We aimed to report outcomes of pregnant patients with asthma under omalizumab treatment and their infants in our country.Patients with asthma who received omalizumab for at least 6 months and at least one dose during their pregnancy were retrospectively evaluated using a questionnaire regarding their disease and therapy and the health of their infants. Twenty pregnant patients and their 23 infant’s data were analyzed. The mean delivery age was 31.8 ± 7.4 years. They received omalizumab for 28.9 ± 21.8 months. Eight (36.4%) patients showed exacerbation of the disease during pregnancy. Forced expiratory volume in 1 s (FEV1) and asthma control test (ACT) scores at the starting time of omalizumab administration, first month of the pregnancy, and after delivery were 71 ± 18%, 83.4 ± 10.5%, and 80.5 ± 13% (FEV1), and 11.9 ± 4.9, 20.2 ± 2.6, and 20.4 ± 2.2 (ACT), respectively. One patient gave birth to twin infants, two patients to two infants each in different years, and 17 to one infant each. Three (13%) infants had low birth weight and five (21.7%) were born prematurely. No congenital anomalies were detected. Seven (30.4%) infants presented atopic diseases during their life. Omalizumab treatment during pregnancy seems to be safe for both patients and their infants.  Asthma affects 330 million individuals worldwide and around 4 million in Turkey . This disease has been reported in 8% of pregnant individuals . The health condition of one-third of pregnant patients with asthma is not affected by the physiological, hormonal, and immune changes that occur during the gestation period, one-third shows improvement, and one-third shows progression and ingravescence .®  during pregnancy (EXPECT), the largest prospective study on this subject, which has examined 228 pregnant women and 233 infants, identified a birth anomaly rate of 8.1% and preterm delivery rate of 15%. These rates are not different from the outcomes of the Quebec External Comparator Cohort (QECC) study, which involves the most extensive overall cohort of pregnant women with asthma [6]. In addition, in EXPECT vs. QECC, there was a lower rate of small for gestational age (SGA) infants of mothers receiving omalizumab (9.7% vs. 15.8%) [6]. In contrast, in the position paper of the European Academy of Allergy and Clinical Immunology (EAACI) Society regarding the administration of biological drugs for allergy during gestation, the rates of congenital anomalies and low birth weight have been reported as 4% each and that of preterm birth in singletons as 14% for omalizumab, based on the outcomes of 11 different publications [7].There are sufficient data concerning the continuation of satisfactory asthma control during pregnancy and therefore appropriate asthma treatment for pregnant women with asthma to deliver a healthy infant [5]. In this context, many reports on omalizumab, which is used by severe allergic asthma patients during pregnancy, have been published . The Observational Study of the Use and Safety of XolairReal-life data on the efficacy of omalizumab in patients with asthma have been collected and released in Turkey; however, no data related to gestation have been reported [8]. Although the case notices of all studies conducted previously across the world reported that the administration of omalizumab is safe in gestation, the number of pregnant patients in these case series was between one and four, and there was only one observational study from the United States . In our study, we worked with the real-life data sample reported from one country: 22 pregnancies and 23 infants. Therefore, we aim to share our experience regarding the safety of omalizumab in both mothers and infants by a retrospective review of the relevant data from Turkey.This retrospective real-life case study was approved by the Institutional Ethic Committee (06.08.2019 date 83045809-604.01.02-123451 number); Helsinki Declaration was signed by all coauthors. Informed consent was obtained from each patient.The centers participating in the Turkish omalizumab data survey were called for participation in this study [8]. Nine centers participated in the study as they had pregnant patients under omalizumab therapy with born infants. This study was conducted in Turkey from August 15, 2019 to October 31, 2019. A structured questionnaire was prepared by the authors to collect information regarding demographic and clinical parameters of the mothers as follows; age, living area, smoking status, body mass index, occupation, education level, prick test results and total IgE levels at the beginning of omalizumab administration; spirometry, asthma control test (ACT), and whole blood count results at the beginning of omalizumab administration, beginning of the pregnancy, and after the delivery of the infant; exacerbation rate and exacerbation trimester time during pregnancy and last year before pregnancy; treatment-related parameters (adherence); infant demographic parameters and health during the whole breastfeeding period, until the end of the study. Patients with asthma who received omalizumab for at least 6 months and at least one dose during pregnancy and had a live birth were retrospectively evaluated using a questionnaire. The data not present in the file of the patient were collected via the questionnaire prepared by the authors when the patients came to the relevant clinics for their omalizumab injections after having their informed consent. The outcome or the safety of omalizumab was attributed as the control status and the exacerbation rate of the pregnant patient, the APGAR score, the prematurity, the birth weight, the rate of malformation, and the allergic diseases of the infants.The data of the patients are presented as exact numbers and percentages. If numerical variables are normally distributed, they are presented as mean ± standard deviation. Nonnormally distributed data are presented as median (min-max). The evaluation of spirometry data, ACT scores, and whole blood count data at different time points were compared using the Friedman variance analysis and the Wilcoxon signed rank test. Pearson’s correlation test was used when two variables were continuous. All data were evaluated within a 95% confidence interval with a significance level of p < 0.05. All statistical analyses were performed using SPSS Version 20.0 (IBM Corp. 2012).The data correspond to 20 pregnant patients with asthma  and their 23 infants. One patient gave birth to twin infants, two patients to two infants each in different years, and 17 to one infant each when they were on omalizumab. Four patients (18%) were over 34 years old. The majority of the patients lived in urban areas (95.5%), and 59% were housewives. The mean asthma duration before treatment with omalizumab was 12.2 ± 8.1 years . All patients were allergic to house dust mite (Dermatofagoides pteronissymus). Five of them had also mold allergy  and 2 of them also had cockroach positive skin prick test. Their total serum IgE level was 242.1 ± 198.8 IU in the beginning of omalizumab treatment. Exacerbation rate  last year before pregnancy was 40%. Only eight (36.4%) of the patients showed exacerbation  during pregnancy and half of the exacerbation were in the third trimester. All of them used inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) with high adherence level in 86.4% of the pregnancies. Demographic and clinical data of the patients are presented in Table 1.Spirometry parameters, ACT, and whole blood count results at the starting time of omalizumab administration, during pregnancy, and after delivery are presented in Table 2. ACT score at the starting time of omalizumab administration was statistically lower than the beginning of pregnancy and after delivery. There were no considerable differences between other results at the beginning of pregnancy and after delivery. No correlation was found between forced expiratory volume in 1 s (FEV1) and the gestational week at the birth of the infant (p > 0.05).Omalizumab exposure level, interval, and duration are presented in Table 3. The patients had asthma for 12.2 ± 8.1 years and they received omalizumab for 28.9 ± 22.3 months. The twins received only one dose of omalizumab, one infant received the drug in the first trimester, four infants in the second and third trimesters, and 16 infants throughout the pregnancy and breastfeeding periods .Ten patients were delivering their first infant. Seventeen (73.9%) patients underwent a cesarean section. No labor complications were noted. Pregnancy and infant outcomes are given in Table 3. The mean maternal age at delivery was 31.8 ± 7.2 years. No congenital anomalies were detected. Seven infants had allergic diseases during their lives. The median APGAR score for newborn infants was 9 . Only one newborn infant had an APGAR score below 8 (5). The mean birth weight was 3055.8 ± 563.3 g. Premature births were seen in five patients (21.7%).In our study of 22 pregnancies and 23 infants, asthma exacerbation was seen only in 36.4% of the pregnancies. FEV1 levels, ACT scores, and eosinophilia at the start of pregnancy were not statistically significantly different than those after pregnancy (p > 0.05). The patients received omalizumab for 28.9 ± 22.3 months before pregnancy. The twins received only one dose of omalizumab, one infant received it in the first trimester (two doses), four infants in the second and third trimesters, and 16 infants throughout the pregnancy and breastfeeding periods. No malformations were detected in the newborns and only one newborn had an APGAR index below 8. Nevertheless, premature birth was seen in five infants (21.7%) and seven infants had allergic diseases during their life.Maternal age is an important risk factor for congenital anomalies. The median age of our patients was 31 years . It was equal to that in the EXPECT cohort and higher than that in the QECC cohort  [6]. Furthermore, the percentage of subjects younger than 35 years was 82% in our study but 74.8% in the EXPECT cohort and 85.7% in the QECC cohort [6]. However, the infants in our study did not present any anomalies.The majority of our patients were from urban areas (95%), 59% were housewives, and 63.6% were high school or university graduates. Compared with other pregnant groups studied in our country, our pregnant patients with asthma were more educated, had different occupations, and were less commonly from rural areas [9]. Coming from