To establish a logistic regression model based on CT and MRI imaging features and Epstein-Barr (EB) virus nucleic acid to develop a diagnostic score model to differentiate extranodal NK/T nasal type (ENKTCL) from diffuse large B cell lymphoma (DLBCL).This study population was obtained from two independent hospitals. A total of 89 patients with ENKTCL (n = 36) or DLBCL (n = 53) from January 2013 to May 2021 were analyzed retrospectively as the training cohort, and 61 patients  from Jun 2021 to Dec 2022 were enrolled as the validation cohort. All patients underwent CT/MR enhanced examination and EB virus nucleic acid test within 2 weeks before surgery. Clinical features, imaging features and EB virus nucleic acid results were analyzed. Univariate analyses and multivariate logistic regression analyses were performed to identify independent predictors of ENKTCL and establish a predictive model. Independent predictors were weighted with scores based on regression coefficients. A receiver operating characteristic (ROC) curve was created to determine the diagnostic ability of the predictive model and score model.via multivariate logistic regression and converted regression coefficients to weighted scores. The independent predictors for ENKTCL diagnosis in multivariate logistic regression analysis, including site of disease (nose), edge of lesion (blurred), T2WI , gyrus like changes, EB virus nucleic acid (positive), and the weighted score of regression coefficient was 2, 3, 4, 3, 4 points. The ROC curves, AUCs and calibration tests were carried out to evaluate the scoring models in both the training cohort and the validation cohort. The AUC of the scoring model in the training cohort were 0.925  and the cutoff point was 5 points. In the validation cohort, the AUC was 0.959  and the cutoff value was 6 points. Four score ranges were as follows: 0-6 points for very low probability of ENKTCL, 7-9 points for low probability; 10-11 points for middle probability; 12-16 points for very high probability.We searched for significant clinical characteristics, imaging characteristics and EB virus nucleic acid and constructed the scoring system The diagnostic score model of ENKTCL based on Logistic regression model which combined with imaging features and EB virus nucleic acid. The scoring system was convenient, practical and could significantly improve the diagnostic accuracy of ENKTCL and the differential diagnosis of ENKTCL from DLBCL. ENKTCL However, endoscopic excisional biopsy, as the gold standard for definite diagnosis of various diseases, has extremely low sensitivity for the diagnosis of lymphoma in the nose-Waldeyer’s ring . LymphomComputed tomography (CT) and magnetic resonance imaging (MRI) have been widely used as the primary imaging modalities for the early diagnosis, staging and treatment evaluation of lymphoma in the paranasal sinuses-Waldeyer’s ring due to their advantages of practicability and convenience . In addiThe objective of this study was to construct a Diagnostic Scoring Model of ENKTCL using logistic regression based on CT and MRI imaging features and EB virus nucleic acid, aiming at improving the diagnostic accuracy of ENKTCL, and the value of differential diagnosis between ENKTCL and DLBCL.22.1.The institutional review board of our hospital approved this retrospective study and waived informed consent for all patients. This study population was obtained from two independent hospitals. A total of 89 patients with ENKTCL (n = 36) or DLBCL (n = 53) from January 2013 to May 2021 were retrospectively collected as the training cohort in The Second Affiliated Hospital of Zhejiang Chinese Medical University and The Second Affiliated Hospital of Zhejiang University School of Medicine, and 61 patients  from Jun 2021 to Dec 2022 were enrolled as the validation cohort. Inclusion criteria: (a) Contrast-enhanced CT, contrast-enhanced MR, and EB virus nucleic acid testing were performed on patients within 2 weeks before surgery; (b) Patients were subjected to Positron Emission Tomography-Computed Tomography (PET-CT) to exclude infiltration in other sites and inside the bone marrow; (c) Patients were postoperatively confirmed by pathological and immunohistochemical examination; (d) Patients with complete clinical data. Exclusion criteria: (a) Patients received related treatments  and needle biopsy before examination; (b) Patients who were unable to cooperate or whose image quality is poor; (c) Patients in the absence of enhanced CT, enhanced MR, or EB virus nucleic acid testing. 