized control studies are needed to investigate whether various calcimimetic agents are able to suppress kidney enlargement as well as enlarged kidney-related symptoms for improving quality of life in hemodialysis patients with ADPKD that use more precise evaluation methods of outcomes.The present study has some limitations. First, the number of hemodialysis patients examined was relatively small, mainly due to the fact that the enrolled study subjects were treated at a single institution and the prevalence of ADPKD in patients undergoing hemodialysis is only 2–3% in Japan. Furthermore, since patients with secondary hyperparathyroidism who received cinacalcet treatment and underwent abdominal CT examinations were needed, it was difficult to obtain an adequate number. Second, all of the patients were of Japanese ethnicity. In the TEMPO 3:4 trial, the efficacy of tolvaptan for TKV was more effective in Japanese, in whom the annual TKV increase rate was 1.3%, as compared to subjects with a different ethnicity, in whom the annual increase was 2.8%The present findings are the first to demonstrate that cinacalcet suppresses kidney enlargement in hemodialysis ADPKD patients with secondary hyperparathyroidism. Cinacalcet treatment may be helpful for patients with ADPKD who are undergoing hemodialysis to suppress progressive enlargement of the kidneys and also relieve enlarged kidney-related clinical problems including gastrointestinal symptoms. Additionally, that may also postpone the requirement of a kidney volume reduction procedure, such as nephrectomy or TAE, for ADPKD patients requiring hemodialysis. Thus, we propose that cinacalcet treatment be considered as an initial therapeutic option to control secondary hyperparathyroidism in ADPKD hemodialysis patients rather than a VDRA. Furthermore, cinacalcet may possibly suppress kidney enlargement even in patients without secondary hyperparathyroidism, though additional large scale studies are needed. In summary, cinacalcet showed protective effects when given to ADPDK patients, and potentially suppresses kidney enlargement as well as hyperparathyroidism.This study was performed according to the ethical guidelines for medical and health research involving human subjects by the Japanese Ministry of Health, Labour and Welfare, and the Declaration of Helsinki. The protocol of this investigation was approved by the Ethics Committee of Shirasagi Hospital (No. 2019005). Written informed consent prior to the study was obtained from the subjects or an opt-out option was chosen, as explained in instructions posted on the website of the institution.Thi s was a retrospective observational study. Initially, we evaluated 40 maintenance hemodialy4.2sis patients with ADPKD who underwent 3- to 4-h hemodialysis sessions 3 times a week at Shirasagi Hospital from January 2008 to December 2020. Changes in TKV were not evaluated in 15, as CT imaging results were not adequate (n = 3), or TAE (n = 10), or as nephrectomy (n = 2) had been already performed at the time of the screening. Of the 25 patients whose TKV changes were evaluated, 9 were scheduled to be treated with cinacalcet hydrochloride. Of whom 1 could not continue cinacalcet due to nausea and a nephrectomy was performed in 1 for kidney cancer. Finally, 7 patients were included in the cinacalcet group. Of the 16 patients not treated with any CaSR, 5 with dialysis duration matched with that of the cinacalcet group were evaluated as controls , since dialysis duration affected TKV volume  (mg/dL) = measured Ca (mg/dL) + [4 − measured albumin (g/dL)]23.Blood samples were obtained from the arteriovenous fistula just prior to the first hemodialysis session of the week, and routine laboratory tests were performed within 3 h of blood sampling using an automated analyzer23.The main entry criteria of cinacalcet treatments were baseline serum levels of intact PTH and calcium greater than 180 pg/mL and 9.0 mg/dL, respectively, even after treatment with VDRAs and/or phosphate binders. Cinacalcet was started at a daily dose of 25 mg, and then gradually adjusted from 12.5 to 75 mg/day when necessary to achieve a target serum intact PTH level between 60 and 180 pg/mL, as defined by the 2006 Japanese Guidelines for management of secondary hyperparathyroidism in chronic dialysis patients37. TKV was estimated from the linear dimensions using an ellipsoid formula, as follows: length × width × thickness × π/646.The kidneys in the present patients were evaluated using CT examinations. At