urban areas means more exposure to traffic pollution, which may lead to preterm birth [10].Only one patient was an ex-smoker. The major comorbidity was allergic rhinitis (72%), and only five patients (22.5%) were obese. In contrast, in the EXPECT study, the rate of obese patients was 46.7% [6]. Furthermore, our patients did not have comorbidities such as diabetes, which might have increased the risk of certain lung diseases in infants [11]. Maternal allergy was not present in all infants. Only seven infants had allergic diseases at time of the study.Asthma duration before omalizumab administration had a range of 2 to 40 years, and all the patients had been using ICS and LABA combinations before and during their pregnancy. Other add-on drugs used during pregnancy were also nonteratogenic; patients had used similar drugs in EXPECT and QECC studies [6]. Moreover, whereas Yilmaz et al. pointed out nonadherence to treatment in pregnant asthma patients, we did not encounter it in our patients [9]. High adherence to medications was found in our study.Exacerbation was observed in eight (36.4%) of our patients. This rate is lower than that before pregnancy. In a study conducted by Schatz et al., with 1739 pregnant patients with asthma, 30% of the patients who had previously been identified as having mild asthma had progressed towards moderate to severe asthma, but in subjects with severe asthma, only 23% had progressed towards moderate and mild asthma [12]. Furthermore, Schatz et al. showed that 13% of mild, 16% of moderate, and 52% of severe asthma cases presented at least one exacerbation case [12]. This suggests that there is a correlation between asthma severity and increased risk of exacerbation. The exacerbation was reported to occur mostly between weeks 17 and 24; in other words, mostly in the second trimester of gestation [3]. In conclusion, even though pregnant women with severe asthma are considered to be at higher risk of an attack, the ones with mild asthma are also at risk.Furthermore, it has been demonstrated that inflammation is associated with a risk of lack of asthma control, which is due to failure to administer ICS, decrease in treatment adherence, or obesity [13]. Uncontrolled maternal asthma results in poor outcomes in infants [14]. Spirometry parameters, ACT scores, and whole blood count results at the beginning of pregnancy and after delivery showed nonconsiderable differences in our patients. However, one-third of the exacerbation cases resulted from oral steroid use. In contrast, an exacerbation rate of up to 45% in pregnant patients with asthma has been reported [4]. However, their exacerbation rate, ACT score, and FEV1, as well as blood test results at the beginning of pregnancy were not different from the ones after pregnancy (p > 0.05); the decrease in eosinophil count after pregnancy was also not significant (p > 0.05). Similarly, Fazel et al. found nonconsiderable differences in eosinophil levels between controlled and uncontrolled pregnant patients with asthma and healthy pregnant women [15]. Meanwhile, Palmsten et al. used a modified ACT (p-ACT) [16]. They reported that lower p-ACT scores were associated with previous exacerbation, and were not associated with future exacerbation during pregnancy. Furthermore, De Araujo et al. evaluated the importance of ACT in pregnancy and pointed out that physicians did not require spirometry to assess the level of asthma control and that ACT can be used in the primary care of expectant mothers with asthma [17].The gestational median age was 37.3 years in our patients, and there was a higher rate of cesarean section (73.9%) in our study patients. Furthermore, five infants (21.7%) had premature birth and three  had low birth weight. Compared to the EXPECT study, the low birth weight rate was similar, but the premature birth rate was higher in our study [6]. As mentioned in EXPECT study among women who took any oral corticosteroid at any time during pregnancy, the prevalence of premature birth was 32.7% in their subcohort [6]. All of our five patients with premature birth used oral steroids for their exacerbation. Additionally, only one infant had a low APGAR score, and we found that the seven infants with allergic diseases demonstrated genetic predisposition, and omalizumab did not have an effect in this situation. Meanwhile, no considerable differences between mothers with and without asthma regarding the duration of gestation, birth weight, low APGAR scores, or neonatal respiratory difficulties were found in the study by Fazel et al. [15]. Furthermore, none of our patients had infants with congenital anomalies; however, this may be due to our small sample size. In fact, in 2008, Blais and Forget reported that the malformation probability in 4300 pregnant women with asthma was increased [18]. It has been reported that this is particularly correlated with exacerbation in the first trimester  [18]. The most notable outcomes in this regard have been suggested by a metaanalysis consisting of 40 studies and 1,637,180 individuals conducted by Murphy et al. in 2011 [19]. In this study, it was observed that the risk of low birth weight infants was increased in pregnant women with asthma , there was a slight decrease in intrauterine growth (IUGR) , preterm delivery was increased , and preeclampsia risk was also slightly higher  [19]. It has been reported that IUGR and preterm delivery are due to maternal hypoxemia and altered placental function in asthma [20]. We did not find any correlation between FEV1 and prematurity. In the study conducted by Murphy et al., it was suggested that preterm delivery and preeclampsia decreased upon ensuring control through proper asthma treatment [19]. Thus, it can be concluded that such complications occur due to the lack of proper treatment.There are some limitations to our study. As the study was retrospective, we could not obtain all the data for the whole duration of the pregnancies. Moreover, other patients on omalizumab during pregnancy may exist in our country; we presented only those cases for which the physicians agreed to participate in the study.In conclusion, about one-third of our patients with severe asthma on omalizumab had exacerbation during pregnancy. However, the spirometry, ACT scores, and blood count results after the delivery of the infants were not considerably different from those before pregnancy. Two-thirds of our patients received omalizumab throughout the gestation and breastfeeding periods, and premature birth was seen in one-fifth of the patients. Overall, omalizumab treatment during pregnancy seems to be safe for both patients and their infants.This study has received no financial support.The study was approved by the Institutional Ethic Committee of Cerrahpaşa Medical Faculty (06.08.2019 date 83045809-604.01.02-123451 number); Helsinki Declaration was signed by all coauthors. Informed consent was obtained from each patient.


Orthostatic blood pressure dysregulation, including orthostatic hypotension (OH) and orthostatic hypertension (OHT), is common in the elderly. The association between OH and, to a lesser extent, OHT with geriatric syndromes is controversial and little investigated.Our objective was to assess the association between orthostatic blood pressure dysregulation and geriatric syndromes in an ambulatory outpatient population.This observational study included all outpatients for whom a one-visit comprehensive geriatric assessment was performed during a year. OH was defined as a decrease of at least 20 mmHg in systolic blood pressure (SBP) and/or 10 mmHg in diastolic blood pressure (DBP) after 1 or 3 min of standing. OHT was defined as an increase of more than 20 mmHg in SBP after 1 or 3 min of standing. Comorbidities, drugs regimen, a history of previous falls, nutritional, frailty, functional and cognitive status were compared between patients with OHT or OH and controls (NOR).p = 0.043) and severe cognitive impairment at MMSe score  compared to NOR. Conversely, OH was associated with a lower grip strength (p = 0.016) than NOR.Five hundred thirty patients (mean age: 82.9 ± 5.1 years) were included. 19.6% had an OH and 22.3% an OHT. OHT patients were more frequently female, had more diabetes and a lower resting SBP than patients with NOR. OH patients had a higher resting SBP than NOR. After adjusting for age, sex, resting SBP and diabetes, OHT was associated with a low walking speed (OR = 1.332[1.009–1.758]; OHT and OH are common in elderly but associated with different geriatric phenotypes.The online version contains supplementary material available at 10.1186/s12877-022-02844-8. Orthostatic blood pressure dysregulation is a common condition in the elderly population and its frequency increases with age. The prevalence of orthostatic hypotension (OH) is about 5% in adults but rises to 30% in the community-dwelling older population aged over 65 years and reached up to 65% in a very old patients when systematic and repeated measurements are performed –4. Many Orthostatic hypertension (OHT), that seems as frequent as OH, has been less investigated. The prevalence of OHT is estimated at 2.4% in young adults but ranges from 4 to 28% in the elderly, especially in those with hypertension or diabetes , 20. TheThe aim of this study was to evaluate the association between orthostatic blood pressure dysregulation and geriatric syndromes in elderly outpatients followed in a geriatric tertiary care center.We prospectively included all outpatients addressed in a day-hospital unit from a geriatric department, from January 1, 2017 to December 31, 2017. In this interdisciplinary outpatient clinic, a trained staff including nurses, neuropsychologists, social workers, physiotherapists and geriatricians performed a comprehensive geriatric assessment based on recommendations in order to explore at least 8 domains . Patientn = 6).For each patient, the SBP, the diastolic blood pressure (DBP) and the heart rate (HR) were measured using an automatic blood pressure monitor  with an adapted cuff in a supine position after at least 5 min of rest and after 1 and 3 min of standing. OH was defined as a decrease of at least 20 mmHg in SBP and/or 10 mmHg in DBP after 1 or 3 min while standing according to the French hypertension society criteria . OHT was2.Demographical data  and comorbidities such as a history of diabetes mellitus, hypertension, atrial fibrillation, heart