Background. Periodontitis is an inflammatory disease of the tooth-supporting structures. Current data suggest that periodontal disease may be a risk factor for asthma. The present study aimed to assess the prevalence of periodontitis and its relationship with the severity of asthma in asthmatic patients. Methods. This study was conducted on 70 newly diagnosed asthmatic patients as the case group and 70 healthy subjects as the control group, aged 20‒50. The asthma was diagnosed by a pulmonologist according to Global Initiative for Asthma (GINA) guideline. All the participants underwent periodontal examinations, which included measuring the pocket depth (PD), attachment loss (AL), gingival index (GI), and plaque index (PI) in one tooth from each sextant, including the incisor/canine and left and right premolar/molar regions for both the maxillary and mandibular dental arches.Results. Periodontal disease was significantly more prevalent in newly diagnosed asthma patients. Patients with asthma had significantly higher PI, GI, PD, and AL scores (P<0.001). Furthermore, dry mouth in asthmatic patients with cough and mucosal changes in asthmatic patients with wheeze were significantly more common than in non-asthmatic patients (P<0.05). The median AL in wheezing patients and the median AL and PD in participants who had asthma attacks within the previous month were significantly higher than in other patients. Furthermore, there was a significant negative correlation between AL with Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) and PD with FEV1 and FVC. Conclusion. Our results showed that periodontal diseases were more prevalent in newly diagnosed asthmatic patients, and asthma was more severe in periodontitis patients. Bronchial asthma is a chronic inflammatory disease of the airways that affects people of all ages around the world.8 For example, previous studies reveal that periodontitis as a disease is associated with a higher risk of atherosclerosis, myocardial infarction, respiratory disease, diabetes, and preeclampsia.9 Periodontitis is a chronic inflammation of the periodontium (tooth-supporting tissues) caused by a bacterial infection.10 Bacterial biofilm on the teeth, genetics, environmental factors, and some inappropriate behavioral habits are involved in the development and progression of this disease.11 In addition, bronchodilators and inhaled medicines used by asthmatic patients are other risk factors for oral hygiene.12 Current data suggest that periodontal disease may be a risk factor for asthma, emphasizing the correlation between oral hygiene and general systemic health.13found a possible association between asthma and periodontal disease in adults after comparing periodontal disease indicators such as plaque index (PI), gingival index (GI), calculus index (CAI), pocket depth (PD), attachment loss (AL), and bleeding on probing (BOP) between asthmatics and healthy individuals. However, they suggested further research to determine the interrelationship of these disorders. Although the exact association between asthma and periodontal disease is unclear, it may involve either pathological activation of the immune and inflammatory responses or side effects of anti-asthma medications, which need to be further considered.13 On the other hand, some results are contradictory due to differences in sample size, sociodemographic factors, and diagnostic criteria used to diagnose periodontal disease. In this regard, some studies have found higher microbial plaque deposition, gingivitis, periodontitis, and reduced salivary flow in asthmatic patients compared to healthy individuals. For example, Kelly et al Therefore, this study aimed to investigate periodontal indices in Iranian asthmatic patients and determine the relationship between these indices and disease severity. The novelty of the research is periodontitis in newly asthmatic patients without inhalation of bronchodilator spray, such as inhaled corticosteroids that affect the orodental system. This experimental study was conducted under the Helsinki Declaration to treat human subjects. The study protocol was also approved by the Ethics Committee of Mashhad University of Medical Sciences, Mashhad, Iran, under the code IR.MUMS.DENTISTRY.REC.1399.113. The participants were informed about the research objectives and written informed consent was obtained. Furthermore, participants were guaranteed that their information would be kept confidential, the research protocol would not interfere with their asthma care, and they would not be charged.14 The inclusion criteria were: newly diagnosed with bronchial asthma, an age range of 20‒50, having natural teeth, and the ability to give informed consent. The exclusion criteria for patients were: wearing partial or complete dentures, nonsteroidal anti-inflammatory drugs (NSAIDs) use in the past three months, smoking and opium addiction, history of diabetes mellitus, collagen vascular diseases, rheumatic diseases, epilepsy and seizures, cardiovascular diseases, hypertension, thyroid disease, hyperlipidemia, chronic renal failure, liver cirrhosis, hematologic disorders, malignancy, and endocrine diseases. The control group included healthy volunteers with no history of bronchial asthma, natural teeth, and an age range of 20‒50. At the beginning of the test, the participants’ demographic data were recorded in the sociodemographic characteristic form. This control‒case study was conducted on 70 patients with bronchial asthma, who were admitted to the Lung Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, between 2020 and 2021. The participants were enrolled by convenience sampling. The sample size was calculated using Epi-info software, based on a 40% prevalence of the periodontal disease among asthmatic patients as indicated by Khassawneh et al.15 The participants were subjected to a spirometry test using a Micro Medical Spirometer  to determine their forced expiratory volume in one second (FEV1). The FEV1 values >80%, 80‒60%, and <60% were considered mild, moderate, and severe, respectively. In addition, forced vital capacity (FVC) and FEV1/FVC were calculated for patients. Asthma was diagnosed by a pulmonologist based on spirometry results according to the Global Infinitive for Asthma (GINA) guidelines. The ACT is a 5-item, self-administered questionnaire used to assess asthma control, independent of pulmonary function measurements. For asthma control, the ACT questionnaire items (14) are rated on a five-point Likert scale from 1  to 5 (never), as well as 1  to 5 (completely controlled). The ACT scores vary from 5 (poorly managed asthma) to 25 (well-controlled asthma), with a score of 19 or above suggesting well-controlled asthma. Furthermore, the incidence of asthma symptoms, including dyspnea, coughing, wheezing, chest tightness, pain, the number of attacks per month, and the amount of medication used, were recorded. Spirometry and ACT questionnaires were performed by one experienced pulmonologist (FR).16 All measurements were made in four areas for each tooth  using a Williams probe  according to the standard method. The probe was placed in the periodontal pocket parallel to the longitudinal axis of the tooth; therefore, it did not pass through the junctional epithelium. Plaque index and gingival index (Silness and Loe)17 were measured, and the means of the recorded values were considered as the plaque index and gingival index and registered for each subject. Furthermore, dry mouth and decreased saliva, changes in the oral mucosa, the presence of oral candidiasis, gingivitis, oral hygiene status, dental caries clinically , and the total number of teeth were examined. Periodontal examinations were carried out by a skilled dentist (AA). They were qualified, calibrated, and approved by a reliable senior professor of periodontology (AM). Patients were subjected to a clinical periodontal examination, including measuring the community periodontal index for treatment needs (CPITN), PD, AL, and GI. A dentist examined one tooth (CPITN index teeth) from each sextant, including the incisor/canine and left and right premolar/molar regions for both the maxillary and mandibular dental arches. CPITN was measured using a standardized protocol to investigate gingival bleeding, calculus, and periodontal pockets. The following ten teeth: upper right: 17 and 16; upper anterior: 11; upper left: 26 and 27; lower right: 47 and 46; lower anterior: 31; and lower left: 36 and 37, were examined, and each tooth was given its highest CPITN score ranging from 0 to 4. Statistical analyses were performed by SPSS 21.0 . Following the Shapiro–Wilk test to determine the normality of the data, intergroup comparisons were performed using the Student’s t-test for parametric data and the Mann–Whitney U test for nonparametric data. The chi-squared test was also used to compare qualitative variables. The quantitative data were expressed as median (interquartile range) and qualitative data as a percentage. A P-value of <0.05 was considered statistically significant. The periodontal indices of 70 asthmatic patients were evaluated in this study to determine the relationship between periodontitis and asthma. The mean ± SD ages of asthmatic patients and healthy controls were 37.67±9 and 38.37±9.7 years, respectively. Furthermore, the asthmatic group consisted of 32 (45.7%) males and 38 (54.3%) females, while the control group included 34 (48.6%) males and 36 (51.4%) females. However, no statistically significant difference in gender distribution was found between asthmatic patients and healthy controls by chi-squared analysis. Furthermore, none of the participants smoked or were drug addicts . The ACT questionnaire