Shirasagi hospital, abdominal CT scans were basically taken almost every year to medical check-up for hemodialysis patients. TKV determination using CT results was performed at least twice, both before and after cinacalcet treatment, with linear kidney dimensions  measured by K.N., who was blinded to the clinical data. The lengths of both kidneys were calculated from axial slices by multiplying slice thickness by number of slices between the superior and inferior tips of the kidneys, as previously describedAnnual changes were calculated as follows.Non-cinacalcet group:Cinacalcet group before cinacalcet treatment:Cinacalcet group after cinacalcet treatment:U was used for comparisons of clinical parameters between ADPKD patients with and without cinacalcet treatment. Paired Student’s t-tests or Wilcoxon signed-rank test were used for comparisons of clinical parameters of ADPKD patients who received cinacalcet between pre-administration and follow-up examinations. Correlation and linear regression analyses were done to examine relationships between TKV change and clinical parameters. In the cinacalcet group, the change of htTKV over time was assessed using a mixed-effect model with a random intercept for each patient. In this model, the difference in the trends between the periods before and after the cinacalcet prescription was also evaluated. To satisfy a normality assumption of an error term, the outcome variable was used with natural log-transformation. Statistical analyses were performed using GraphPad Prism, version 6.0  or the JMP software package, version 10 , or R version 4.0.3 (https://cran.r-project.org/). p values < 0.05 were considered to indicate statistical significance.Continuous variables are expressed as the mean ± SD, and categorical variables as numbers and percentages. Student’s t-test or Mann–Whitney Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5.


Transplant renal artery stenosis (TRAS) is a post-operative complication which most often occurs between 3 months and 2 years after transplantation. TRAS is associated with kidney failure and hypertension and, thereby, with an increased risk of cardiovascular events.The purpose of this retrospective study was to report our experience of perfusion computed tomography angiography (P-CTA) to identify a 50% lumen reduction , assess its subjective image quality and evaluate if contrast-induced acute kidney injury (CI-AKI) occurred.All 13 patients who had undergone P-CTA for suspected TRAS at our institution were retrospectively evaluated. At P-CTA, eight or 12 g of iodine were administered intravenously, and five to seven scan sequences were merged into time-resolved images after motion correction. Eight patients underwent subsequent DSA.P < .01). The diagnosis at P-CTA was verified in all eight patients who underwent DSA. However, in two cases with suspected stenosis, renal function was restored without angioplasty.The average patient weight was 76 kg (range 55–97 kg). Image quality was rated as good or excellent for all patients, and pathological changes were shown in 10 of 13 patients undergoing P-CTA. Two patients had a serum creatinine increase of >26 μmol/L during the first 3 days, but serum creatinine was significantly lower in all patients 1 month after P-CTA (165+/−69 μmol/L versus 232+/−66 μmol/L, Anatomy and blood flow of the transplant renal artery can be visualized using less than a third of the standard contrast media dose by using P-CTA technique. In clinical practice, TRAS is diagnosed primarily by Doppler ultrasound (DUS). The reference test for the definitive diagnosis of arterial stenosis is digital subtraction invasive angiography (DSA).5 Alternative non-invasive techniques for diagnosing TRAS are magnetic resonance angiography (MRA) and intravenous contrast media (CM)–enhanced computed tomography angiography (CTA).7 However, the nephrotoxicity of intravenous iodine contrast media (CM) is still a challenge to CM-enhanced imaging. Gadolinium-enhanced MRA is also contraindicated in patients with severe renal failure due to the risk of nephrogenic systemic fibrosis (NSF).9Transplant renal artery stenosis (TRAS) is a post-operative complication which most often occurs between 3 months and 2 years after transplantation. TRAS is associated with kidney failure and hypertension and, thereby, with an increased risk of cardiovascular events. The reported risk of TRAS varies among different studies, ranging from 1% to 23% in all kidney transplantations.13 The high temporal