failure, stroke, coronary artery disease, peripheral vascular disease and/or carotid atheroma were listed from medical charts. Vascular impairment was defined as a composite of history of stroke, coronary artery disease, peripheral vascular disease or documented carotid atheroma. Glomerular filtration rate (GFR) was estimated by the CKD-Epi formula and chronic kidney disease was defined as a GFR lower than 30 ml/min/mAntihypertensive drugs regimen was detailed.Falls, at least one self-reported fall within the last 6 months,Walking speed, a walking speed over 4 m ≤ 0.8 m/s was considered as slow and as a marker of frailty ,Hand-grip strength, assessed with Jamar dynamometer. A low strength was defined according to threshold depending on sex and was considered as probable sarcopenia. If associated with low walking speed, patients were considered as highly probable sarcopenia ,Basic activities of daily living (BADL) and instrumental activities of daily living (IADL), 6-items and 8-items assessments respectively. A loss in one or more BADL defined disability,Short version of the Geriatric Depression Scale (mini-GDS), a score of one or more was associated with a high probability of depression. A history of depression was also recorded,Malnutrition, defined by a body mass index (BMI) lower than 21 kg/m2 and/or an albuminemia lower than 35 g/L,Mini-Mental State examination (MMSe) score and the clock drawing test (French GRECO version) was also performed to assess global cognitive performance . MMSe waStatistical analyses:p < 0.05.The population was divided into 3 groups: OHT, OH, or the absence of changes in orthostatic blood pressure . Quantitative variables are presented as mean ± SD and qualitative variables as percentage. Groups were compared using a one-way ANOVA, followed by a Bonferonni test for two-by-two comparisons for the quantitative variables and by a Chi-square test for the qualitative variables. For ordinal qualitative variables whose variation is linear, a Cochran-Armitage trend test was used. Statistical significance was set at Multivariate analysis of geriatric factors associated with the presence of OHT or OH was performed by logistic regression for qualitative variables and by a General Linear Model for quantitative variables after adjustment for sex, age, resting SBP and diabetes, with the NOR group as reference. The results are in Odds Ratios [95% confidence interval] and by the degree of significance p. SPSS® software  was used for all the analyses.In addition, we performed an exploratory analysis of the relationship between change in SBP change after 3 min of orthostatism and some geriatric factors identified in the multivariate analysis, to evaluate the impact of the magnitude of change in SBP at orthostatism on geriatric syndromes. For qualitative parameters, we described the repartition of change in SBP at orthostatism according to each category using violin plots. For quantitative parameters, we performed a second-order polynomial regression  because their relationship with SBP change at orthostatism was nonlinear. These complementary analyses were performed with R Studio®, Version 1.3.1093.The following geriatric parameters were evaluated:Five hundred and thirty patients were included  with a mean age of 82.9 ± 5.1 years. In this population, 104 patients (19.6%) had OH, 118 (22.3%) had OHT and 308 (58%) had NOR. The distribution of the magnitude of postural change of SBP, DBP and HR in the entire population at the third minute is shown in Fig. Mean BADL was 5.0 ± 1.0 with a half (48.7%) of the population with a loss of one or more BADL. Mean IADL was 3.0 ± 2.6. Depression was common , with a pathological GDS in 40.3% of patients. 362 patients (68.3%) had dementia and the mean MMSe was 19.2 ± 5.8. A mild impairment in MMSe was observed in 113 patients (31.2%), a moderate impairment in 195 patients (53.8%), and a severe impairment in 54 patients (14.9%). Two hundred and thirteen patients (40.3%) experienced at least one self-reported fall within past 6 months. Mean BMI was 27.1 ± 4.8 kg/m2 and mean albuminemia was 39.8 ± 4.3 g/L. Malnutrition was observed in 97 patients (18%). According to criteria, 365 patients (70%) had a low walking speed, 402 (76%) a low grip strength and 305 (57%) had simultaneously these two conditions supporting highly probable sarcopenia.p = 0.051 and p < 0.001 respectively). Resting DBP, PP and MBP followed the same trends and are presented in Table Resting SBP was lower in the OHT group than in the NOR group, the latter itself being lower than the OH group . Patients with OHT had more diabetes than patients with NOR  but less vascular diseases (10.2%) than patients with OH (18.2%) and those with NOR (17.8%) (p = 0.005 and p = 0.042 respectively). The other comorbidities and patients’ characteristics were similar in the three groups   than in the NOR (5.5%) and the OH (4%) groups (y) Table .p = 0.005 and p = 0.006 respectively). Similarly, the walking speed was lower in the OHT group compared to the NOR group . The grip strength was significantly lower in the OHT group compared to the NOR group   were different between the three groups. The prevalence of a severe impairment of the MMSe tended to be higher in the OHT group compared to NOR (21.3% vs. 12%) (Table There was no significant difference between the 3 groups (and according to the repartition of the change in SBP at orthostatism) concerning the other geriatric syndromes, such as disability in BADL, malnutrition, depression, sarcopenia or falls. Consistently, the distribution of the population according to change in SBP at orthostatism was similar regardless disability in BADL, malnutrition or depression . Neither%) Table .p = 0.043) and with a severe impairment at MMSe score . Consistently, we observed a significant inverse J-shaped relationship between walking speed and change in SBP after 3 min of orthostatism , more pronounced for positive than negative changes. Moreover, the highest population density of patients with severe MMSE was centered on an orthostatic SBP change value of + 20 mmHg, while that of patients with mild or moderate impairment was close to 0 mmHg  (Table p = 0.032), more pronounced for negative than positive changes , malnutrition (B) or depression (C). These violin-plots show that the highest population density of patients with or without disability in BADL (A), malnutrition (B) or depression (C) is centered on an orthostatic SBP change value close to 0 mmHg. ∆SBP 3’: change in systolic blood pressure after 3 minutes of orthostatism, BADL: basic activities daily living.


The kidney-heart relationship has raised interest for the medical population since its vast and complex interaction significantly impacts health. Chronic kidney disease (CKD) generates vascular structure and function changes, with significant hemodynamic effects. The early arterial stiffening in CKD patients is a consequence of the interaction between oxidative stress and chronic vascular inflammation, leading to an accelerated deterioration of left ventricular function and alteration in tissue perfusion. CKD amplifies the inflammatory cascade's activation and is responsible for altering the endothelium function, increasing the vascular tone, wall thickening, and favors calcium deposits in the arterial wall. Simultaneously, the autonomic imbalance, and alteration in other hormonal systems, also favor the overactivation of inflammatory and fibrotic mediators. Thus, hormonal disarrangement also contributes to structural and functional lesions throughout the arterial wall. On the other hand, a rise in arterial stiffening and volume overload generates high left ventricular afterload. It increases the left ventricular burden with consequent myocardial remodeling, development of left ventricular hypertrophy and, in turn, heart failure. It is noteworthy that reduction in glomerular mass of renal diseases generates a compensatory glomerular filtration overdriven associated with large-arteries stiffness and high cardiovascular events. Furthermore, we consider that the consequent alterations of the arterial system's mechanical properties are crucial for altering tissue perfusion, mainly in low resistance. Thus, increasing the knowledge of these processes may help the reader to integrate them from a pathophysiological perspective, providing a comprehensive idea of this two-way path between arterial stiffness and renal dysfunction and their impact at the cardiovascular level. A robust functional relationship exists between the kidneys and the cardiovascular system, and this vast and proven interaction has acquired progressive notoriety.The evidence from population studies clearly shows that renal and cardiac diseases are strongly associated , 2. ThisOf particular interest is the relationship between the heart and kidneys when both are functionally insufficient. This interplay is known as the cardiorenal syndrome, and the most relevant are chronic types 2 and 4 of the original description by Ronco et al. . This inThe pathophysiological and histopathological concepts involved, including the graphics and figures, are designed to understand better the kidney and the heart's role as principals organs involved.However, these conceptual proposals do not define the precise role or sequence of the macro and microcirculation structures in this process. Therefore, we tried to analyze the process of vascular injury in CKD –10, giviThe essential objective of blood traveling through the arterial system is the perfusion and oxygenation of peripheral tissues. Under normal conditions, the cardiac pump discharges the systolic volume (SV) of blood received by the large-caliber elastic arteries, mainly the aorta. However, ~50% of the previously mentioned SV is dampened due to the compliance of its walls.The remaining 50% of the SV continues its way to the peripheral arteries. Once the aorta returns to its initial caliber in diastole, its elastic capacity, if it is healthy, sends the remaining volume forward, transforming the arterial flow from pulsatile to continuous in the peripheral circulation. This fact is known as the “Windkessel Phenomena” in comparison to the old fire extinguishing pump.At the distal level, the arteries have a structural component mainly integrated by smooth muscle cells coupled “in series” with collagen fibers, all influenced by neural and hormonal factors. This massive parallel resistance system