was employed to assess asthma severity. According to the results, asthma was well controlled in 2 (2.9%) patients, partially in 28 (40%) patients, and uncontrolled in 40 (57.1%) patients. Three (4.3%) of the patients had also experienced an emergency in the last month. Furthermore, coughing, wheezing, dyspnea, and chest tightness were also reported in 50 (71.4%), 35 (50%), 64 (91%), and 30 (42.9%) patients, respectively. Twenty-eight (40%) patients had a history of nocturnal asthma attacks. In addition, 55 patients had no asthma attacks in the previous month; five had one, one had two, one had three, and eight had four attacks. On the other hand, spirometry values revealed that the mean ± SD of FEV1, FVC, and FEV1/FVC ratio were 2.21±1.30 L/s, 2.9±1.1 L/s 70%±14.88%, respectively. According to the results, FEV1/FVC was abnormal in 48 (86.6%) patients. In contrast, the percentage of people in the asthmatic patients’ group with CPITN scores of one, two, and four was significantly higher (P<0.001). Furthermore, most participants had gingivitis, and the groups did not differ significantly in this regard. In addition, candidiasis was also not observed in any of the participants. It should be noted that asthmatic patients had a significantly higher incidence of dry mouth than healthy subjects (P=0.014), and their oral hygiene was considerably worse . Accordi Furthermore, we investigated the periodontal indices and oral hygiene in asthmatic patients based on gender. The results revealed that males had significantly weaker oral hygiene status than females, with 62.5% having poor oral hygiene compared to 34.2% (P<0.05). Moreover, 21.9% of males had moderate oral hygiene, and 15.6% had good or excellent oral health. These values were 52.6% and 13.2% in female patients, respectively, which was significantly higher than in males (P<0.05). However, there was no statistically significant difference between male and female patients regarding other parameters. Based on asthmatic variables, we evaluated the periodontal indices and oral hygiene in asthmatic patients. The results of a chi-squared analysis showed that dry mouth was significantly more common in asthmatic patients with cough (46%) than in those without cough (15%) (P<0.05). Furthermore, the total number of teeth in asthmatic patients who did not have wheezing was 28, which was significantly higher than the 24 teeth in asthmatic patients with wheezing (P=0.008). In addition, the AL and mucosal changes were significantly higher in asthmatic patients with wheeze (P<0.05). Moreover, in patients who had not experienced an asthma attack in the previous month, AL and PD parameters increased from 2.5 and 1.7 to 2.9 and 1.8 in patients who had an asthma attack in the previous month, which was significant . On the other hand, dyspnea, chest tightness, nocturnal asthma, and asthma control had no significant effect on periodontal parameters. In addition, correlation analysis of respiratory variables and periodontal indices revealed a significant negative correlation between AL and FEV1 and FVC . There w The present study aimed to assess the incidence of periodontitis in asthmatic patients. This research investigated periodontal indicators in asthmatic patients and their relationship with asthma severity. The importance of inflammation and infection as risk factors for bronchial asthma has been considered. Asthma appears to be associated with immune cells and inflammatory mediators like cytokines, leukotrienes, and immunoglobulins. In this regard, periodontal diseases are inflammatory conditions of the oral cavity that cause inflammation of the tissues surrounding the teeth and chronic immune system disturbance. Periodontal diseases aggravate inflammatory and immunological responses by transferring bacteria into the bloodstream, which affects the progression of the disease in patients with bronchial asthma by altering the airway epithelium. The present study found a significant increase in periodontal disease in newly diagnosed asthma patients. Despite having a higher number of decayed teeth and higher CPITN scores in healthy controls (P<0.001), asthmatic patients had significantly higher PI, GI, PD, and AL scores (P<0.001). In addition, dry mouth in asthmatic patients with cough and mucosal changes in asthmatic patients with wheeze was significantly more common than in other patients who did not have these symptoms (P<0.05). The median AL in patients with wheeze, and the median AL and PD in participants who had asthma attacks in the previous month, were significantly higher than in other patients.8 Harshita et al18 reported that periodontal diseases are more common in asthmatic patients compared with healthy people. Furthermore, the oral hygiene index in healthy individuals was better than in asthmatic patients, consistent with the current study. They found that the type of asthma medication used by asthmatics affected the extent of periodontitis rather than the severity of asthma. Their findings also showed that, despite the lack of differences in GI between asthmatics and healthy individuals, the mean PD and AL were significantly higher in asthma patients, which was consistent with our findings.18 It should be emphasized that measures for AL and PD in the current study were taken between 6 teeth in the CPITN index rather than all teeth. Another study by Shen et al19showed that the incidence of periodontal disease was significantly higher in patients with newly diagnosed asthma than in healthy subjects. They suggested that asthmatic patients are more likely to develop periodontal disease.19 Furthermore, Yaghoobi et al20 reported that periodontal parameters in asthmatic patients were weaker than in healthy subjects, providing additional support to previous studies that advocated an association between respiratory disease and periodontal health status.20 In a study on a representative sample of Korean adults, Lee et al21 discovered a relationship between asthma and periodontitis in patients with a recent asthma diagnosis. Patients taking anti-asthmatic drugs regularly were also less likely to be diagnosed with periodontitis. According to their findings, poorer oral hygiene was associated with older age, female gender, less physical activity, lower socioeconomic status, smoking, and alcohol consumption.21 In a similar study, Moeintaghavi et al22found a strong negative correlation between FEV1 and FVC with PI and AL levels in patients with COPD. There was also a significant positive association between the COPD severity score with PI and AL. Similarly, FEV1/FVC was also found to have a negative correlation with PD and AL.22 To explain the difference between Moeintaghavi’s work and the present study, it can be concluded that COPD usually has a chronic course and is associated with older age groups who have a history of smoking. Also, evidence indicated that the prevalence of periodontitis in patients with severe asthma was much greater than in the healthy control group. Recent research has suggested that periodontal involvement in asthma may be due to immunological and inflammatory processes, asthma drug adverse effects, or both. The main cause of periodontal disorders is likely a decrease in the protective impact of saliva during the dry mouth. Mouth breathing, changes in salivary composition, or decreased salivary flow can all contribute to this issue. A dry mouth can diminish the concentration of IgA in saliva and disrupt the balance of bacterial and immunological components in the oral cavity. Higher levels of calcium and phosphate in saliva and increased IgE concentrations in gingival tissues can contribute to periodontal diseases.24 Inhaled corticosteroids used to treat asthma, on the other hand, may lower bone mineral density, including the mandible, and increase the risk of pathological fractures, especially in those using moderate to high doses.26 Alveolar mucosal dehydration, altered immune response with increased IgE and IgA concentrations, decreased salivary flow, increased mass deposition due to increased salivary calcium and phosphorus levels, and reduced jaw bone density as a result of steroid use are all possible causes of periodontal disease in asthma patients.27 Generally, the findings of this study are consistent with previous research on the association between asthma and periodontal disease. Patients with newly diagnosed asthma are far more likely than healthy individuals to develop periodontal diseases and poor dental hygiene. This study also revealed that periodontal disease is more common in individuals with severe asthma. These findings emphasize the significance of regular oral health monitoring in asthmatic patients, specifically those with severe asthma. Due to the impossibility of obtaining dental radiographs for all patients, dental caries was evaluated only clinically . Therefore, we may not be able to accurately evaluate the results of caries prevalence . This may be the reason for the discrepancy between the results of caries prevalence and oral health status in the two groups of asthmatic and healthy subjects. This study was financially supported by the Research Vice-Chancellor, Mashhad University of Medical Sciences . The authors declare no conflict of interest related to the study. AM, AA, and FR designed and carried out the research, collected the data, interviewed the patients, coordinated the study, participated in the research and prepared the manuscript. AA performed the statistical analyses and revised the English manuscript. All authors have read and approved the content of the manuscript. There was no funding support for the study. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. .