resolution guarantees that a short CM bolus will be detected with optimal arterial enhancement. Using post-processing of image data, the rendered images can be shown as a movie, and the inflow of the CM in the vessels can be visualized as high-resolution time-resolved images.The rapid evolution of CT technology has enabled the development of perfusion computed tomography angiography (P-CTA), by which multiple passages/sequences over the organ of interest are acquired. The technique can also be used for minimizing the CM dose at CT angiography (CTA).The purpose of this retrospective study was to report our experience of P-CTA to identify a 50% lumen reduction (as compared to DSA), assess its subjective image quality, and evaluate if contrast-induced acute kidney injury (CI-AKI) occurred.This retrospective study was approved by the Regional Ethics Board, and informed consent was waived. All methods used in this study were carried out in accordance with local clinical radiology guidelines. The study complies with the Declaration of Helsinki. The inclusion criteria were a) patients in whom DUS had difficulty visualizing the renal artery and b) referred for P-CTA examination of the transplant kidney renal artery between April 2012 and Feb 2019. In total, 13 patients with clinical signs of TRAS were retrospectively included in the study. There were seven men and six women, aged 26–67 (mean 50) years and the time between kidney transplantation and P-CTA ranged between 12 and 270 days. All 13 patients had acute onset of hypertension and reduced kidney function .Table 1.14 The CM enhancement of the iliac and renal arteries was monitored visually while scanning the different series, and the scan was manually ended when the enhancement started to decrease. Time resolution between series was 1.5 s.All patients were scanned with a dual source 2 x 64 detector row MDCT . The position of the transplant kidney was defined by non-CM scanning over the pelvis using automatic dose modulation, 100 kVp and 45 reference mAs. During P-CTA, a total volume of 20–30 mL (8–12 g (g) iodine) of iomeprol 400 mg I/mL,  was administered at 6 mL per second, followed by a saline chaser with the same injection flow through a 16-gauge peripheral venous access inserted in the antecubital vein. A fixed dose of 12 g of iodine was administered to the first four patients. From patient five and onward, the dosage was adjusted through visual assessment according to the patient’s body constitution. The scan delay was set to 15 s after the start of the CM injection. The P-CTA consisted of 5–7 scan repetitions over a range of 15 cm covering the transplant kidney, using 100 kVp and 70 mAs, giving a radiation dose below <9 millisievert (mSv).16 Luminal stenosis was assessed by visual assessment. Both reviewers were blinded to the DSA results. Reader disagreement was solved in consensus. Eight patients underwent DSA after the P-CTA. In six patients, DSA was performed within 1 month from P-CTA  and in two patients 53 and 62 days after P-CTA. The consensus from the P-CTA was compared with the findings reported by the interventionist at DSA.All reconstructed series were sent to a dedicated post-processing workstation for motion correction and creation of a time-resolved merged data set . All multiplanar reformats (MPR), 3D volume rendering (VR), and 4D post-processing were carried out at a separate workstation . The total post-processing time, including image transfer time between the CT and SyngoVia workstation, image motion correction, 3D reconstruction, 4D movie and image reformates, was approximately 45 min. With regard to retrospective analysis, two radiologists with 8 and 14 years of experience rated image quality on a five-grade scale . The five-degree assessment of image quality summarized the visualization of the renal arteries, vascular anastomosis, and iliac arteries. The transplant renal artery was evaluated for the absence or the presence of luminal diameter reduction. From the thin axial slices, multiplanar reconstructions (MPR) were performed in order to visualize the artery in its long axis and in cross-sectional section perpendicular to the vessel long axis. When luminal reduction was present, the stenosis was graded as above or below 50 per cent luminal diameter narrowing.. Student’s paired t-test, without Bonferroni correction, was used to test for changes in sCr, that is, to evaluate whether contrast-induced acute kidney injury (CI-AKI) had occurred. CI-AKI is defined as an increase