is responsible for peripheral vascular resistance and the dissipation of at least two-thirds of the cardiovascular system's pulsatile energy. This fact allows arterioles to adapt to different situations, organs, and pathophysiological circumstances. However, this regulable system loses efficacy because of aging  and other conditions—such as high blood pressure, diabetes, and CKD—that cause a decrease in arterial compliance due to the loss of the vessel's elastic components. The half-life of elastin, the main factor responsible for the aorta's elasticity, is measurable in years. Continuous and intermittent distension of the aorta with each heartbeat and during the lifespan causes fatigue and fracture of the elastin fiber, leading to increasing stiffening of the aorta's wall . In thisDuring the development and progression of CKD, the aortic compliance decreases, reducing SV's buffering capacity, resulting in an exaggerated increase of the systolic pressure (SP) and a drop of the diastolic pressure (DP).The pulse pressure (PP) or pulsatility is the difference between SP and DP in mmHg. Hence, it is an easy parameter to be observed during the medical examination when measuring blood pressure.A stiff aorta produces the loss of its properties as a second pump, or “second heart” (a consequence of the lack of elastic recoil of a distensible aorta), with the consequent drop in the diastolic vascular flow and pressure. Aortic stiffness also increases the pulsatility in the peripheral vessels and their irrigated tissues. Due to these conditions, the SV is no longer buffered and continues toward the periphery.On the other hand, arterial wall stiffening increases the pulse wave velocity (PWV), the speed at which the pulse wave travels through the large arteries' wall, and is currently considered the gold standard for arterial stiffness measurement. It is also an independent prognostic marker of CVE , 14. TheAnother physiological phenomenon is related to the highest speed of the PWV. Under physiological conditions, the incident wave, generated from the systolic discharge, propagates through the arterial system to the reflection points. These sites are the arterial bifurcations or regions of the most significant change in the arterial wall's viscoelastic components. A reflected wave returns in the opposite direction during late systole and adds to the new incident wave, giving rise to the augmentation wave phenomenon, measured as “augmentation index” (Aix) .In situations of increased arterial stiffness, as occurs in CKD, through mechanisms described in this review, the wave's reflection occurs earlier and arrives prematurely, worsening the Aix, considered an marker of arterial stiffness . TherefoA direct relationship stands between renal function impairment with CAP and Aix. Thus, the more significant the CAP and Aix are, the more influential they are on renal function deterioration and death, as was demonstrated by Towsend et al. in the CRIC study , 16. RecIn other words, the increase in arterial stiffness -represented by the rise in PWV- is usually associated with an increase in the SP with consequent LV overload. In addition, the increase in PWV and vascular stiffness speeds up the pulse wave's reflection, generating an increase in the aortic augmentation that further increases the CAP, and therefore, left ventricle contractile effort.So, EVA is a consequence of cardiovascular risk factors (CVRF), amplified by CKD, and this cluster of factors lead to premature cardiovascular events (CVE) –20, as wThe different tissue lesions associated with CVRF are also related to the activation of diverse inflammatory ways. Initially, they act as a protective response of the organism to control the cause, but finally, they turn into a disease. The inflammatory response to stressors acts on the endothelium and vascular smooth muscle; therefore, serum and tissue inflammatory markers are tools that help to predict cardiovascular disease (CVD) –23. FiguThe association between chronic inflammation and arterial wall disease is complicated and multifactorial . InitialThe subsequent transformation of these macrophages within the arterial wall into foamy cells predisposes to their necrosis; when the necrotic nucleus appears in the plaques, the amplification of the inflammatory stimulus favors the progression of already advanced vascular lesions .This inflammatory cascade also alters the endothelium's function that interacts and conditions the remodeling of the tunica media and changes of the artery's mechanical properties . EndotheSimultaneously, the increase in arterial stiffness and the dysfunctional endothelium activate adhesion molecules like MCP-1 and cytokines favoring thrombotic events , 29, 30.Vascular inflammation enhanced by CKD promotes the vessel's stiffening by stimulating fibrosis and proliferation of the vascular smooth muscle cells (VSMC) .CKD, defined as a structural and functional alteration of the kidney for more than 3 months . CKD is CKD resembles an experimental oxidative stress model which produces severe alterations in many cells , tissues, serum, and urinary markers. Oxidative stress is an initial and central contributor to endothelial dysfunction and the inflammatory process, conducting atherosclerotic vascular injury, premature aging, and CVD . A decreInflammation that accompanies kidney disease seems to play a significant role in telomeric shortening and mitochondrial dysfunction . AdditioAt the same time, the kidney itself is vulnerable to this inflammatory process. The kidneys are intensely and heterogeneously vascularized and regulated by hormones and vasoactive molecules  , 40. SysSystemic inflammation eases the development of renal injury and is co-responsible for the high morbidity and mortality of these patients and the development of an accelerated aging phenotype.In CKD, calcification of the middle layer of the arteries is a part of the accelerated EVA process. Therefore, the extent of vascular calcium vascular deposits is related to vascular estimated age. That is why in CKD, the age of the vasculature is practically always older than the chronological age, at least partially, due to an early and persistent inflammatory process.Unlike what happens in individuals with preserved kidney function, those with CKD have a process of accelerated cellular and vascular senescence, tissue aging, persistent inflammation, loss of muscle mass, osteoporosis, and early general fragility.In other words, EVA in patients with CKD is part of the price paid for the enormous allostatic load, a consequence of multiple physical and inflammatory stressors associated with CKD.It is to point out that recovering kidney function with a kidney transplant (Tx) decreases the mortality rate by 50% compared to the same patient population submitted to dialysis treatment. Hence, it raises whether a kidney transplant may reduce the described vascular changes suffered along with CKD.Few studies have shown after transplant regression of the large arteries remodeling; however, there is evidence about the decrease of the PWV after Tx, which increases the patient and the graft survival rate , 42.p < 0.001). After the multivariate analysis, the patients who received Tx living donor allograft had a more significant decrease of the PWV (p < 0.001). Furthermore, the patients who received deceased allograft with standard donors had better vascular performance than those who received allograft from donors with expanded criteria (older donors and pre-establish cardiovascular disease). An interesting point to highlight in this study is the non-relationship between vascular function improvement and glomerular filtration level (p < 0.0001)  .Korogiannou et al. recently confirmed the relevance of PWV in the prognosis of Tx patients been a strong predictor for cardiovascular events, renal events, and mortality in these individuals .Although scientific facts are clear enough, there are still two significant aspects to consider. First, there are no clinical trials about the impact of therapeutic interventions on arterial stiffness and its consequence on the kidney Tx population. Also, mechanistic studies are required to identify the best ways to address arterial stiffness in Tx patients.Hyperphosphatemia and its consequences: During CKD, an imbalance between the inhibitors and inducers of vascular calcification occurs  . CalciumUric acid increases in CKD due to the decrease excretion by the failing kidney. This mentioned uric acid elevation decreases endothelial Nitric Oxide Synthase (eNOS) activity, reducing the production of NO, the proliferation of VSMC , 51, theAdvanced glycation ends products (AGEs): AGEs accumulate in CKD progressively as their production increases and elimination decreases. Thus, significant accumulation may occur even in non-diabetic patients. AGEs, among other things, affect the activity of eNOS  resulting from increased production and less excretion, contributing to a significant reduction of eNOS and consequent endothelial dysfunction. Increased ADMA also causes sympathetic stimulation, inflammation, vascular stiffness, and LVH –56.Increment of endothelin-1 (E-1) level: E-1 is a potent vasoconstrictor implicated in cardiovascular and renal diseases. An increase of E-1 has the same origin as the increase of ADMA and uric acid. It acts on receptors with antagonistic function (ETA and ETB receptors), predominantly the action of ETA receptor, which is responsible for: endothelial dysfunction, increased vascular tone, inflammation, and calcification , as well as high-sensitivity C-reactive protein and fibrinogen. Albumin, as an acute-phase reactant, is decreased .Frequent infections, thrombotic events, dialysate quality, and its impurities are also powerful inflammatory stimuli. Uremia increases intestinal permeability to bacteria, and this, in turn, generates more inflammation. The diets indicated in these patients (Low in potassium and phosphorous) alter the microbiota, causing dysbiosis with significant inflammatory effects. Dialysis patients usually have markedly high inflammatory markers associated with severe arterial injuries that, in turn, progress faster .The baroreflex system regulates blood pressure changes, and their proper function enables immediate regulation of it at practically constant values. Its appropriate process depends mainly on arterial compliance. Vascular lesions are widespread at