Background: Intradialytic hypotension (IDH) is a frequent complication of hemodialysis (HD). Current methods of IDH prevention are insufficient. Methods: We analyzed the intradialytic time course of systolic (SBP), diastolic (DBP), mean arterial (MAP), pulse pressure (PP), and heart rate (HR) in a group of chronic kidney disease (CKD) patients. First, 30 min into HD, a 40% glucose solution was injected into the venous line of the extracorporeal circulation at a dose of 0.5 g/kg of dry weight. Pressures and HR were measured in frequent intervals. Relative volume overload was determined by bioimpedance spectroscopy. Results: Thirty-five participants were studied. SBP increased after 5, 10, and 20 min of glucose infusion. DBP increased after 2 and 3 h and also at the end of HD. PP increased after 5, 10, and 20 min of glucose infusion and fell after the 2nd and 3rd hour and also at the end of HD. MAP increased after 2 and 3 h of glucose injection and at the end of HD. Significant interactions of the time course of SBP, DBP, MAP, with HR at baseline and of the time course of PP with fluid overload were observed. Symptomatic hypotensive episodes were absent. Conclusions: Glucose infusions during HD prevent symptomatic IDH and do not cause severe hypertensive episodes. Intradialytic hypotension (IDH) is defined as a decline of blood pressure during hemodialysis (HD). IDH occurs in approximately 17% of hemodialysis treatments and is associated with elevated cardiovascular and all-cause mortality . The defThe purpose of this study was to evaluate the hemodynamic response after intravenous injection of glucose in a mixed group of maintenance dialysis patients. We estimated whether intravenous administration of glucose would be beneficial to prevent a fall of blood pressure during hemodialysis.This is the continuation of a study on glucose and insulin kinetics performed in chronic and stable hemodialysis patients during their regular dialysis treatment using the infusion of concentrated glucose solution, which has been reported elsewhere ,18. The -30); at the time of glucose injection (T0); and 5, 10, 20, 30, 60, 120, and 180 min after glucose injection ; and at the end of HD (Tend). Pulse pressure (PP) was calculated from the difference of SBP and DBP. Mean arterial pressure (MAP) was calculated as MAP = DBP + PP/3.We performed an experimental study in the group of patients with chronic kidney disease (CKD) treated with hemodialysis. After 30 min of the beginning of hemodialysis, a 40% glucose solution was injected into the venous line of extracorporeal circulation at a dose of 0.5 g per kg of dry weight comparable to the dose of an intravenous glucose tolerance test. Systolic and diastolic arterial blood pressures (SBP and DBP) and heart rate (HR) were measured by an automatic oscillometric method and an inflatable arm-cuff located on the upper arm of the contra-lateral side of the vascular access, then manually recorded in the database. Measurements were taken at the beginning of HD , at the time of glucose injection (T0), and 5, 10, 20, 30, and 60 min after glucose injection .Blood samples for measuring glucose, sodium, and potassium concentrations were drawn from the arterial blood line of the extracorporeal circulation 30 min before the start of glucose injection  after 5 min supine rest to quantify the relative extracellular volume overload (Vo%). Electrodes were placed on one hand and one foot of the contra-lateral side of the vascular access in a tetrapolar configuration.The study sample consisted of 35 CKD patients treated with HD in the Dialysis Department of the Military Institute of Medicine, Warsaw, Poland. The inclusion criteria of the study were age above 18 years, HD treatment for more than 3 months using a peripheral arterio-venous access with an access flow of more than 600 mL/min, and a minimum extracorporeal blood flow of 250 mL/min. Adequate dialysis dose was quantified as Kt/V > 1.2. Clinical signs of infection, symptomatic anemia, wasting disease, hormonal therapy, diabetogenic drug prescription, and the lack of agreement to participate in the study were the exclusion criteria. More information on the material and methods can be found in the companion papers to this work ,18.t-test was applied. To investigate changes of continuous parameters over time and to compare the time course of these parameters between different subgroups, MANOVA for repeated measurements was used. Mauchly’s test for sphericity and Greenhouse–Geisser adjustment were employed if necessary. A p-value < 0.05 was considered to be statistically significant. Statistical analyses were run in IBM SPSS ver. 25.Results are presented as means ± standard deviations (SD) for normally distributed data or medians and interquartile ranges (IQR) for non-normally distributed variables. The Kolmogorov–Smirnov test was performed for evaluating distributions for normality. For comparison of observations between time points, the paired 2. Type 2 diabetes mellitus was diagnosed in 14 patients (40%). Median dialysis vintage was 2 years, and the mean ultrafiltration volume was 2.8 L with the IQR of 1.8–3.0 L. The mean SBP, DBP, and MAP at the beginning of dialysis (T30) were, respectively, 132.5 ± 23.0, 61.8 ± 14.8, and 85.4 ± 14.1 mmHg. HR was 69.5 ± 10.8 beats per minute (bpm), and PP was 70.7 ± 23.6 mmHg at the beginning of dialysis. The median serum glucose concentration at T-30 was 102 mg/dL (IQR 90 to 128 mg/dL); mean serum sodium and potassium concentrations were 144.5 ± 3.0 mmol/L and 5.0 ± 0.8 mmol/L. Relative volume overload (Vo%) before dialysis was 12.4% with IQR of 3.7–16.4%. Clinical data of the studied sample are presented in The study population consisted of 12 women (34.3%) and 23 men (65.7%). The average age was 61.2 ± 13.6 years, and the mean body mass index (BMI) was 28.2 ± 5.2 kg/mp < 0.001, p = 0.003, p = 0.023, respectively) compared to the time of glucose injection (T0). A statistically significant rise of DBP after 2 and 3 h  and also at the end of dialysis (p < 0.001) was observed. HR increased significantly after 3 h of the glucose bolus (p = 0.027) and at the end of the experiment (p = 0.002). PP increased after 5, 10, and 20 min of the glucose bolus  and fell significantly after second hour (p = 0.037) and third hour (p = 0.019) and also at the end of the experiment (p = 0.002). We observed a statistically significant increase of MAP after 2 and 3 h of glucose injection  and at the end of the experiment (p = 0.003)  . However= 0.003) .p = 0.009). In individuals with diabetes, SBP increased after 30 min of glucose infusion, contrary to patients without diabetes, where we observed the systematic fall of SBP after 5 min of glucose bolus to the end of HD. We also found an interaction of the time course of SBP with HR at T-30. SBP increased after one hour of glucose infusion in patients with HR < 60 bpm at the beginning of HD, contrary to those with HR 60–100 bpm in T-30 of the experiment, where we observed the systematic fall of SBP during HD (p = 0.001)  .p < 0.001).Additionally, patients with SBP above 140 mmHg at the beginning of HD had on average higher SBP throughout HD than participants with SBP ≤ 140 mmHg at baseline (-30 (p = 0.014) (-30 (p = 0.001) were statistically significant.In multivariate analysis, only an interaction of the time course of SBP with HR at T= 0.014)  and diff-30 (p = 0.005) and by sex (p = 0.034). Patients with HR from 60 to 100 bpm at baseline had higher DBP than participants with HR < 60 bpm up to 60 min after the glucose infusion. Two hours after glucose injection, DBP of patients with HR < 60 bpm at the beginning of dialysis increased, and readings levelled off in patients with low and normal HR before dialysis. In addition, men had higher DBP than women up to 60 min after the glucose bolus. Two hours after glucose injection, DBP readings levelled off in both sexes .Additionally, patients with diabetes had systematically lower DBP throughout the whole HD compared to those without diabetes (-30 (p = 0.017) (p = 0.028) were statistically significant.In multivariate analysis, only an interaction of the time course of DBP with HR at T= 0.017)  and diffp = 0.020). We also observed that individuals with HR < 60 bpm at the beginning of dialysis had lower HR throughout the whole HD compared to those with HR from 60 to 100 bpm at baseline (p < 0.001). Additionally, during the experiment, diabetic patients had significantly lower HR than those without diabetes (p = 0.006)  . p = 0.001) and the differences in HR throughout the whole HD for participants with diabetes compared to patients without diabetes (p = 0.015) were statistically significant.In multivariate analysis, only the differences in HR throughout the whole treatment for participants with HR < 60 bpm at the beginning of dialysis compared to participants with HR from 60 to 100 bpm at baseline (p = 0.047). We also observed that the decrease in PP after 20 min of glucose infusion was significantly lower in patients with fluid overload > 15% compared to subjects with a volume overload of ≤ 15% (p = 0.005)  .p = 0.009). We also found systematic differences in the time course of PP between patients with elevated SBP > 140 mmHg at the beginning of dialysis compared to patients with SBP ranging from 90 to 140 mmHg. Those with higher SBP at baseline had significantly higher PP during dialysis compared to participants with low SBP ranging from 90 to 140 mmHg at baseline (p < 0.001). Patients with relative fluid volume overload > 15% at the beginning of dialysis also had higher PP throughout the experiment compared to participants with a relative volume overload ≤ 15% (p = 0.021).Additionally, PP was higher in diabetic patients compared to individuals without diabetes throughout the whole dialysis session (p = 0.006) (p = 0.012), and systematic differences in PP during the experiment for participants with higher vs. lower SBP at baseline (p < 0.001) were statistically significant.In multivariate analysis, only an interaction of the time course of PP with fluid overload at the beginning of dialysis (= 0.006) , differep = 0.001). We also observed differences in MAP increase after 60 and 120 min of glucose infusion between patients with and without diabetes and where the increase of MAP was significantly higher in diabetic individuals (p = 0.020)  .-30 (p = 0.005) was statistically significant  decrease lasting until the end of dialysis. This increase is essentially caused by the osmotic action of glucose expanding the circulating blood volume and which is studied in a companion paper [Patients with CKD treated with HD are prone to have fluctuations in blood pressure values depending on hemodialysis schedule. Blood pressure tends to be highest in predialysis period, then decreases during HD, and after that rises again in the next interdialytic time period. The average decline of blood pressure during HD is about 28 to 40 mmHg [-30 (p = 0.014) and higher SBP throughout the whole HD for those with higher SBP at T-30 (p = 0.001). The infusion of glucose did not cause a long-lasting rise of SBP in patients with normal HR values at T-30, but on the other hand, it caused an increase of SBP after 60 min in those with HR < 60 bpm at T-30. Thus, we may state that the glucose infusion prevents a serious fall of SBP in those with HR < 60 bpm, who may not be able to compensate the fall of blood pressure with an adequate increase in HR, which is one of the physiologic responses to hypovolemia . However, this physiologic response is often impaired in CKD because of frequent cardiovascular complications including heart failure [The results of our report show that glucose infusion in the large dose of 0.5 g/kg of dry weight prevents a serious fall of blood pressure during HD. When we analyzed the relationship between the time course of SBP and selected clinical and dialysis parameters, we found an interaction of time course of SBP with HR at T failure . The usep < 0.001). They also had lower DBP in each moment of HD compared to participants with SBP ≥ 100 mmHg. Patients with at least one episode of SBP < 100 mmHg during HD were older, had lower BMI, and had lower HR at the beginning of HD compared to those with SBP ≥ 100 mmHg. Participants with episodes of SBP < 100 mmHg and those with SBP ≥ 100 mmHg during HD did not differ in terms of sex or diabetes. Despite the fact that ten patients had at least one episode of SBP < 100 mmHg, these episodes were not diagnosed as IDH. Participants with SBP < 100 mmHg during HD had lower SBP at the beginning of HD, they did not have clinical symptoms of hypotension, and they did not require medical intervention throughout the whole HD. However, we also observed an increase in arterial blood pressure one hour after glucose infusion in patients with baseline HR-30 < 60 bpm: 14 participants had at least one episode of an increase of SBP > 20 mmHg in relation to SBP-30. The rise of SBP was noticed immediately after glucose infusion, and SBP remained high for the following two hours. Participants with a rise in SBP > 20 mmHg during HD had higher DBP throughout the whole HD, they were older than those without such an increase, they had higher glucose and sodium concentrations at the beginning of HD, they had lower ultrafiltration volumes, and had increased fluid overload compared to individuals without episodes of SBP rise > 20 mmHg. Overall, 57% of participants with episodes of SBP rise > 20 mmHg were diabetic patients. Despite the rise of SBP > 20 mmHg during HD, participants did not report clinical symptoms of hypertension and also did not require medical intervention or additional hypotensive treatment throughout the whole HD. We therefore conclude that glucose infusion did not cause the severe hypertensive episodes in the study population.In the course of the experiment, we found that ten patients had at least one episode of SBP < 100 mmHg, and among them, three participants had at least one episode of SBP < 90 mmHg. Patients with at least one episode of SBP < 100 mmHg during HD had significantly lower SBP at the beginning of dialysis compared to those with SBP ≥ 100 mmHg . Our observation that patients with diabetes and HR < 60 bpm at T30 experienced a rise in DBP after 60 min of the glucose infusion without serious side effects is crucial to predict that this may be a potential preventive method of IDH episodes in the diabetic dialysis population.We also found that patients with HR < 60 bpm at baseline had lower DBP in comparison to participants with HR from 60 to100 bpm for the 60 min period following the glucose infusion. After one hour of glucose infusion, DBP in patients with HR < 60 bpm at baseline rose and remained elevated compared to participants with HR from 60 to100 bpm . Howeverimpaired . Moreovep = 0.012). This chronic difference is essentially explained by stiff arteries found in diabetic subjects. The meta-analysis by Kodama based on almost 58,000 patients showed that increased PP is associated with future cardiovascular risk in diabetic individuals [p = 0.006) (p < 0.001). An isolated increase in SBP already leads to an increase in PP. Isolated systolic hypertension is diagnosed in around 65% of hypertensive elderly patients and is connected with atherosclerosis and arterial stiffness [Heart failure occurs in up to 65–70% of patients with CKD . Both syividuals . Dillingividuals . The mosividuals . We also= 0.006) . CKD andtiffness . Cardiov30 was statistically significant (p = 0.005)  . One houdiabetes . This coThe small sample size is one limitation of our study. A much larger number of patients would be required to analyze effects of age, comorbidities, and medication. The high age of the study population could be considered as a limitation as well, especially as the effect of age on IDH remains unclear.IDH is associated with increased cardiovascular and all-cause mortality, and that is why it is necessary to examine new methods that prevent a fall in blood pressure during HD but do not lead to volume overload and do not cause a severe rise in arterial blood pressure. Glucose infusion seems to combine those advantages. From our study, we may conclude that glucose infusion prevents episodes of IDH during HD and does not cause severe hypertensive episodes. However, more studies on delayed rise of arterial blood pressure after glucose infusion injection in patients with low HR and/or diabetes are needed.