in sCr of ≥26 μmol/l in the 48–72 h following CM administration or a sCr increase of ≥1.5–1.9 times baseline.17Kidney function was evaluated by measurement of serum creatinine (sCr) on the day of the P-CTA examination, 3 days after and approximately >30 days after the P-CTA examination by calculating the estimated glomerular filtration rate (eGFR) using the Lund-Malmö formulaAverage body weight was 76 kg range 55–97 kg). The renal artery of the transplanted kidney was successfully imaged with image quality graded as good or excellent in all 13 patients by both reviewers . All art5–97 kg. As a by-product of the P-CTA, it was also possible to demonstrate whether the vessel stenosis was accompanied by a decreased parenchymal perfusion .P < .01) . When analyzing the whole group of patients, there was no significant change in average sCr 3 days after the examination, 219 ± 76 μmol/l, compared with before, 232 ± 66 μmol/l. At 30-day follow-up, sCr had significantly decreased  to 165 ± 69 μmol/l (P < .01)  Table 1P < .01 (P < .01) .Figure 6The renal artery was successfully visualized by P-CTA in all 13 kidney transplant patients. The image quality was rated as good or excellent in all patients. Six out of eight diagnosed significant stenosis, and two arteries without significant stenosis, were verified at subsequent DSA. In two patients, a stenosis was suspected, but kidney function was regained before DSA. These might constitute false positive cases.When a small amount of CM is injected, as in our study, the CM bolus duration will be very short, which means an increased risk of scanning at the wrong time-point. Through repeated scanning and the use of the same software as that used for reconstruction and analysis of CT-perfusion studies, it was possible to obtain approximately 2000 low-resolution images at five to seven time-points, which eliminates the risk of scanning at the wrong time-point .Figure 7Volume rendering technique (VRT) enabled the imaging of the vascularity of the kidney to be demonstrated with a so-called 4D-movie . Such a 18 In most patients with renal transplants, the kidney is easily imaged as it is located rather superficially and not affected by patient habitus and bowel gas. However, DUS is also user-dependent, and the lack of images that can easily be interpreted by the clinician makes alternative imaging and diagnostic techniques valuable. Gadolinium-enhanced MRA is an appealing alternative,9 but as mentioned previously, the risk of NSF in patients with severe renal failure and scanner availability limit its use. Non-contrast MRA has shown promising results,20 but the technique is not yet widely available and there is a risk of occasional false positive results with overestimation of the severity of vascular stenosis.21 Standard CTA is not an alternative due to the high CM dose needed, almost 40 g of iodine.23 A technique to combine CTA with invasive placement of a micro-catheter in the supplying artery has successfully reduced the dose to 5–20 mL,24 but this is an invasive technique and requires the interaction of an interventionist. A one-stop-shop alternative is to perform DSA without prior imaging. This would make it possible to diagnose and treat any stenosis at the same time. However, availability, high cost, radiation, and contrast media dose, combined with the invasiveness of the procedure, are limiting factors. P-CTA has the great advantage of using only 8–12 g of iodine, which is less than both DSA, typically 18–33 g of iodine,25 and standard CTA.Several other reference tests are available to evaluate the renal arteries. The least non-invasive and simplest for the patient is DUS.27 whereas others argue that there is a considerable risk of CI-AKI in certain patient groups.28 However, in clinical practice, it is considered that the risk of kidney damage increases with the dose of injected CM, which is especially important to consider in kidney transplant patients.30 When developing the technique of P-CTA for TRAS, the dosage of CM was based on our previous experience from perfusion CT of the liver using 20 gI (50 mL). As there was no intention to evaluate renal parenchyma enhancement, it was considered that 12 g (30 mL) would suffice. After scanning the first five patients, it became clear that the dose could be further reduced depending on patient habitus. Still, despite the low CM dose, two patients had a serum creatinine increase of >26 μmol/l during the first 3 days. Both patients were diagnosed with severe stenosis of