the carotid and aortic levels and affect the baroreflex system's receptors. Receptors activation requires good arterial compliance; potassium channels and sodium-potassium pump regulated by a paracrine function, mainly by prostacyclin.The combination of endothelial dysfunction and arterial stiffness produces a decrease in prostacyclin production and less arterial compliance. Consequently, less baroreflex activation occurs, causing more significant variability in arterial pressure . Simultaneously, there is a greater renal afference toward the central nervous system in CKD. An increase in the sympathetic activity, a further increase in the vascular tone favors LVH, CVD, and increased mortality . The higArterial stiffness and CKD volume overload generate myocardial dysfunction directly proportional to the degree of renal failure .This myocardial involvement resulting from increased pre and afterload is also associated with cardiac interstitial fibrosis, alteration of the cardiac microcirculation, and myocardial neuro-humoral activation .The most common and earlier stage of ventricular dysfunction in CKD patients is diastolic failure. It is also known as HF with preserved ventricular function, the usual echocardiographic finding in CKD patients .These patients frequently have other risk factors for diastolic failures, such as type 2 diabetes, high blood pressure, coronary heart disease, and accelerated aging, all contributing to maintaining and worsening diastolic dysfunction.The structural changes of the heart in CKD include myocardial hypertrophy and thickening of the intramural arteries  as an adOther CKD alterations that further aggravate myocardial dysfunction are the over activation of systemic and intrarenal RAAS, the anemia that characterizes patients with CKD, vitamin D deficiency, and other mechanisms recently described, such as activation of mTOR, G-protein activation, and T-cell activation ; all of The clinical consequence of all these processes is a shift to the left of the pressure-volume curve. Small changes in volume significantly increase intraventricular pressure due to cardiac compliance loss and can cause pulmonary congestion. Conversely, slight volume depletion can impair left ventricular filling and cause a decrease in systolic volume, leading to hypotension and hemodynamic instability .In other words, patients with CKD have a low range of tolerance to volume changes, extrapolated to body weight, to go from volume overload to hypotension, generating an increase in hospitalizations for decompensated heart failure. In addition, in some patients, particularly the young, functional damage to the left ventricle due to volume overload may not be evident, but it will deteriorate cardiac function if overhydration persists .In addition to the CKD-dependent changes in vascular structure and function already described, we must add those that depend on the diseases frequently associated. Those most common are coronary artery disease, vascular injuries, and remodeling that depends on high blood pressure, atherogenic dyslipidemia, diabetes, and their associated metabolic disorders, together with accelerated vascular aging to these pathologies.The detailed description of these processes exceeds the objective of this publication. Several reviews –75 are aUnder a healthy vascular condition, the large arteries' elasticity moderates the cardiac pulse pressure, dampening its intensity, achieving a continuous flow of blood, in most tissues, with a low variation in arterial pressure between systole and diastole. That means a low pulse pressure. This low arterial pulsatility enters from the macrocirculation to the microcirculation, where it receives additional attenuation in the arterioles and results in microvasculature protection. However, in response to aging , obesityAs a result, the high pulsatility introduced into the organs; of particular interest are those tissues with high viscous components such as the brain and the kidneys; both are characterized by low resistance and high flow systems, thus receiving a high volume of blood , 78. TheSeveral renal diseases that reduce renal mass generate an adaptive high filtration rate by a single nephron. This process also happens in diabetes, obesity, hypertension, and aging. These clinical conditions are of great interest due to their high frequency.Glomerular hyperfiltration (GHF) or single nephron hyperfiltration is an increased glomerular filtration rate above normal values due to increased filtration per nephron unit. There is robust evidence that GHF is a risk factor for the progression of chronic kidney disease and CV events, independently of albuminuria and other factors. Remarkably, in patients with GHF, an increase in PP was proved, measured during 24-h, suggesting an association with increased large-artery stiffness and vascular damage, leading to increased CV events , 82.GHF can occur in individuals with high, normal, and low GFR, as happens in most CKD patients moderate/severe stages . In CKD Pieces of evidence generated more than two decades ago confirmed that pulsatile hypertension-induced glomerular distention produces changes at a cellular level and the extracellular matrix's metabolism. The changes due to mesangial cell mechanical strain occur in the remnant kidney and play an essential pathogenetic role in renal lesions. These changes were initially described in experimental diabetes and renal failure by glomerular mass reduction as the experimental model of 5/6 nephrectomy , 85.Of interest, renal blood flow increases together with dilation of the afferent arteriole in the enlarged glomeruli of both models, animals with diabetes, and subtotal nephrectomies. Therefore, systemic blood pressure is transmitted into the glomerulus without the usual regulation, generating a high pulsatile stretching in the glomerular and surrounding structures. This persistent pulsatile stretch, in turn, changes the phenotypes of mesangial cells that increase the production of different cytokines producing the recruitment of cells leading to inflammation and kidney fibrosis , 87.More recently, using Doppler devices, it is possible to evaluate renal microvascular pulsatility. The pulsatility index derived from pulsed-wave Doppler measurements correlates with effective renal plasma flow in CKD patients and predicts renal disease progression , 89.These pathophysiological mechanisms described before are in line with consistent epidemiological results that show the association between arterial stiffness, microcirculation pulsatility, and the incidence and progression of renal diseases, as well as hard renal endpoints , 91.Reducing or controlling GHF and restoring to normal the disturbed glomerular hemodynamics has been the most crucial strategy for glomerular protection and to slow the progression of chronic kidney disease. Paradigmatic drugs in kidney protection, such as those that block the renin-angiotensin system (RAS inhibitors), or the new ones such as sodium-glucose cotransport type 2 inhibitors (iSGLT2), and the GLP-1 receptor agonists (GLP-1), produces, by different mechanisms, a consistent reduction of GHF .In summary, a complex variety of mechanisms leading to the damage of arteries in CKD patients, generating stiffness in the aorta and central arteries and increased PP and CAP. Additionally, a higher central pulsatility is transmitted into the microcirculation of various tissues, including kidneys, favoring and accelerating its deterioration. A better knowledge of these pathways and processes leading to this vicious circle of the two-way path between arterial stiffness and renal dysfunction will give the medical community better possibilities to improve preventive and therapeutic strategies to reduce vascular injuries and CKD progression, and finally, cardiovascular events.FI, PF, and CC conceived of the presented idea. AC wrote the paper with input from the other authors. All the authors reviewed the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Native kidney hydronephrosis occurred more frequently in the UTUC group . Multivariate analysis showed that native kidney hydronephrosis and female gender were significantly associated with UTUC with odds ratios of 35.32  and 3.37 , respectively. UTUC in the post-KT patients also showed aggressive pathological characteristics and a tendency toward bilateral lesions (41.8%). Conclusions: Native kidney hydronephrosis is significantly associated with post-KT UTUC patients in Taiwan. Native kidney hydronephrosis may be a deciding factor for standard nephroureterectomy and bladder cuff excision in selected patients. Nevertheless, almost half of the patients with kidney hydronephrosis do not present with UTUC at the end of our study.Background: Upper urinary tract urothelial carcinoma (UTUC) is the most common malignancy occurring after kidney transplantation (KT) in Taiwan. The aim of this study was to investigate the association between native kidney hydronephrosis and UTUC in post-KT patients. Methods: From 2003 to 2018, we conducted a retrospective cohort study that enrolled 1005 post-KT patients, 67 of whom were subsequently diagnosed with UTUC. We divided patients into two groups based on whether or not they had UTUC. Multivariate analysis and Kaplan-Meier plot were used to evaluate if native kidney hydronephrosis was associated with post-KT UTUC. Results: The total cohort consisted of 612 men (60.9%) and 393 women (39.1%) with a mean age of 48.2 ± 12.0 at KT. The mean follow-up time was 118.6 ± 70.2 months, and mean time from KT to UTUC was 7.53 years. There was a significant gender difference with a female predominance among the UTUC patients (73.1% versus 26.9%,  For end-stage renal disease (ESRD) patients, kidney transplantation (KT) is an important treatment in renal replacement therapy. With the benefits from advances in medical procedures and immunosuppressive agent use, long-term overall survival and graft survival in KT recipients have improved. However, KT recipients are known to have a higher incidence of de novo malignancy as compared with the general population because of their use of immunosuppressive agents and chronic inflammatory status. It remains one of the lingering causes of mortality among KT recipients .Among different ethnic populations and geographic regions, the types of post-KT malignancy vary. Skin cancer and lymphoproliferative disorder are frequent post-KT