The new onset of hyperlipidemia was similar between both CNI groups and de novo appearance of DM was only documented in those LTRs receiving tacrolimus. In this LTRs retrospective study, it was observed that having ≥ 4 tacrolimus trough levels above the upper limit of the proposed interval for each specific post-LTx period was associated with an increased risk for developing renal impairment. No other statistically significant association was found between supratherapeutic CNIs blood levels and the evaluated toxicities.Patients undergoing lung transplantation (LTx) need administration of immunosuppressive therapy following the procedure to prevent graft rejection. However, these drugs are not exempt from potential risks. The development of cardiovascular risk factors and impaired renal function in the post-transplantation period are conditions that may be favoured by the use of calcineurin inhibitor (CNI) drugs which could have repercussions on the quality of life and the post-transplantation evolution. To evaluate the cardiovascular and renal toxicity following the administration of CNI as maintenance immunosuppression in lung transplant recipients (LTRs) we reviewed a total number of 165 patients undergoing LTx between 01/01/2015 and 08/12/2018. They were divided into two groups according to the CNI drug administrated: cyclosporine (CsA-group) with 11 patients or tacrolimus (Tac-group), with 154 patients. We evaluated the de novo occurrence of arterial hypertension (HTN), diabetes mellitus (DM), hyperlipidemia and impaired renal function after initiation of CNI administration. In addition to that, the time until each of these events was assessed. A higher rate for developing HTN ( Although cyclosporine is still used in certain recipients, there has been a progressive decline in its administration compared to tacrolimus in recent timesIt is necessary to be aware of the toxicities that may result from the use of these drugs in the post-transplantation management of these patients in order to cope with them.4.In the case of LTx, a number of specific assumptions must also be considered: this regimen must be maintained for life and the intensity of immunosuppressive therapy is usually stronger due to the higher risk of rejection compared to other types of solid organ transplantation (SOT)Because of the above mentioned issues, LTRs are exposed to a higher risk of toxicities from immunosuppressive therapy.5, in LTRs with long-term survival, particular attention should be focused on the cardiovascular toxicities such as arterial hypertension (HTN), hyperlipidemia and diabetes mellitus (DM)_ and also to the development of impaired renal function. These comorbidities should be taken into account as they relate with increased morbidity and decreased survival after transplantation6.Although the information of immunosuppression effects is usually mostly derived from results observed in other types of transplantation7 was the last one where information on the development of post-LTx HTN, renal dysfunction, hyperlipidemia and DM was collected. The 2017, 2018 and 2019 annual reports only contained data on renal dysfunction and DM, but there is no longer any reference to the development of those comorbidities in the following annual reports.Despite its importance, the incidence of these comorbidities is no longer reported in the annual reports published by ISHLT in the area of LTx. In fact, the 2016 annual report6.The risk of developing HTN, hyperlipidemia and/or DM increases in post-transplant recipients in direct association with the use of immunosuppressive drugs2.When evaluating the percentage of deaths due to cardiovascular causes in LTRs after the first month post-transplantation, the percentage is estimated to be around 5–6%2; while the median survival time among kidney recipients has been reported to be 12.4 years; 11.1 years in the case of adult cadaveric liver transplantation and 9.4 years for adult heart transplantation8.However, it should be noted that this low percentage may be related to the smaller incidence of cardiovascular events in LTRs in relation to their lower survival rate when compared to other SOT. In this regard, assessing overall survival after transplantation, the ISHLT reports that for adults who had undergone primary LTx in recent years (data obtained between 2010-June 2017), the median survival is 6.7 years9, mechanisms related to the sympathetic nervous system10, alterations in regulation of intracellular calcium ions, excess production of vasoconstrictors and reduction in the production of vasodilatory prostaglandins7.CNIs are known to raise blood pressure through different mechanisms: vasoconstriction of the afferent renal arteriole 11 or mammalian target of rapamycin (mTOR) inhibitors when combined with CNIs12.In addition to the risk associated with the use of CNI, in transplant recipients there are other immunosuppressive drugs that have also proven to increase blood pressure, such as corticosteroids 13.The occurrence of hyperlipidemia is a common condition after transplantation. But it is important to bear in mind that in addition to CNIs, other drugs used in the post-transplantation immunosuppressive protocol may contribute to the development of hyperlipidemia, such as corticosteroids or mTOR inhibitors14, although significant increases may occur throughout the first-year post-transplantation.It has been reported that the increase in total cholesterol concentration may be of particular significance in the earliest post-transplant stage, especially between 3 and 6 months after transplantation6. This percentage is lower than that documented in other types of SOT. As an example, for cardiac transplant recipients who survive the first year, hyperlipidemia has been reported to be 60% and this rate was 88% for those who survived beyond 5 years15.The ISHLT registry reported de novo development of this comorbidity for the last time in 2016, where it was stated that up to 20–30% LTRs developed hyperlipidemia beyond the first year post-LTx in most casesThe development of de novo DM in the post-transplant period is sometimes referred to by the term NODAT, which stands for new onset diabetes mellitus after transplant.16. In relation to impaired insulin secretion, this effect may in turn be related to another common side effect of CNIs themselves such as hypomagnesemia, which contributes to this impairment17 by promoting increased calcium levels in pancreatic beta cells18.The mechanisms by which CNIs produce this alteration in glucose metabolism are multiple. It has been documented that these drugs produce an alteration in pancreatic beta cells that lead to a reduction in insulin secretion, and it has also been observed that there is evidence of an increased resistance to the effect of insulin in the rest of the body's cells19. Moreover, it should not be forgotten that the use of methylprednisolone boluses is a common practice in the treatment of acute rejection episodes, which significantly increases the dose of corticosteroid exposure in recipients who suffer rejection20.Although, as mentioned, CNIs are drugs that favor the development of DM, it is important to note that they are not the only ones to be considered when talking about transplant recipients. Corticosteroids, commonly used as part of post-transplant immunosuppressive maintenance treatment, are also known to favor the development of NODAT when used over a prolonged period of timeAlthough there are other causes in the early post-transplant period that may lead to the development of renal function impairment that should not be overlooked , it is important to consider renal impairment caused by CNIs as well.21 and an inadequate vasodilatory response, particularly in the afferent arteriole22. When CNIs concentration in whole blood is elevated, this vasoconstriction is thought to be potentiated, leading to acute kidney damage23. In the specific field of LTx, supratherapeutic tacrolimus levels have been considered to be related to the development of renal failure25. However, it should not be forgotten that nephrotoxicity can occur even with immunosuppressant blood levels within the therapeutic range, when there is a high plasma fraction of CNI that is not bound to proteins28.CNIs nephrotoxicity is related to vasoconstriction of afferent and efferent arterioles29. When reviewing prevalence of chronic kidney disease among LTRs, values range from 15 to 20% after 5 years and kidney transplantation has also been pointed a reasonable option30.The magnitude of this issue is noteworthy, and it is widely recognized that chronic kidney disease among non-renal SOTs often requires renal replacement techniques such as dialysis or even kidney transplantationIn the post-transplantation period, CNIs therapeutic drug monitoring is essential to assess recipients' level of immunosuppression.There are reference intervals to be followed depending on the type of transplant and the post-transplant stage of the recipient.33.It is important to attempt that the immunosuppression blood level is the appropriate for each post-transplantation stage, avoiding both levels that are below the reference interval (which are related to risk of rejection) and levels that are above the reference interval The aim of this study was to evaluate different toxicities following the administration of CNI drugs as maintenance immunosuppression in LTx and to assess whether blood levels of immunosuppressants are related to the occurrence of these events.We examined recipients who received their lung allografts at the Marqués de Valdecilla University Hospital (HUMV) between 1 January 2015 and 8 December 2018.We conducted a retrospective study using the electronic medical records of the recipients and the LTx database of the center as sources of information.Inclusion criteria were as follows: (1) having had LTx; (2) being aged 18 years or above at the moment of LTx; (3) post-transplant immunosuppressive treatment regimen that included a CNI drug.Patients presenting any of the following criteria were not selected for participation in this study: (1) patients who were not prescribed immunosuppressive treatment with CNIs; (2) patients who had previously expressed their refusal to participate in research studies.As demographic variables, we included data on the gender of the recipients, their age at the time of transplantation and specific transplant-related data: type of LTx and underlying lung disease.We evaluated the de novo occurrence of HTN, hyperlipidemia, DM and impaired renal function after initiation of immunosuppressive therapy with CNIs. In addition, we assessed the time until each of these events.In our center, the standard immunosuppression protocol consists of a triple immunosuppressive therapy that includes a CNI (preferably tacrolimus), mycophenolate mofetil or mycophenolic acid and corticosteroids. In April 2016 basiliximab induction started to be used routinely. Before that date, it was just employed in selected cases, such as elderly patients or in cases of renal dysfunction or severe pulmonary hypertension.