the renal artery [The risk of causing contrast-induced AKI (CI-AKI) is increased in patients with deteriorating renal function. Some authors argue that the risk of CI-AKI is greatly exaggerated,l artery , providiThis study has several limitations. A direct comparison with DSA or MRA to verify the findings in all patients would have been desirable. However, performing DSA in patients with normal findings or stabilized renal function was considered unethical. Furthermore, the reason for developing the low contrast media technique was due to the low availability of MRA. There is also a risk of false positive stenosis at MRA. A possible reason for misinterpretation might be the strong curvature at the anastomosis to the iliac artery that is often observed. Unfortunately, this is also where stenosis most often develops. However, the lack of comparative DSA or MRA means that definite conclusions about the ability of P-CTA to determine if stenosis is present or absent cannot be drawn regarding the remaining five patients.As this study describes a new technique in a vulnerable group of patients, the patients referred had a high risk of TRAS. This might have biased the reviewers’ evaluations.It might be possible to use even lower doses of iodine than those used in this study. However, as only two patients out of 13 had possible CI-AKI, it was considered that the risk of non-diagnostic imaging by reducing the dose further would exceed the eventual benefit. The radiation dose during P-CTA was below <9 mSv, equivalent to a standard parenchymal phase liver CT scan. However, the local organ/tissue dose over the transplant kidney and its surroundings was higher due to the repeated scanning over the 15 cm scan length. Regarding availability, the technique of P-CTA should be increasingly available with the greater spread of modern multi-detector CT (MDCT) scanners, provided that it is accepted among radiologists and clinicians. In conclusion, perfusion technique CTA enables imaging of the transplanted kidney by using only a low dose of iodine, reducing the risk of CI-AKI.


A total of 1872 patients with type 2 DM  were enrolled. In multivariable analysis, 11 high obesity-related indices  were significantly associated with albuminuria. In addition, high BMI, WHR, WHtR, LAP, BRI, CI, VAI, and AVI were significantly associated with eGFR <30 ml/min/1.73 m2. The results of this study showed that various obesity-related indices were significantly associated with albuminuria and advanced kidney disease in patients with type 2 DM. Screening may be considered in public health programs to recognize and take appropriate steps to prevent subsequent complications.Obesity is an important risk factor for the development of diseases including diabetes, hypertension, and cardiovascular disease. However, few reports have investigated the relationships between these obesity-related indices and diabetic nephropathy. The aim of this study was to evaluate associations between obesity-related markers with albuminuria and advanced kidney disease in patients with type 2 diabetes mellitus (DM). Obesity-related indices including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body roundness index (BRI), conicity index (CI), lipid accumulation product (LAP), visceral adiposity index (VAI), body adiposity index (BAI), abdominal volume index (AVI), body shape index (BSI), and triglyceride glucose (TyG) index were measured. Albuminuria was defined as a urine albumin/creatinine ratio of ≥30 mg/g. Advanced kidney disease was defined as an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m Chronic kidney disease (CKD) is an increasing global public health problem due to the high risk of progression to end-stage renal disease (ESRD) and associated morbidity and mortality . Taiwan Obesity is also a global public health problem with an increasing prevalence . ObesityTherefore, in this study, we collected the data of more than 1800 patients with type 2 DM in southern Taiwan to explore associations between obesity-related indices  with albuminuria and advanced kidney disease.All patients with type 2 DM who visited the diabetes outpatient clinics of two hospitals in southern Taiwan were included in this study. The exclusion criteria were patients: (1) with type 1 DM ; (2) receiving dialysis; and (3) who had received a renal transplantation. The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E-20150029), and all methods were carried out in accordance with the approved guidelines. In addition, all