cancers in Western countries. In contrast, high incidence 3.5~4.1%) of urothelial carcinoma (UC) in Taiwan has been elucidated before % of urot,3,4,5. TThus, the early detection of UTUC in post-KT patients is an important issue for improving oncologic outcomes. However, hematuria as a diagnostic basis for UTUC in post-KT patients has shown disappointing results. To make matters worse, it often delays diagnosis . NeverthThis retrospective cohort study was approved by the Institutional Review Board of Chung Shan Medical University Hospital (IRB number: CS1-20219). We enrolled cases of patients over 18 years of age with regular medical visit records or lost follow-up for a known reason, and a systemic examination was carried out to confirm that no malignancy, including UC, had existed before KT. From January 2003 to September 2018, we retrospectively analyzed 1005 KT patients in our hospital, 67 of whom were subsequently diagnosed with UTUC. The immunosuppressive agent protocol consisted of a calcineurin inhibitor (cyclosporine or tacrolimus), mycophenolate mofetil or azathioprine, and steroids without CD3 monoclonal antibody or anti-thymocyte globulin induction therapy. The kidney transplantation follow-up protocol at our institution included blood examination, routine urine and sediment analysis, and urine cytology monthly for 6 months and then quarterly thereafter. Post-KT renal sonography was performed every 3 months during the first year, then biannually. Hydronephrosis in a native or graft kidney was defined based on an image interpretation or documented image report in the medical records. Patients with kidney hydronephrosis before KT were excluded. Unilateral or bilateral native kidney hydronephrosis was generally categorized to the hydronephrosis group. In patients with hematuria or kidney hydronephrosis in native kidneys, we performed cystoscopy with bilateral retrograde pyelography or URS. Urine cytology was collected with voiding or washing during URS. Abdominal computed tomography (CT) scan was performed when the findings from the above-mentioned examinations were inconclusive or abnormal. Smoking and hypertension histories were obtained from the medical record documentation. Elderly was defined as age >65 years. Other patient characteristics, such as diabetes, dyslipidemia, hyperuricemia, hepatitis B virus (HBV), hepatitis C virus (HCV), and BK virus infection diagnosis, were based on laboratory examinations or serological tests. A UTUC diagnosis was confirmed by a peer reviewed pathological examination, and specimens were obtained by initial URS biopsy or subsequent nephroureterectomy. Once patients had been proved to have UTUC by URS biopsy or suggestive UTUC by image study, simultaneous bilateral nephroureterectomy and bladder cuff excision were the standard surgical procedures in our cohort.t tests, and chi-square tests were used to compare the categorical variables in the different groups. Univariate analysis was conducted and significant risk factors from univariate analysis were put in multivariate analysis. Multivariate logistic regression analysis was used to determine the factors significantly associated with UTUC. Kaplan-Meier curves and log-rank tests were used to compare the time to UTUC events between the post-KT cohorts with and without native kidney hydronephrosis. Statistical analysis was performed using SPSS . A two-tailed p-value of <0.05 was regarded as statistically significant.Continuous data were analyzed using The total cohort consisted of 1005 KT patients, including 612 men (60.9%) and 393 women (39.1%), with a mean age of 48.2 ± 12.0 years old at KT . The meap = 0.046). The mean age of UTUC diagnosis was 57.6 ± 11.3. The mean length from KT to UTUC was 7.35 ± 4.72 years. There were more females in the UTUC group . Smoking histories were obtained via electronic medical records and showed lower rates in the UTUC group . Dyslipidemia was commonly noted in the post-KT patients but was more prominent in the UTUC group . However, there were no significant differences for hypertension, diabetes mellitus, hyperuricemia, HBV infection, HCV infection, or BK virus infection between the two groups. There were 46 cases with native kidney hydronephrosis, 39 unilateral (84.8%) and 7 bilateral (15.2%), among the 67 patients in the UTUC group. Native kidney hydronephrosis occurred more frequently in the UTUC group than the non-UTUC group . However, graft kidney hydronephrosis was not significantly different between groups  (= 0.652) .p < 0.001), and women also showed a statistically higher risk for the development of post-KT UTUC   . Figure p = 0.569).We also demonstrated the tumor characteristics of the 67 post-KT UTUC patients based on whether they had native kidney hydronephrosis or not, which can be seen in Generally speaking, UTUC is relatively rare and accounts for only approximately 2% to 5% of all UC . HoweverResearch has suggested that the urine of patients with ESRD contains toxins that may induce carcinoma, especially for UC . Most pap < 0.001), but graft kidney hydronephrosis did not. Graft kidney hydronephrosis is mainly caused by surgical complications and most often occurs within the first year after transplantation [The clinical presentation of UTUC with kidney hydronephrosis is as usual and easy to understand when kidneys present with continuous urine flush. On the contrary, the consequence between little or no washing effect in native ESRD with UTUC remains unclear. Previous studies have also noted that ESRD patients with UTUC had higher incidence of kidney hydronephrosis ,16. Therantation . The exaantation . Our datThere are two compound factors in post-KT UTUC: KT and UTUC. Concerning KT, sex disparities on cancer incidence and mortality after KT have been noted and assessed in recent years . It has As compared with ESRD without KT patients, post-KT patients with UTUC have more aggressive pathological features and possibly worse oncological outcomes ,16. PostThe present study had several limitations. First, it was a retrospective cohort study within only one medical center in Taiwan. Incompleteness of urinalysis, cytology, and survival data precluded their further analysis and interpretation. However, we collected more than 1000 cases during our 15-year study period and with a mean follow-up time of 118 months. Second, immunosuppressive agent use is diverse based on different nephrologist care, which makes analysis difficult. Third, native kidney hydronephrosis was only diagnosed by one sonogram or CT scan. We did not trace the kidney hydronephrosis condition during the entire follow-up period. Fourth, not all patient in non-UTUC group had a pathological diagnosis. Forty-two patients with native kidney hydronephrosis were considered to have no UTUC. However, UTUC could occur with longer follow-up period or be too tiny to be identified at that time. Fifth, the causes of ESRD and place of residence in Taiwan of our subjects were unknown. Chinese herbs and analgesic nephropathy may lead to more UTUC. So-called blackfoot disease is an endemic disease caused by the intake of arsenic-contaminated groundwater that has occurred in southern Taiwan. Inhabitants of the blackfoot disease region have presented with much higher UTUC incidence. This may skew our interpretation and analysis. Therefore, we have to speculate about our results using a more conservative explanation.Post-KT patients presented with higher UTUC incidence and the onset was younger than in general population of Taiwan and Western countries. Post-KT UTUC is characterized with pathologically aggressive and bilateral lesions in the native kidneys. Native kidney hydronephrosis is strongly associated with UTUC. Failure is common in obtaining tissue proof of native upper UTUC in post-KT patients due to anatomical and technical difficulties. Native kidney hydronephrosis may be a deciding factor for standard nephroureterectomy and bladder cuff excision in selected patients. Nevertheless, almost half of the patients with kidney hydronephrosis do not present with UTUC at the end of our study.


After 3 months, the CAVI group exhibited a significant reduction of body weight  and abdominal circumference  and a trend to lower doses of diuretics compared to OMT. Renal and hepatic function parameters did not change significantly. Within a short-term follow-up, CAVI led to an improvement of clinical signs of venous congestion and a non-significant reduction of diuretic doses compared to OMT.Due to progressive abdominal-venous congestion severe tricuspid regurgitation (TR) is a common cause of cardiorenal and cardiohepatic syndrome. We initiated the TRICAVAL study to compare interventional valve implantation into the inferior vena cava (CAVI) versus optimal medical therapy (OMT) in severe TR. In the present subanalysis, we aimed to evaluate the effects of CAVI on clinical signs of congestion, renal and hepatic function. TRICAVAL was an investigator-initiated, randomized trial. Twenty-eight patients with severe TR were randomized to OMT or CAVI using an Edwards Sapien XT valve. Probands who completed the 3-month follow-up (CAVI [ It exacerbates right heart failure and patients with severe TR typically exhibit an increased demand for diuretic therapy1. Right heart and kidney function are closely related with each other and severe TR associated right heart failure may finally lead to renal function impairment6. The mutually influencing dysfunction of both organs is subsumed under the term cardiorenal syndrome7. Analogous, cardiohepatic syndrome describes an association between heart failure and hepatic malfunction8. Severity of TR was described as an independent risk factor for hepatic dysfunction, which implies liver deterioration due to abdominal-venous congestion9.Severe tricuspid regurgitation (TR) is associated with high morbidity and mortality10. Novel interventional therapies such as cava valve implantation are being evaluated as alternative treatment options for severe TR14.Symptomatic medical therapy and surgical reconstruction, or replacement of the tricuspid valve are recommended for the treatment of severe TR according to current guidelines18. These studies suggested an improvement of symptoms of right heart failure16 and a reduction of venous congestion18. However, a focused investigation on the effect of vena cava valve implantation on renal and hepatic function is still lacking. On