® platform (Abbot Diagnostics).The blood level determinations of CNI in our center are routinely performed in the Clinical Pharmacology laboratory by chemiluminescent microparticle immunoassay in an ARCHITECT i-1000In this study, we classified as LTRs with appearance of de novo HTN those patients who were prescribed an antihypertensive drug due to confirmation of sustained elevated arterial blood pressure levels.Recipients were classified with de novo development of hyperlipidemia if they were prescribed a statin due to confirmation of elevated cholesterol levels, the upper limit of the reference range being set at 200 mg/dL in our center laboratory.We defined de novo onset DM when elevated post-transplant blood glucose levels were documented and required some sort of corrective intervention .2 is assumed to be normal.The category of recipient with impaired renal function was given to those patients with a marked increase in serum creatinine and a significant decrease in glomerular filtration rate compared to their pre-transplant baseline . The upper limit of the reference range for the serum creatinine value in the laboratory of our center is 1.18 mg/dL. The glomerular filtration rate is calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula, where ≥ 90 mL/min/1.73 mThe date of onset of these events was defined as the date on which the event was first recorded in the clinical history, either as a diagnosis or as first reference made to the administration of a specific treatment.We evaluated CNI blood levels at specific timepoints on dates coinciding with routine post-LTx control examinations: 3rd month, 6th month, 9th month, 1st year, 18 months, 2nd year and 3rd year. Thus, the maximum number of analytical results available per patient was seven.These are the points that were selected for this study although the follow-up of LTRs includes many more evaluation points, which are particularly frequent in the immediate post-transplantation period. In our center these evaluations are set every 2 weeks for the first 6 months; every month in the period from 6 to 12 months; once every 2 months between 12 and 24 months and once every 3 months beyond 24 months, as well as whenever there is a clinical deterioration.For each blood level test, we assessed whether the result obtained was within or above the therapeutic range proposed for the specific post-LTx stage.For this purpose, each specific result was assessed on a case-by-case basis, considering the CNI drug that the patient was receiving.For tacrolimus it is usually determined the trough level or C0, which is the level just before the dose is taken. In LTx, the trough levels of tacrolimus are maintained between 10 and 15 mcg/L the first 12 months and afterwards the reference interval is established at 8–10 mcg/L.For cyclosporine, blood determinations can be made both at the trough level (C0) and 2 h after the dose is taken (C2). The reference blood levels also differ according to the post-LTx stage: first 6 months after the procedure (C0: 250–350 mcg/L and C2: 800–1000 mcg/L), 6–12 months post-LTx (C0: 200–250 mcg/L and C2: 600–800 mcg/L) or > 12 months (C0: 125–250 mcg/L and C2: 400–600 mcg/L).For the data analysis Software IBM SPSS Statistics 20 was used.Qualitative variables were expressed as frequencies and percentages, while quantitative variables, depending on their homogeneity, were expressed as the mean ± standard deviation  or median with the interquartile range . To determine if the continuous quantitative variables followed a normal distribution the Smirnov–Kolmogorov test or the Shapiro–Wilk test were used.To compare quantitative variables, the Student's t-test and the Mann–Whitney U-test were used, depending on the homogeneity of the parameters.For categorical variables, chi-square or Fisher's exact test were used.Analysis on CNI blood levels and their association with each of the studied events was performed and the results are given as an odds ratio (OR). The confidence interval (CI) was established at 95%.Finally, a log-rank test was carried out to study each of the different event-free periods . These findings were represented with Kaplan–Meier graphs. For time-to-event analysis, follow-up of recipients not experiencing the event of interest were censored.A probability value of less than 0.05 was considered statistically significant.The study was conducted in accordance with the Declaration of Helsinki, and approved by the Drug Research Ethics Committee of Cantabria (Spain), with protocol code IDI-ICN-2020-01 .Patient consent was waived due to the retrospective, observational nature of this study.We reviewed a total number of 165 LTRs. From the total group of patients reviewed, 109 men and 56 women were included. The additional demographic characteristics are shown in Table Patients were divided into 2 groups according to the CNI drug: cyclosporine (CsA-group) or tacrolimus (Tac-group). The study included 11 patients treated with cyclosporine (6.67%) and 154 patients treated with tacrolimus (93.33%).Among the 11 LTRs treated with cyclosporine, all but one of them , were initially on an immunosuppressive regimen with tacrolimus since in our center, according to our protocol, tacrolimus is used as the CNI of choice in first instance, and the switch to cyclosporine is only made in case of very specific situations. The reason for the change from tacrolimus to cyclosporine in these 10 LTRs was the suspicion of neurotoxicity in relation to tacrolimus: several patients presented visual and auditory hallucinations, agitation and nervousness, disorientation episodes, and behavioral alterations including aggressiveness. One of them presented seizures and another presented a global polyneuropathy. After switching the CNI from tacrolimus to cyclosporine, an improvement was observed in terms of clinical evolution in all of them.When analyzing de novo development of cardiovascular risk factors and deterioration of renal function during follow-up after LTx, we came across the following results Table .Table 2Dp = 0.003).There were 49 LTRs who developed HTN in the follow-up period (36.84%), with a higher percentage of this event within the CsA-group .When reviewing new onset of hyperlipidemia, we found a total number of 82 LTRs (64.57%) who developed a de novo increase in cholesterol levels in their post-transplant blood tests, with no differences between both groups .With regard to the analysis of the development of DM de novo, this event was only reported on LTRs undertaking tacrolimus treatment, where 41 out of 137 LTRs which could potentially develop this event, finally presented it .When assessing the development of renal function impairment, we found 76.69% recipients who developed renal impairment from the total number of LTRs that were susceptible to this event. When looking at the type of immunosuppressant they were being treated with, 10 were documented in the group treated with cyclosporine (90.91% from the CsA-group) and 115 in the Tac-group (75.66% from this group) , in good relationship with the higher doses employed in those stages.p = 0.152, Fisher's exact test), hyperlipidemia  nor renal impairment .In the CsA-group, we evaluated the relationship between the presence of ≥ 2 C0 levels above the proposed interval for each post-LTx stage and the occurrence of the different events studied, without finding any statistically significant relationship regarding the development of de novo HTN (p = 0.008).In the Tac-group, we also evaluated the relationship between the presence of blood levels above the target for each post-LTx stage and the development of the different comorbidities. In this group of patients, due to their greater representation in number, the available number of tests was also higher. For each patient a record was made of whether they had ≥ 2, ≥ 3 or ≥ 4 tacrolimus trough levels above the upper limit of the target interval for each post-LTx stage. No statistically significant relationship was found for HTN, hyperlipidemia nor DM, but for those LTRs with ≥ 4 tacrolimus C0 determinations above the recommended blood levels we found a higher risk for developing renal impairment   Fig. .Figure 2This study evaluates the development of cardiovascular risk factors and renal impairment related to CNI drugs in the post-transplant period in a group of LTRs.In the last years, the ISHLT annual reports do no longer reflect this information for LTRs.Our study aims to describe the situation in our population, which is representative from LTx at the North of Spain. To the best of our knowledge, this study is the first of our region to evaluate the association between the development of de novo cardiovascular risk factors and renal impairment in the post-transplant period of LTRs in our country.36. This is due to the fact that they bind to different proteins , so some differences in their effect can be expected. For example, in the case of tacrolimus, it has been reported that its effect on systemic vascular resistance is weaker than that reported with cyclosporine37.In our work, a higher incidence of HTN was observed within the CsA-group. Although both tacrolimus and cyclosporine share the same mechanism of action, as both drugs belong to the CNI group, a lower incidence of cardiovascular effects has been reported with tacrolimus in previous studiesp < 0.001)38. For this reason, it is common in clinical practice to switch from cyclosporine to tacrolimus in an attempt to control cholesterol levels41.Focusing on the specific effect of CNIs on the development of hyperlipidemia, a recent literature review comparing the effects of tacrolimus versus cyclosporine showed that there were a greater number of studies that associated the use of cyclosporine with an increased risk for hyperlipidemia . In the field of LTx, there is also a systematic review of RCTs that compares tacrolimus with cyclosporine43 where a higher rate of DM de novo was observed among LTRs