of the participants provided written informed consent to participate in this study.1c), triglycerides [TGs], total cholesterol, high-density lipoprotein [HDL]-cholesterol, and low-density lipoprotein [LDL]-cholesterol were also recorded. Data on the use of medications including oral anti-diabetic agents, insulin, angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs), statins, and fibrate during the study period were obtained from medical records.Data on age, sex, and comorbidities were obtained from medical records and interviews with the patients. Fasting blood samples were obtained from all of the patients and analyzed using a COBAS Integra 400autoanalyzer . Serum creatinine was measured using the compensated Jaffé method as previously reported , and estCoronary artery disease was defined as a history of angina, ischemic changes on electrocardiography, old myocardial infarction, or having received coronary bypass surgery or angioplasty. Cerebrovascular disease was defined as a history of cerebrovascular events including infarction and cerebral bleeding.2, 15–29 mL/min/1.73 m2, and <15 mL/min/1.73 m2 were classified as having CKD stages 3, 4 and 5, respectively. Advanced kidney disease was defined as an eGFR <30 mL/min/1.73 m2 in this study.Urine levels of albumin and creatinine were measured from spot urine samples using a COBAS Integra 400 plus autoanalyzer . Albuminuria was defined as a urine albumin/creatinine ratio of ≥30 mg/g. Patients with evidence of kidney damage for >3 months and an eGFR of 30–59 mL/min/1.73 m1. BMI was calculated as:2. WHtR was calculated as:3. WHR was calculated as:4. LAP was calculated as:5. BRI was calculated as:H(m))2 .6. CI was calculated using the Valdez equation based on BW, BH, and WC as:7. VAI score was calculated as described previously  using th8. BAI was calculated according to the method of Bergman and colleagues as:3/2 −18.9. AVI was calculated as))21000.10. ABSI was calculated as:1/2(m)].11. TyG index was calculated as/dL)/2].t test/Wilcoxon Rank Sum test and the Chi-squared test/Fisher exact test, as appropriate, for comparisons between groups. Multiple logistic regression analysis was used to identify the factors associated with albuminuria and advanced kidney disease. There were four different sets of adjustments depending on which obesity index is being studied to avoid repeated adjustments in multivariable model. Different multivariable logistic regression analyses were performed for different indices as follows:1c, log TGs, total cholesterol, HDL-cholesterol, LDL-cholesterol, eGFR, and use of medications for BMI, WHR, WHtR, BRI, CI, BAI, AVI, and ABSI.Adjusted for age, sex, cerebrovascular disease, coronary artery disease, systolic and diastolic blood pressures, fasting glucose, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, and the use of medications for LAP.Adjusted for age, sex, cerebrovascular disease, coronary artery disease, systolic and diastolic blood pressures, fasting glucose, HbA1c, total cholesterol, LDL-cholesterol, and the use of medications for VAI.Adjusted for age, sex, cerebrovascular disease, coronary artery disease, systolic and diastolic blood pressures, fasting glucose, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, and the use of medications for TyG index.Adjusted for age, sex, cerebrovascular disease, coronary artery disease, systolic and diastolic blood pressures, HbAData are presented as percentage, mean ± standard deviation, or median (25th–75th percentile) for TGs. Characteristics of the study patients for the continuous and categorical variables were analyzed by p value was <0.05. All statistical analyses were performed using SPSS version 19.0 for Windows .A difference was considered significant if the A total of 1872 patients  were included in this study, of whom 34.7% had albuminuria and 3.0% had advanced kidney disease.1c, TGs, total cholesterol, and a lower eGFR and lower level of HDL-cholesterol. They also had higher rates of insulin, ACEI and/or ARB and fibrate use. Moreover, the patients with albuminuria had higher values of all of the obesity-related indices .Comparisons of the baseline characteristics between the patients with and without albuminuria are shown in p = 0.003), high WHR (p < 0.001), high LAP (p < 0.001), high BRI (p < 0.001), high CI (p < 0.001), high VAI (p = 0.006), high BAI (p = 0.006), high AVI (p < 0.001), high ABSI (p = 0.011), and high TyG index (p = 0.032) were significantly associated with albuminuria.2 are shown in 