24 patients with ENKTCL and 27 with DLBCL were excluded according to the above criteria, actually leaving 36 patients with ENKTCL and 53 with DLBCL finally included 2.2All patients were performed with required examination. The clinical data and biomarker included age, gender, clinical symptoms , and EB virus nucleic acid  of patients were recorded. EB virus nucleic acid detection whole blood samples were collected and quantitative real-time PCR method was used to detect EBV DNA content in the samples to determine the positive or negative EBV.2.3CT examinations were carried out using GE Light speed 16-slice and Siemens SOMATOM Definition 40-slice spiral CT scanners. Axial and coronal plain scanning and enhanced axial venous scanning were performed. Scanning parameters: tube current: 300mA; tube voltage: 120kV; matrix: 512x512; layer thickness: 3mm; window width: 250HU; and window level: 50HU. MR examinations were conducted using Siemens 1.5T, GE 3.0T magnetic resonance scanners, and quadrature head coil. Axial and coronal plain scanning, and enhanced axial, coronal and sagittal scanning were performed. Scanning parameters: T1WI: TR=230, TE=2.30; T2WI: TR=2800, TE=82.12; STIR sequences in coronal positions: TR=3200, TE=2.70; matrix: 256x256, layer thickness: 4mm, and interval: 1mm. Contrast-enhanced CT and MR scanning were respectively administered with the contrast agents of non-ionic iodine  and Gd-DTPA  intravenously injected through the cubital vein with high-pressure syringe. The scanning range of CT and MR: the axial scanning was from the upper edge of the frontal sinus to the lower edge of the second cervical vertebra, while the coronal scanning was from the frontal sinus to the posterior edge of the sphenoid sinus, and the sagittal scanning covered the whole nasal cavity and paranasal sinuses.2.4The CT and MR images of all patients were retrospectively reviewed and analyzed by two doctors  from the Department of Head & Neck Radiology, and consensus was reached through discussion when disagreements arose. All assessments were performed blindly. The main contents of image analysis are listed as follows: (1) Site ; (2) Distribution ; (3) Range ; (4) Edge ; (5) Density/signal ; (6) Hemorrhage (yes/no); (7) Cystic ; (8) Pharyngeal recess involvement (yes/no); (9) Carotid artery involvement (yes/no); (10) Sinus complex involvement (yes/no); (11) Bone destruction (yes/no); (12) Tonsil enlargement (yes/no); (13) Cervical lymph node enlargement ; (14) Maximum diameter ; (15) Non-enhancement CT . (16) Enhancement CT . (17) D-value ; (18) T1WI ; (19) T2WI ; (20) Gyrus like changes (yes/no); (21) Degree of MR enhancement .All imaging features from the two radiologists were used to assess the interobserver agreement. To assess the intraobserver agreement, the first radiologist re-assessed the abovementioned indexes 2 weeks later.2.5The intra- and interobserver agreements in imaging features were assessed with interclass correlation coefficient (ICC) in the training cohort. ICC values between 0.61 and 0.80, and greater than 0.80 are indicative of good and excellent agreements, respectively; otherwise, the agreement is unsatisfactory .According to the nature and number of covariates, different methods were used to correct covariates. When the main outcome variable was continuity index, difference method or covariance analysis can be used. Hierarchical analysis can be used when the main outcome variables and covariables were categorical indicators. Data distributions were measured using the Kolmogorov-Smirnov test or the Shapiro-Wilk test. Continuous data with normal distribution are shown as mean ± standard deviation and data with a non-normal distribution are shown as median (interquartile range). One-way Analysis of Variance (ANOVA) was performed if the variance was homogeneous, while Kruskal-Wallis H test was conducted if the variance was hierarchical. In univariate analysis, independent-sample t test was used to measure and calculate the continuous variables between the two groups. Categorical variables between the two groups were measured using the chi-square test or Fisher’s exact test. P < 0.05 indicated that the difference was statistically significant. Statistically significant variables were analyzed using multivariate logistic regression in a reverse stepwise way to identify independent predictors of ENKTCL. To obtain an optimal score that is easy to calculate, we converted the regression coefficients to weighted scores by dividing the regression coefficients for each independent predictor by 1/2 of the smallest coefficient, rounding it to the nearest integer or taking the integer part. The scores of independent predictors of each patient were added, and a total score was obtained ranging from 0 to 16 points. According to the score distribution, they were divided into 4 groups, and the diagnostic accuracy of ENKTCL in each distribution area were shown. The goodness of fit of the logical model was calibrated and assessed