undergoing tacrolimus treatment . In addition, it has also been described that the risk for DM increases with higher blood concentrations of tacrolimus44.In our cohort of LTRs, DM de novo was only documented in the Tac-group. The fact that this event was not observed in the CsA-group may be clearly influenced by the lower number of LTRs receiving this drug as CNI. Nevertheless, the incidence of DM de novo is known to be more frequent with the use of tacrolimus as a maintenance CNI according to medical literature. In this way, Webster et al. conducted a systematic review including publications on randomized controlled trials (RCTs) in renal transplantation. Data from 30 trials (n = 4102 patients) were included and, after a meta-analysis, it was noted that at one year, those recipients treated with tacrolimus had more insulin-requiring DM 46.In our study, a higher incidence of impaired renal function was documented within the CsA-group. Although this finding, as the previous one, should also be considered with caution due to the same reason: a lower number of LTRs in our study receiving cyclosporine. When looking for data in the literature, CNI induced nephrotoxicity appears to be lower in patients undergoing tacrolimus treatment47 and renal impairment has been described in association with increased blood levels of both CNIs48.With regard to the correlation between CNIs blood levels and the development of these events, some studies suggest that high levels of tacrolimus may be related to de novo appearance of DM or hyperlipidemia in the post-transplantation periodFrom a clinical point of view, it therefore becomes clear that it is important to have strategies to reduce, as far as possible, the potential development of toxicities related to the use of CNIs.49. A sample of this is what is sometimes referred to as “CNI minimization protocols”50. An example of the aforementioned consists in attempting to reduce CNIs blood levels, by the association to the immunosuppressive maintenance treatment of a drug from the mTOR inhibitors family. This type of association has proved that, besides achieving an improvement in renal function in patients with renal impairment, it does not increase the risk of acute rejection51. It has been described that the results are especially favorable when the deterioration of renal function is significant (glomerular filtration rate < 40 mL/min)52.To specifically reduce CNIs-related nephrotoxicity, some strategies have been described. The medical administration of two or more immunosuppressants with different mechanisms of action is widely used nowadays, with the aim of reducing the prescribed dose of each drug and thereby minimizing the side effects of their administration53, but always being mindful that recovery from surgery should be awaited as mTOR inhibitors delay wound healing56. Although this strategy may be useful for patients whose main post-transplantation impact is on their renal function, this drug combination would not be a solution to the problem of the development of cardiovascular risk factors, as it has been documented that the concomitant use of steroids, CNI and mTOR inhibitors can lead to the development of HTN, hyperlipidemia and DM57.The addition of an mTOR inhibitor to the therapy makes it possible to reduce the CNI prescribed dose, maintaining good results in the evolution of the lung graft, and their results are the better the earlier this addition is made to the treatmentIt is therefore essential to adjust treatment on an individual basis, with the aim not only of improving graft survival, but also the impact on transplant recipients’ life quality  and this must always be done on a case-by-case basis for each patient.Among the limitations of this study, it should be firstly noted that it is a single center study with a retrospective basis, so information biases should be considered. The CsA-group was much smaller in number, so the observed results may not be representative. In our work, we have included a description of the two CNIs treatment options we have encountered, but due to differences in the number of patients with each type of CNI, we would like to point out that a statistically significant result in the CsA-group does not necessarily imply a correspondence in terms of clinical relevance.58.When reviewing the available evidence in the medical literature, we found that there are several difficulties in exploring the toxicities associated with CNIs, not only because there is a lack of consensus on how to define each event, but also because different approaches are used for correlating eventsEach of the events studied  have multiple other conditioning factors that are beyond the scope of this study, but which should be taken into consideration.Additionally, the available follow-up period is too short to assess cardiovascular risk factors' impact on the associated mortality risk, which also would certainly be of interest.In this review of 165 LTRs on CNI treatment, a higher incidence of developing HTN and deterioration of renal function was found within the CsA-group, while hyperlipidemia was observed with a slightly higher frequency in the Tac-group, that was not statistically significant. In the meanwhile, de novo appearance of DM was only described in patients treated with tacrolimus.When assessing the relationship between the appearance of these events and CNIs blood levels, we found that LTRs with ≥ 4 tacrolimus C0 determinations above the upper limit of the proposed interval for each specific post-LTx stage had a higher risk for developing renal impairment. No other statistically significant association was found between supratherapeutic CNIs blood levels and the development of these comorbidities.These events, widely described in other types of transplantation, are also confirmed in our LTRs sample, but further studies in this transplant population are required to confirm these data.


Beat‐to‐beat blood pressure variability (BPV) is associated with an increased risk of stroke but can be driven by both healthy physiological processes and failure of compensatory mechanisms. Blood pressure (BP) complexity measures structured, organized variations in BP, as opposed to random fluctuations, and its reduction may therefore identify pathological beat‐to‐beat BPV.P<0.001) and was similarly reduced in patients with hypertension or diabetes (P<0.001). However, although BPV coefficient of variation had a U‐shaped relationship with age, BP complexity fell systematically across age quintiles (quintile 1: 15.1 [14.0–16.1] versus quintile 5: 13.8 [12.4–15.1]) and was correlated with markers of autonomic dysfunction  and arterial stiffness , even after adjustment for clinical variables .In the prospective, population‐based OXVASC (Oxford Vascular Study) Phenotyped Cohort with transient ischemic attack or minor stroke, patients underwent at least 5 minutes of noninvasive beat‐to‐beat monitoring of BP (Finometer) and ECG to derive the following: BPV (coefficient of variation) and complexity  of systolic BP and diastolic BP, heart rate variability , and baroreflex sensitivity , in low‐ (0.04–0.15 Hz) and high‐frequency (0.15–0.4 Hz) bands. Associations between BPV or BP complexity with autonomic indexes and arterial stiffness were determined (linear regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. In 908 consecutive, consenting patients, BP complexity was inversely correlated with BPV coefficient of variation (Loss of BP complexity discriminates BPV because of pathological failure of compensatory mechanisms and may represent a less confounded and potentially modifiable risk factor for stroke. BPVblood pressure variabilityBRSbaroreflex sensitivityCVcoefficient of variationDBPdiastolic blood pressureHFhigh frequencyHRVheart rate variabilityLFlow frequencymodMSEmodified multiscale entropyOXVASCOxford Vascular StudyPPpulse pressureSBPsystolic blood pressureBeat‐to‐beat blood pressure (BP) variability shows a U‐shaped relationship with age.“Complexity” of BP, representing structured as opposed to random variability, is more linearly and inversely associated with age.Reduced complexity of BP is associated with major cardiovascular risk factors and markers of autonomic dysfunction and vascular aging.Increased BP variability can be driven by either intact physiological processes in the young or pathological failure of compensatory mechanisms that are more common in older patients.The nonlinear relationship between BP variability and age confounds understanding of the relationship between underlying mechanisms, risk of stroke, and response to treatment.Complexity discriminates organized and structured variations in BP from increased BP variability attributable to autonomic dysfunction and vascular aging, and may be a more precise marker of future modifiable vascular risk.Uncontrolled high blood pressure (BP) increases the risk of stroke and all cardiovascular events,Entropy‐based complexity analysis of BP measures variations in BPReduced complexity of physiological signals has been associated with aging,Therefore, we hypothesised that (1) beat‐to‐beat BPV has a similar physiological basis to heart rate variability, as well as longer forms of BP variability, and therefore BPV may be increased in both healthy patients and patients with age‐related, vascular dysfunction,peter.rothwell@ndcn.ox.ac.uk).Access to the data that support the findings of this study will be considered on application to the chief investigator on reasonable request. Please contact Professor Peter Rothwell for further information  were recruited between September 2010 and November 2019, as part of the Phenotyped Cohort of the OXVASC (Oxford Vascular Study).All consenting patients underwent a standardized medical history and examination, ECG, blood tests, magnetic resonance imaging of brain and contrast‐enhanced magnetic resonance angiography (or computed tomography of brain and either carotid Doppler ultrasound or computed tomography angiogram), an echocardiogram, and 5‐day ambulatory cardiac monitoring. All patients were reviewed by a study physician, the diagnosis was verified by the senior study neurologist (P.M.R.), and patients were followed up face‐to‐face for up to 10 years.As part of the phenotyped cohort, a routine prospective cardiovascular physiological assessment is performed at the 1‐month follow‐up visit in a quiet, dimly lit, temperature‐controlled room (21 °C –23 °C). Continuous 3‐lead ECG and noninvasive finger arterial BP  were measured over at least 5 minutes, and up to 10 minutes, at 200 Hz during supine conditions via a Powerlab 8/35 (ADInstruments) software, preferentially measured from the middle phalanx of the middle finger of the nondominant arm when possible.Consecutive R‐R intervals of the ECG waveforms and beat‐to‐beat averages of systolic (SBP) and diastolic (DBP) components of BP were automatically derived and median filtered, with quadratic interpolation of the peak of the QRS complex and linear interpolation across ectopic beats.Beat‐to‐beat SBP and DBP signals were detrended by linear regression. Because of the relatively short recording length of measurements, complexity of beat‐to‐beat BP was determined by the modified multiscale entropyhttp://www.car‐net.org/]) with criterion of default coherence threshold as set in the script, based on the 95% CI of the null hypothesis of no relationship between input and out signals.Heart rate variability (HRV) was estimated by the SD of R‐R intervals and root mean square of the successive beat‐to‐beat difference.