the assumption that a singular implantation of an Edwards Sapien XT valve into the inferior vena cava in patients with severe TR leads to an improvement of abdominal-venous congestion, the TRICAVAL trial  was initiated19. Patients were randomized either to valve implantation into the inferior vena cava (CAVI) or optimal medical therapy (OMT)19. All valve implantations were performed successfully20. Nevertheless, two valve dislocations and two stent migrations occurred within the first 48 h after implantation20. Therefore, the study was stopped due to safety concerns20. The present subanalysis of TRICAVAL aimed to evaluate the effect of CAVI on clinical signs of congestion as well as on renal and hepatic function parameters.First-in-human studies and a case series investigated the effects of bioprosthetic valve implantation into the inferior vena cava or in both—inferior and superior vena cava20. Briefly, TRICAVAL was an investigator-initiated, randomized trial performed in accordance with relevant guidelines and regulations including the Declaration of Helsinki.The study design of TRICAVAL was previously published by Dreger et al.n = 14) or OMT group (n = 14)  class ≥ II, optimal medical treatment and high surgical risk were randomized to CAVI , aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (gamma-GT) and bilirubin. Glomerular filtration rate (GFR) was estimated using creatinine according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI equation)2, stage I), mild , moderate , and severe GFR reduction  as well as kidney failure 23.In accordance with the National Kidney Foundation, chronic kidney disease was graded in five stages (CKD stages): kidney damage with normal GFR 20. Including a drop-out rate of 15%, 40 patients were designated for randomization20. Further statistical analyses were carried out using SPSS Statistics version 25 . Continuous variables are shown as mean and standard deviation or median and interquartile ranges depending on the distribution of parameters (uniform per variable); categorical variables are given as absolute number with percentages. The distribution of parameters  was evaluated by skewness. For intergroup analyses, independent-samples t test was used for normally distributed continuous parameters and Mann–Whitney-U-test for not normally distributed continuous parameters. To compare values between baseline and 3-month as well as 12-month FUP time-points, paired-samples t test was used for normally distributed continuous parameters and Wilcoxon-test for not normally distributed continuous parameters. As the variables were mainly used to generate hypotheses, an adjustment of the P values was not carried out. Categorical variables were evaluated by Chi squared test using Fischer’s exact test. P < 0.05 was considered statistically significant.Sample size of the TRICAVAL study was calculated taking into account the maximal oxygen uptake after 3 months (primary endpoint). An intergroup difference of 8 ml kgThe TRICAVAL study was approved by the local ethics committee  and state authorities .Written informed consent was obtained from each participant.Baseline characteristics of the 18 participants of the TRICAVAL study, who completed the 3-month FUP, are shown in Table At 3-month FUP, the CAVI group exhibited a significantly lower body weight and reduced abdominal circumference compared to baseline Table , 3, whilp = 0.225 for OMT group, p = 0.144 for CAVI group).There was no significant change in levels of laboratory parameters including serum creatinine, cystatin C, urea, serum protein, serum albumin as well as calculated GFR (based on creatinine and cystatin C) between baseline and 3-month FUP within each group, nor a significant difference in these parameters between both groups at 3-month FUP  and effective regurgitant orifice area did not change significantly24. Similarly, TAPSE (3-month FUP: 16.0 [13.0–18.8] mm) remained unchanged24. The reduction of abdominal-venous congestion as shown in both clinical and echocardiographic data implies sufficient sealing of the inferior vena cava after valve implantation and thereby the effectiveness of the valve implantation. This was additionally reflected by improved symptoms of abdominal-venous congestion and increased quality of life after CAVI at 3-month FUP20.This subanalysis of the TRICAVAL study represents the first controlled, prospective, randomized study to evaluate renal and hepatic function in patients undergoing CAVI compared to an OMT control group. We found that renal and hepatic function remained unchanged in both groups at 3-month FUP, but deteriorated further over time in the OMT control group. The CAVI group exhibited a significantly lower body weight paralleled by a reduction of diuretic doses after 3 months, both suggesting a decrease of TR-induced venous congestion. These results extend our previously published echocardiographic data of TRICAVAL, which demonstrated decreased systolic hepatic vein reflux volume and hepatic vein diameter after CAVI28. The interaction between haemodynamic changes and renal function was reported by Firth et al. using an isolated rat kidney27. A stepwise increase in venous pressure in the presence of stable arterial perfusion resulted in a decrease in GFR, sodium excretion and fractional sodium excretion27. The worsening of renal function was reversible after lowering venous pressure27. The development of renal dysfunction caused by haemodynamic changes in the venous system was also detected in patients with TR and with decompensated heart failure28. In advanced cardiac decompensation due to heart failure with reduced ejection fraction, an elevated central venous pressure measured with a balloon-tipped catheter predicted a deterioration in renal function28. Measurements were performed at baseline and discharge after intensive care treatment with diuretics and intravenous vasodilators and, at both time-points, an elevated central venous pressure but not a reduced cardiac index was associated with renal worsening28. In the present study, the reduction in diuretic doses after CAVI may indicate a functional improvement of fluid balance by the kidneys. Creatinine and cystatin C levels as well as calculated GFR, remained unchanged 3 and 12 months after CAVI, while calculated GFR using cystatin C decreased at 12 months in the OMT group.Based on the reduction of TR-induced congestion after CAVI, we hypothesized that renal function would improve—particularly since a pathophysiological connection between congestion and deterioration of renal function is well established18. Analogous to our findings, a postprocedural reduction of abdominal congestion was observed18. Studies investigating a different interventional therapeutic approach of severe TR treatment—edge-to-edge therapy by implantation of MitraClips—demonstrated a stable renal function  and constant diuretic doses prior to discharge and 6 months after intervention29. Prior to discharge following tricuspid edge-to-edge therapy, the diameter of the inferior vena cava remained unchanged after intervention versus baseline indicating a smaller reduction in abdominal-venous congestion compared to CAVI13; this discrepancy may be an explanation for the different findings on diuretic doses between both interventional approaches.In accordance with our findings, other interventional TR studies did not describe an improvement of renal function after TR therapy: a recent study with single and bicaval valve implantation in patients with severe symptomatic TR reported a postprocedural deterioration of renal function (increase in creatinine levels), which may partly be explained by the application of contrast medium during the intervention17. Heart failure patients frequently present in advanced stages of TR with large defects not amenable for interventional repair by edge-to-edge techniques or annuloplasty. Therefore, improving symptoms and outcome of these patients remains an unmet clinical need. While our approach was associated with major complications, CAVI as a principle might confer some benefit on patients in advanced stages of TR with significant systolic hepatic vein reflux, who are anatomically unsuitable for other interventional therapies.Our subanalysis thus demonstrates an effective reduction of abdominal-venous congestion after heterotopic valve implantation. Improvements in the implantation technique using dedicated devices like TricValve  have proven to be technically safe9. A first study on tricuspid edge-to-edge valve repair reported an improvement of AST, ALT and bilirubin in patients with abnormal hepatic function 6 months after intervention29. These results imply a potentially reversible hepatopathy after interventional TR therapy. In the CAVI group of the present study, hepatic parameters were mainly within a normal range at baseline indicating no advanced hepatopathy in our cohort. Accordingly, significant improvements within the normal range may not be expected.In the present study, hepatic parameters remained stable after CAVI. Severity of TR is associated with laboratory changes in gamma-GT and bilirubin due to congestive cardiac hepatopathyThere are some limitations to the present study. Following major complications, including two valve dislocations and two stent migrations in the CAVI group, the study was stopped prematurely resulting in a small study sample size for the present subanalysis. Therefore, our findings can only be considered hypothesis-generating and require confirmation by further studies using dedicated devices with improved safety. Due to the short FUP period and only two-time laboratory FUP-measurement, potential changes in laboratory parameters may have been missed. Short-term fluctuations as well as long-term effects were not considered in the subanalysis. The decrease in body weight and abdominal circumference may be influenced by cardiac cachexia, which occurs particularly in advanced stages of heart failure. As baseline laboratory parameters of hepatic function were mostly within the normal range, no conclusions can be drawn for TR patients with severely impaired hepatic function.CAVI leads to a reduction of clinical signs of congestion and reduction of diuretic doses in patients with severe TR. Over the next few years, novel catheter-based techniques will provide more information on long-term effects of interventional TR treatment on renal and hepatic function.