2, those with eGFR <30 mL/min/1.73 m2 were older, had higher rates of coronary artery disease and cerebrovascular disease. In addition, they had higher systolic blood pressure, higher BW, higher WC, higher HC, lower fasting glucose, lower HbA1c, higher TG level, lower HDL-cholesterol, and lower eGFR. They also had a lower rate of oral anti-diabetic drug use, and higher rates of insulin, ACEI and/or ARB, statin and fibrate use. Moreover, the patients with eGFR < 30 mL/min/1.73 m2 had higher values of all of the obesity-related indices  except TyG index.Comparisons of the baseline characteristics between the patients with and without eGFR <30 mL/min/1.73 m2 in the study patients as determined in multivariable logistic regression analysis. After multivariable logistic regression analysis, high BMI (p = 0.016), high WHR (p = 0.007), high WHtR (p = 0.004), high LAP (p = 0.001), high BRI (p = 0.003), high CI (p = 0.034), high VAI (p = 0.002), and high AVI (p = 0.004) were significantly associated with eGFR < 30 mL/min/1.73 m2, whereas BAI, ABSI, and TyG index were not.2) in the enrolled patients.In this study, we enrolled patients with type 2 DM, and found that all of the studied obesity-related indices  were associated with albuminuria  in the patients. In addition, BMI, WHR, WHtR, LAP, BRI, CI, VAI, and AVI were significantly associated with advanced kidney disease  were significantly associated with albuminuria in the enrolled patients. The Prevention of Renal and Vascular End-stage Disease (PREVEND) study conducted in the Netherlands and published in 2003 reported a prevalence of microalbuminuria of 21% or 13% depending on central or peripheral obesity patterns . Approxi2 at 20 years of age was associated with a three-fold higher risk of developing new-onset kidney disease, even after correcting for hypertension and diabetes. Moreover, the coexistence of diabetes and obesity in their study was associated with a two-fold higher risk of new-onset kidney disease [2 and negative microalbuminuria completing a 3-year follow-up. They found TG ≥1.7 mmol/L increased the risk of eGFR <60 mL/min/1.73 m2 by 1.44-fold, of microalbuminuria by 32%, and of developing both abnormality by 1.41-fold. Besides, WC (≥90 cm in men and ≥85 cm in women) were associated with a 1.68-fold higher risk of eGFR <60 mL/min/1.73 m2 and a 1.43-fold risk of microalbuminuria and a 1.89-fold risk of developing both abnormality. High TG levels and central obesity are risk factors for kidney injury in 3 years. The exact mechanisms by which obesity may worsen or cause CKD remain unclear. However, it is possible that excess fat mass increases the risks of type 2 DM, hypertension, and atherosclerosis, thereby indirectly leading to CKD [The second important finding of this study is that BMI, WHR, WHtR, LAP, BRI, CI, VAI, and AVI were significantly associated with advanced kidney disease in the enrolled patients. Munkhaugen et al.  evaluate disease . Cao et  disease  evaluateg to CKD ,38. Seveg to CKD ,40. Evidg to CKD ,43. Thesg to CKD . This meg to CKD ,47. In pg to CKD ,49. WHtRg to CKD ,51. TakeThere are several limitations to this study. First, the study included patients with type 2 DM regardless of its duration, and the duration of DM can affect the inhomogeneity of the effects of diabetes on nephropathy. Second, the diagnosis of albuminuria was based on a single laboratory measurement. However, this limitation was minimized by the accuracy of the urinary albumin and creatinine assays as described in the Methods section. Third, data on some important variables that can influence diabetic nephropathy, such as smoking history, albumin, C-Reactive protein, and CKD etiology, were lacking. Finally, this study was cross-sectional in design, and so causal relationships and long-term clinical outcomes could not be confirmed. Nonetheless, the results may help to shed light on the importance of obesity-related indices on diabetic nephropathy in this population. Further prospective studies are needed to evaluate the development and progression of diabetic nephropathy in patients with diabetes.In conclusion, the results of this study showed that various obesity-related indices were significantly associated with albuminuria and advanced kidney disease in patients with type 2 DM. It is, therefore, important to reduce obesity through lifestyle changes and regular exercise. Screening may be considered in public health programs to recognize and take appropriate steps to prevent subsequent complications.