(PP=SBP‐DBP), and the systolic and diastolic BPV were calculated as the coefficient of variation (CV=100%×(SD/mean)) of the continuous beat‐to‐beat BP monitoring .Aortic arterial stiffness was estimated by carotid‐femoral pulse wave velocity, measured by applanation tonometry2 test for categorical variables and ANOVA for continuous variables. Associations between BP complexity with HRV, BRS, and continuous clinical characteristics were assessed by linear regression with a log transformation to normalize the data and improve validity of the regression model, both unadjusted and adjusted for clinical characteristics, reported as partial correlation coefficients , stratified by sex, age in quintiles , and hypertension or diabetes.The distributions of continuous variables were assessed by histograms and tested for normality (Shapiro‐Wilk). Clinical characteristics were compared by the χP<0.05 was considered to be statistically significant. All analysis was performed in Microsoft Excel, Matlab r2017, and R.For all analyses, a value of A total of 959 of 1013 (95%) eligible, consenting patients had at least adequate beat‐to‐beat BP recordings, of whom 51 (5%) had inadequate recording quality or atrial fibrillation during testing, 3 (0.3%) had poor quality ECG recordings, and 93 (9.7%) did not have pulse wave velocity assessed because of technical limitations, such as body habitus or significant carotid stenosis  were strongly positively skewed and nonnormal , with a linearly falling trend when stratified by quartiles . SBP‐CV and DBP‐CV were nonlinearly related to age, with greater BPV in the bottom quintile compared with the second and third quintiles, followed by a progressive increase in upper quintiles , and a linear trend across quartiles , before and after adjustment for clinical variables (Table P‐trend <0.001), with a consistent result of association of complexity of DBP with BRS , implying a reduced sympathetic to parasympathetic autonomic balance .Greater complexity of SBP and DBP was correlated with impaired autonomic function, with a positive association with both SD of R‐R intervals and root mean square of the successive beat‐to‐beat difference , with a linear trend across quartiles . However, there was no significant association between complexity and PP after adjustment for clinical variables  is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Wellcome Trust, Wolfson Foundation, British Heart Foundation, and the European Union Horizon 2020 programme . Dr Rothwell is in receipt of an NIHR Senior Investigator award. Dr Webb is funded by a Wellcome Trust Clinical Research Development Fellowship (206589/Z/17/Z) and British Heart Foundation Project Grant (PG/16/38/32080). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.None.Data S1Tables S1–S4Figures S1–S6Click here for additional data file.


Consequently, patients with T2DM had higher concentrations of oxidant markers, NO (p < 0.01), inflammation markers, IL-6 (p < 0.01), and TNF-α than patients without T2DM. CKD stages were not related to oxidative, antioxidant, and inflammatory marker outcomes in T2DM patients. Patients without T2DM presented an increase in SOD (p = 0.04) and a decrease in NO (p < 0.01) when the stage of CKD increased. In conclusion, patients with T2DM present higher levels of oxidative and inflammatory markers accompanied by a decrease in antioxidant defense. However, these oxidative status markers were associated with CKD stage progression in patients without T2DM. Thus, NO and SOD markers could help detect the early stages of CKD in patients who have not yet developed metabolic comorbidities such as T2DM.Early Chronic Kidney Disease (CKD) is a condition that tends to progress to End-Stage Kidney Disease (ESKD). Early diagnosis of kidney disease in the early stages can reduce complications. Alterations in renal function represent a complication of diabetes mellitus (DM). The mechanisms underlying the progression of CKD in diabetes could be associated with oxidative and inflammatory processes. This study aimed to evaluate the state of inflammation and oxidative stress (OS) on the progression of CKD in the early stages in patients with and without type 2 diabetes mellitus (T2DM). An analytical cross-sectional study was carried out in patients with CKD in early stages  with and without T2DM. The ELISA method determined the expression of pro-inflammatory cytokines IL-6 and TNF-α as well as lipoperoxides (LPO), nitric oxide (NO), and superoxide dismutase activity (SOD). Colorimetric methods determined glutathione peroxidase (GPx) and total antioxidant capacity (TAC). Patients with CKD and T2DM had significantly decreased antioxidant defenses for SOD ( Albuminuria  ≥ 30 mg/g, urinary sediment abnormalities, electrolyte abnormalities, tubular disorders, histologically detected abnormalities, and imaging-detected structural abnormalities also define CKD. CKD is associated with decreased renal function related to increasing age and the presence of hypertension, diabetes mellitus (DM), obesity, and primary renal disorders [Chronic kidney disease (CKD) is defined by the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 misorders . If CKD isorders . Extensiisorders . DM is tisorders Other factors, such as oxidative stress and low-grade inflammation, may be linked to the pathological development of CKD in T2DM ,10.Currently, the diagnosis of CKD is made by blood urea and serum creatinine (sCr) levels; however, sCr concentration is not very reliable due to its dependence on the patient’s body weight, age, and gender . HoweverLow-grade inflammation is considered a hallmark of CKD and is involved in developing all-cause mortality, even in the early stages .2O2) or singlet oxygen (1O3). OS reactions also involve oxygen compounds, such as non-radical compounds (peroxynitrite (ONOO-) and hypochlorous acid (HOCl) [Oxidative stress (OS) is defined as the imbalance between reactive oxygen species (ROSs), reactive nitrogen species (RNS), and free radicals as oxidants . Oxidantd (HOCl) . The metd (HOCl) . In diabd (HOCl) . Increasd (HOCl) This study aimed to evaluate inflammation and OS state in the early stages of CKD in patients with and without T2DM.p = 0.04), with T2DM (p < 0.01), and between those without DM and with T2DM (p < 0.01). A similar decrease was observed in hematocrit, with a significant difference in patients with DM (p < 0.01), even between patients with and without DM (p < 0.01). As expected, glucose was found to be increased in patients with T2DM (p < 0.01). sCr levels increased as the disease stage progressed in patients with and without DM (p < 0.01). Low-density cholesterol and very-low-density cholesterol showed altered levels in patients with DM compared to patients without DM (p = 0.04). Patients with and without DM in the three stages did not show a trend toward decreasing or increasing vitamin D. FGF23 levels decreased as the CKD stage progressed in T2DM patients. Patients in stage 3 with T2DM showed significantly lower levels of FGF-23 (p = 0.05).p = 0.03) and were higher in patients with T2DM. A significant difference was found between patients without DM and an increase in parathyroid hormone in patients with T2DM (p < 0.01). GFR decreased as the stage of kidney disease progressed, both in patients with and without DM (p < 0.01).Parathyroid hormone levels increased as kidney disease progressed in patients without DM . However, NO levels in patients without DM decreased as the early stage of kidney disease progressed (p < 0.01)  .p < 0.01) compared to the activity in the group of patients without DM, 17.24 ± 7.02 U/L. SOD enzyme activity increased as the stage of kidney disease progressed in patients without DM (p = 0.04) and with T2DM , compared to the group of patients without DM, 10.79 ± 0.38 nmol/min/mL. However, the activity of the antioxidant enzyme in the early stages of kidney disease in patients with and without DM did not show statistical significance . In the early stages of kidney disease, no significant differences were observed in patients with and without DM  compared to the group of patients without DM, 45.81 ± 11.25 pg/mL. However, in the early stages of kidney disease, no significant differences were observed in both patients with and without DM , compared to patients without DM, 6.31 ± 2.01 pg/mL. The analysis of TNF-α in the early stages of kidney disease in the groups of patients with and without DM did not show significant differences  is by itself a diagnostic parameter of CKD when it persists for a period ≥ 3 months [The definition of CKD is a broader concept than simply chronic renal failure because it encompasses patients who may have relatively preserved renal function. In the early stages of kidney disease, patients may be at risk, as there may be increased severity of the disease, which increases the risk of CVD. A decreased GFR  homeostasis, CKD being an especially prominent risk factor for the development of hyperkalemia . The abi2 . Some ob2 ,24. In tsCr is a product of muscle metabolism, which, like urea, is excreted by the kidneys. The sCr level is relatively stable and is therefore considered a reliable indicator of renal function . sCr lev2 in adulthood [GFR is considered the gold standard for the evaluation of renal function. GFR is relatively low at birth but increases during childhood to approximately 120 mL/min/1.73 mdulthood . In the dulthood . 