In contrast, HRV and BRS decreased immediately after exercise and remained lower for 20 min after RE. We conclude that a single bout of RE induced an increase in vascular reactivity and reduced the pressure load by attenuating AUC of DBP in hypertensive individuals who had never been treated with antihypertensive medications.The aim of this paper is to assess the integrated responses of ambulatory blood pressure (BP), cardiac autonomic modulation, spontaneous baroreflex sensitivity (BRS), and vascular reactivity after a single bout of resistance exercise (RE) in men with stage 2 hypertension who have never been treated before. Ten hypertensive men were subjected to a RE session of three sets of 20 repetitions and an intensity of 40% of the 1-repetition maximum (RM) test in seven different exercises. For the control (CTR) session, the volunteers were positioned on the exercise machines but did not perform any exercise. Forearm blood flow was measured by venous occlusion plethysmography. We also analyzed the heart rate variability (HRV), ambulatory BP, blood pressure variability (BPV), and BRS. All measurements were performed at different timepoints: baseline, 20 min, 80 min, and 24 h after both RE and CTR sessions. There were no differences in ambulatory BP over the 24 h between the RE and CTR sessions. However, the area under the curve of diastolic BP decreased after the RE session. Heart rate (HR) and cardiac output increased for up to 80 and 20 min after RE, respectively. Similarly, forearm blood flow, conductance, and vascular reactivity increased 20 min after RE ( Hypertension is one of the most prevalent chronic medical conditions in modern society, affecting more than one billion people in the world. Although hypertension often lacks symptoms, it is a major risk factor for the incidence of coronary artery disease, stroke, and all causes of mortality . SeveralStudies in humans, as well as in animal models, have demonstrated that, immediately after aerobic exercise, there are several changes in the mechanisms that regulate BP . These cβ-blockade use in hypertensive patients increased BRS and decreased the pressor response to exercise [Most people with different degrees of hypertension take prescribed medications to treat the disease, and autonomic nervous system, baroreflex mechanism, and vascular reactivity are potential therapeutic targets of several classes of antihypertensive drugs , 13. Losexercise .A classic study carried out by Wilcox et al.  observedThus, the present study aimed to evaluate the integrated responses of ambulatory BP, cardiac autonomic modulation, BRS, and vascular reactivity after a single bout of RE in men with stage 2 hypertension who have never been treated with any antihypertensive drug before.The Ethical Committee for Research at Antônio Pedro University Hospital, Fluminense Federal University, approved all procedures used in this study (CEP-CCM/HUAP 180/08). According to the Declaration of Helsinki, all individuals agreed to participate in the study through written informed consent obtained before participation.2, (4) being not physically active, (5) being free of medication , (6) normal resting electrocardiogram (ECG), and (7) absence of albumin in urine test.After an initial selection of 93 volunteers from our laboratory database, seventy-eight were excluded after a telephone interview. Five others were excluded after physical/blood examination because they did not meet the study's inclusion criteria. Ten hypertensive patients were then recruited for the study. The inclusion criteria for the study were the following: (1) age between 20 and 60 years, (2) stage 2 hypertension (systolic BP between 140 and 159 mmHg and/or diastolic BP between 90 and 99 mmHg) , (3) bodA complete description of the study design is presented in After 24 hours of clinical exam and biochemical profile, the subjects performed 1-repetition maximum (1-RM) test for seven intercalating exercises for upper and lower limbs in the following order: chest press, leg extension, front pulldown, leg press, lateral raises, standing hip adduction, and standing knee flexion. There was a 30 min interval between exercises to allow the individuals to completely recover. The 1-RM tests were performed according to Kraemer and Fry's protocol . BrieflyAt the end of both the RE and CTR, heart rate (HR) was recorded using a 12-lead electrocardiogram (ECG) . BP was obtained noninvasively using a servo-controlled finger plethysmography . The model flow calculation was used to estimate cardiac output and derivate from the finger pressure pulse waveform  and assumed values for aortic diameter . An osciThe FBF was determined by venous occlusion plethysmography  using caSimultaneously, a cuff placed on the third finger of the left hand was used to measure noninvasive beat-to-beat BP continuously . Forearm conductance and vascular resistance were calculated using blood flow and mean arterial pressure (MAP) and expressed as an arbitrary unit (a.u.), according to the following formula:For the heart rate variability (HRV) and BP analysis, time series 300 events of pulse intervals and systolic BP were interpolated (cubic spline) and decimated to obtain a series equally spaced in time . The serα-index (α-LF) [Spontaneous baroreflex sensitivity (BRS) was evaluated by systolic BP (SBP) and R-R interval in time and frequency domains. The sequence method was used to evaluate spontaneous oscillations in SBP, and R-R sequences were characterized by a simultaneous increase or decrease of both. We used the SBP and R-R average sequences as a BRS index (BRS). In the frequency domain, the average of the square root sum of the R-R and SBP spectral power in the LF band was indicated as x (α-LF) .versus RE day 142 ± 5 mmHg, n = 4). A sample of at least six individuals was required to ensure a 95% confidence interval. Data distribution and homogeneity of variances were verified by Shapiro-Wilk and Levene's test, respectively. Logarithmic transformation was performed (when necessary) to allow the application of parametric tests. Two-way ANOVA, followed by the Student-Newman-Keuls post hoc test, was used between conditions (exercise day versus control day) and different moments . Data is presented as mean ± standard deviation. Statistical significance was considered when p < 0.05.We computed the effective sample size and statistical power using the pilot study data. The statistical power of 80% was used to an alpha error of 0.05. Systolic blood pressure was used as the primary outcome .p < 0.05) after the RE session, the effect size magnitude between the moments was considered small by Cohen's d test (d < 0.02).Forearm Vascular Reactivity, Basal Forearm Blood Flow, and Forearm Vascular Conductance.p < 0.05) (Forearm vascular reactivity (FVR), forearm blood flow (FBF), and forearm vascular conductance (FVC) did not differ significantly from RE and CTR at baseline. However, FVR, FBF, and FVC were significantly increased up to 20 min after the end of RE ( < 0.05) .HRV indexes are shown in α-LF and BRS index (p < 0.05) and CTR trial , respectively, for α-LF and BRS index, indicating BRS's impairment in the individuals evaluated.BRS was quantified by the HR response to changes in BP and determined by the variables RS index . RE reduThe present study investigated the effect of acute RE on autonomic and vascular responses in stage 2 hypertensive individuals who have never undergone treatment with antihypertensive medications. The main findings of this study are as follows: (i) PEH was observed only in diastolic BP after RE. (ii) The spectral analysis of HRV showed a reduction in the cardiac autonomic regulation of the heart  and attenuation of spontaneous BRS up to 80 min after RE. (iii) FVR, FBF, and FVC were significantly increased up to 20 min at the end of RE. (iv) The cardiac output increased up to 20 min after RE and it is probably involved in the attenuated PEH, even with the increase in the vascular reactivity.As demonstrated by our experimental data, although ambulatory BP did not decrease after exercise, we observed a reduction in the area under the diastolic BP curve, promoting a decrease in BP load to the arteries and heart. Despite this result's clinical relevance, our data do not corroborate previous studies that demonstrated a hypotensive effect of great magnitude after RE. For example, it was observed in a previous study that the association of low-intensity RE and captopril promoted a significant decrease in blood pressure up to 10 hours in hypertensive women . Cavalca1-imidazoline agonist, was able to reverse functional and structural capillary rarefaction in the skeletal muscle of obese rats, as well as reducing blood pressure, heart rate, and plasma catecholamine levels [Treatment of hypertension markedly reduces the cardiovascular risk and end-organ damage in prehypertension and stage 1 hypertension , but it e levels .Thus, several studies support the hypothesis about the interaction between exercise and antihypertensive drugs, and it can be a plausible explanation for the different PEH magnitude and duration observed in previous studies , 29.α-adrenergic receptor activation [In this present study, vascular reactivity increased 20 min after RE even with an increased sympathetic drive. Previous studies have shown that sympathetic vasoconstriction is attenuated in exercising muscle by local metabolites and other substances that reduce vascular responsiveness to tivation , but thetivation .Although RE improves vascular reactivity in hypertensive individuals, this type of exercise does not reduce the sympathetic influences on HR and cardiac output , 40. HR The frequency-domain index of HRV  was reduced up to 20 min after RE. Total power reflects the overall autonomic activity, but changes in total power also influence LF and HF in the same direction, when these variables are expressed in absolute units .Similarly, all time-domain variables  were reduced up to 80 min during recovery after exercise. Time-domain variables reflect the parasympathetic branch function of the autonomic nervous system . Thus, rPrevious studies have shown a large increase in sympathetic cardiac autonomic modulation up to 75 minutes after 40% ER and 80% 1-RM until fatigue. However, these results indicate that the increase in cardiac sympathetic modulation after ER depends on the exercise's intensity and the number of repetitions .α-LF) decreased at the same moments of exercise recovery in comparison to baseline. In the spectral analyses, the total power and absolute values of high and low frequencies were lower in recovery than the baseline condition.Baroreflex mechanism plays an essential role in the dynamic adjustment of circulation . Our resPrevious studies reported similar hemodynamic and autonomic effects after RE in normotensive and hypertensive individuals . NonetheIn summary, we found that a single RE session induced an increase in vascular reactivity and reduced pressure load. Furthermore, apparently the increase in cardiac autonomic activity and attenuated spontaneous BRS after ER did not interfere with BP's dynamic or vascular reactivity. The results of the present study indicated that RE can reduce the pressure load by attenuating AUC of DBP in hypertensive patients who have never been treated with antihypertensive drugs.From a practical point of view, even with the modest magnitude of changes in blood pressure observed in the study patients, a low-intensity ER routine for the whole body is recommended as a complement to treat hypertension at different stages of the disease. Moreover, based on the pool of different side effects observed by regular use of antihypertensive medications, RE looks like an efficient approach to treat the disease and lower medicine dosages.This study has limitations that must be considered. We did not have a group taking antihypertensive drugs for comparison with our experimental group to determine whether the drugs could positively affect PEH. Thus, future studies are required to clarify if the antihypertensive medication can impact the magnitude and duration of PEH after ER in hypertensive individuals.