2, and phosphate is retained. PTH synthesis and secretion are stimulated [FGF-23 is a phosphaturic hormone that is elevated in the later stages of kidney disease, followed by a reduction in 1,25-dihydroxy-vitamin D  and an increase in parathyroid hormone (PTH) . It was imulated ,33. In timulated .2, phosphate is retained, and PTH synthesis and secretion are stimulated [As GFR falls below 60 mL/min/1.73 mimulated ,33. In timulated . It has imulated . In expeimulated . Vitamin D metabolism is disrupted by the failure of the second hydroxylation step of 25-hydroxyvitamin D to occur, converting it to the active form 1,25-dihydroxy vitamin D produced in the kidney . InhibitMalnourished patients have elevated levels of C-reactive protein (CRP), IL-6, TNF-α, and concomitant CVD when they reach the end stage. Many diseases that cause CKD, such as DM and hypertension, are associated with CVD. The direct effect of renal failure per se that directly contributes to the inflammation–malnutrition–atherosclerosis paradigm is not fully established in the early stages of CKD ,41. The imbalance between oxidants and the reduction in antioxidant defenses favor kidney damage, limit cell repair mechanisms, and accelerate functional deterioration. In several cross-sectional studies, plasma levels of OS and markers of inflammation were found to be associated with advanced stages of CKD. However, this did not correlate with decreased GFR . In longIn the present study, Hb decreased as the stage of kidney disease progressed. Various factors could explain this; we must consider that erythrocytes play a fundamental role in maintaining the oxidative status of the blood. There are several mechanisms by which oxidative damage and inflammation cause a decrease in Hb by iron deficiency in patients with CKD, including a reduction in antioxidants and oxidation of erythrocyte membrane phospholipids . Other mFurthermore, CKD predisposes patients to vitamin and mineral deficiencies, which contribute to anemia, CVD, and metabolic imbalances . There aNO is a molecule with a wide variety of physiological functions, including; maintaining muscle tone and functions as an intracellular messenger and cytotoxic agent. NO has a substantial effect on the vascular endothelium through its bioavailability. When NO levels increase significantly, it is considered an RNS . In the The SOD enzyme is the body’s first antioxidant defense . The act2O2 to organic peroxides by acting in conjunction with the enzyme peroxynitrite reductase [The GPx enzyme uses glutathione to reduce Heductase . In the eductase . The reseductase .status. The high antioxidant activity reflects protection or benefits in response to chronic OS [TAC measures the global effect of antioxidant mechanisms on serum oxidative ronic OS . In thisronic OS ,60.The expression of the pro-inflammatory cytokines TNF-α and IL-6 was similar between patients with and without DM in the early stages of kidney disease. However, when the groups with and without DM were analyzed, a significant increase in pro-inflammatory cytokines IL-6 and TNF-α was observed in the T2DM group, suggesting that DM plays an essential role in the CKD evolution compared to patients without DM. It is important to consider that diabetic nephropathy is the most common complication of T2DM and is the leading cause of ESRD worldwide .Arterial hypertension, DM, dyslipidemia, and microalbuminuria are essential predictors of identifying people at risk of kidney disease . In the The kidneys play an important role in maintaining homeostasis in the body. Early recognition and intervention are essential to delaying disease severity, maintaining quality of life, and improving survival. Primary care physicians have the opportunity and responsibility to assess at-risk patients, identify affected patients, and facilitate the impact of early stage kidney disease by initiating early therapy and monitoring disease severity. The basic recommendations consist of intensive blood pressure control, with a goal of ≤130/80 mmHg. Angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists are the most effective due to their unique ability to decrease proteinuria. Hyperglycemia with an AIC concentration <7% should be recommended. Anemia should be maintained at hemoglobin levels of 11-12 g per dL (110-120 g per L). Dietary restrictions on Pi are imperative to prevent hyperparathyroidism disease as much as possible, in addition to using antacids and vitamin D supplements. In conclusion, oxidative imbalance was determined in patients with and without T2DM. The presence of OS in T2DM was characterized by an increase in oxidative markers and a decrease in antioxidant defenses . Only patients without T2DM showed a significant increase in the activity of the antioxidant enzyme SOD and a substantial decrease in NO when the CKD stage increased. In the present study, SOD and NO markers changed during the early stages of CDK, similarly to those of the clinical parameters Hb, hematocrit, and sCr frequently used to assess CDK progression. NO and SOD markers could help detect the early stages of CKD in patients without T2DM. Detecting and treating early kidney disease offers an invaluable opportunity to use the different actions available to delay the progression of the disease and prevent its evolution to ESRD.2), systolic blood pressure (SBP) and diastolic blood pressure (DBP), hemoglobin (Hb), hematocrit, glucose, sCr, total cholesterol, high-density cholesterol, low-density cholesterol, very-low-density cholesterol, triglycerides, albumin, sodium, potassium, chlorine, calcium, phosphorus, magnesium, FGF-23, vitamin D, parathyroid hormone, 24 h urine protein, and GFR.An analytical cross-sectional study was carried out on patients diagnosed with CKD in early stages  with and without T2DM treated at the Department of Nephrology of the Civil Hospital of Guadalajara “Juan I. Menchaca” in Guadalajara, Jalisco, Mexico, who agreed to participate in the study and signed informed consent. Male and female patients aged 18–60 years were included. Patients who ingested antioxidants  within the three months before the study, patients with clinical or biochemical data of an infectious process, and patients who were undergoing renal replacement therapy (RRT) were not included. Anthropometric, clinical, and biochemical data were measured: body mass index  for plasma and 5 mL in a dry tube for serum. Plasma and serum were extracted at 1800 revolutions per min (rpm) for × 10 min. The samples were then stored at −80 °C until final processing.® Inc. was used. The method is a sandwich ELISA assay. Absorbance at 405 nm with 650 nm correction was recorded. The standard curve was prepared simultaneously to interpolate the concentrations of each sample.The commercial kit 900-K25 from the manufacturer Peprotechg for ten min at 4 °C. The colorimetric method was used according to the kit  to determine NO. The plate was read at 540 nm in a spectrophotometer within the first twenty min of completion of the procedure.Before determining the NO levels, the serum samples were deproteinized by adding six mg of zinc sulfate to four hundred μL of the example, vortexed for one min, and the samples were centrifuged at 10,000× ®). The limit of detection for this test was 0.1 nmol/mL. The chromogenic reagent reacts with malondialdehyde (MDA) and 4-hydroxy-alkenes to form a stable chromophore. The pattern curve with known concentrations of 1,1,3,3-tetra methoxy propane in Tris-HCl was used. The intra-assay CV was 8.5%.According to the manufacturer’s instructions, the levels of LPO in plasma were measured through the FR22 assay kit . The reaction of tetrazolium salts made it possible to detect the O2- generated by the enzymes xanthine oxidase and hypoxanthine. The serum samples were diluted 1:2 in the sample buffer. The absorbency was read at 440 wavelengths of nm. The levels are reported in IU/mL.We followed the kit manufacturer’s instructions  with GP× of the sample studied in the presence of NADPH. The absorbance obtained at 340 nm was recorded for 30, 60, 90, 120, 150, and 180 s. Subsequently, the rate of decrease in absorbance per min related to the concentration of NADPH consumed in the reaction was determined.Glutathione peroxidase was determined according to the commercial kit 703102 from the manufacturer Cayman chemical Company®, MI, USA) to obtain the concentration in mM equivalents of uric acid. The detection limit was 0.075 mM. The dilution factor was considered in the result. The intra-assay CV was 7.8%.The evaluations of TAC were made following the instructions of the kit manufacturer . The method was followed as suggested by the manufacturer of the ELISA kit. This experiment uses the double-sandwich ELISA technique. The optical density was read at 450 nm. The Synergy HT (BIOTEK) microplate reader was used for all of the technical readings of optical density.To determine FGF23, protein concentration was analyzed by an FGF23 ELISA . The manufacturer’s instructions were followed. This ELISA detects only the protein’s intact, biologically active portion. The optical density was read at 450 nm. The PTH concentrations were determined through the use of a commercial kit . This assay utilizes a competitive ELISA technique. The optical density was read at 450 nm. The kit manufacturer’s instructions were followed (25 (OH)—vitamin D direct Elisa Kit No. K2109KO, ALPCO p ≤ 0.05 (Dunn-Bonferroni). Any value of p ≤ 0.05 was considered significant. All tests were performed with IBM SPSS statistics version 23.Quantitative variables are shown as mean ± standard deviation (SD). Nominal variables in numbers. The Kolmogorov–Smirnov test was performed to determine the data distribution of the entire sample. Comparisons were made using the Mann–Whitney U test. For multiple differences between groups, the Kruskal–Wallis test was used, followed by Dunn’s test with Bonferroni adjustment at This study adhered to the ethical principles for medical research on human beings stipulated in the Declaration of Helsinki 64th General Assembly, Fortaleza, Brazil, October 2013, in the Belmont Report and Standards of Good Clinical Practices according to the guidelines of the International Conference on Harmonization by the provisions of the General Health Law by the Regulations of the General Health Law on Research for Health art. 17. This study corresponds to category II . It required an Informed Consent Letter. This study was authorized by the Research and Ethics Committee of the Civil Hospital of Guadalajara “Juan I. Menchaca” with the State Registration Number 069/15 HCJM/2015.