using Hosmer-Lemeshow test. The area under the ROC curve was used to evaluate the diagnostic efficacy of the prediction model and the score model, and the accuracy, sensitivity, specificity and optimal cutoff point were recorded. The maximum sum of sensitivity and specificity was defined as the optimal cutoff point. All statistical analyses were carried out using SPSS software .33.1In this study, a total of 89 patients, comprising 36 with ENKTCL and 53 with DLBCL were enrolled as the training cohort. The mean age of patients with ENKTCL was (55.42 ± 10.13) years, and that of patients with DLBCL was (60.16 ± 10.48) years. No significant difference was found between the two groups (P=0.620). The male-to-female ratio of patients with ENKTCL was 29:7, and that of patients with DLBCL was 26:27, indicating statistically significant differences between the two groups (P=0.003). The initial clinical symptoms of patients with ENKTCL: 27 cases presented with nasal congestion, 5 with pharyngeal discomfort, 4 with facial discomfort, 6 with neck discomfort, and 5 with eye discomfort. The difference demonstrated was statistically significant (P<0.001). Among the 36 patients with ENKTCL, 26 (72.22%) were tested positive for EB virus nucleic acid, while only 13 (24.53%) of 53 patients with DLBCL were tested positive, and the difference was statistically significant (P< 0.001) Table 1.There were 61 patients were studied in the validation cohort, which contained 27 with ENKTCL and 34 with DLBCL. The CT and MR imaging features of patients with ENKTCL and DLBCL in the training cohort were shown in 3.2 were screened out and included in multivariate logistic regression analysis.Through univariate analysis 3 of the2 = 7.202, P = 0.515; χ2 = 5.306, P = 0.652) indicated that the multivariate logistic model established based on our research data fits well with the real data and is authentic and reliable to reflect the relationship between real variables.Five independent predictors were identified for the diagnosis of ENKTCL 6. For t3.3A diagnostic scoring model of ENKTCL was built after the score of each independent predictor was weighted, and the results were described as follows: site (nose): 2 points; blurred edge: 3 points; high-intense signal on T2WI: 4 points; gyrus like changes: 3 points; positive EB virus nucleic acid: 4 points 6. The s3.4. In the training cohort, no statistical difference was demonstrated in the AUCs between the two models (P=0.743), indicating that the score model made full use of the information of the prediction model, and was simple, practical for the diagnosis of ENKTCL by distinguishing it from DLBCL. The AUC of the score model was 0.948 , which was close to that of the prediction model whose AUC was 0.949 . According to the optimal value of AUC in the training cohort, when the value is assigned to 10, a relatively high diagnostic efficacy can be achieved, with a sensitivity of 77.8%, a specificity of 94.3% and an accuracy of 91.7% , and an increasing trend of accuracy was revealed with the increase of scoring stages  Table 8.3.6. The median score was 8 with extremes of 0 and 16. The specificity was 87.7% and the sensitivity was 86.4% when the cutoff value was 6 points .In the validation cohort, Hosmer-Lemeshow test of the models presented good calibration (P>0.05). The AUCs of the predictive model and scoring model were 0.967  and 0.959 , respectively. The comparison of ROCs between two models in the validation cohort showed no statistical difference (P=0.694> 0.05) testified by DeLong test . The med4NHL is a relatively common extranodal lymphoma in the head and neck, commonly occurred in the nose and Waldeyer’s ring . ENKTCL ENKTCL is an invasive subtype of NHL prevalent in East Asia and Latin America, especially in China, Japan and Korea . The aveThrough univariate analysis of the CT and MR imaging features of patients with ENKTCL and DLBCL, statistically significant differences were revealed in site, edge, sinus complex involvement, bone destruction, tonsil enlargement, cervical lymph node enlargement, non-enhancement CT, enhancement CT, signals on T1WI and T2WI, and gyrus like changes. Among the 36 patients with ENKTCL in the nose-Waldeyer’s ring in the present study, the lesions of 26 patients were found in the nasal cavity and paranasal sinuses, with irregular or cast growth, and is easy to invade the nasal septum, turbinate, sinus complex, and surrounding bone. Among the 53 patients with DLBCL, the lesions of 35 patients were found in the Waldeyer’s ring, showing diffuse soft tissue thickening or prominent soft tissue mass, with little infiltration and growth deep into the tissues of pharyngeal wall , 23, 29.Previous studies conducted on the diagnosis and differential diagnosis of ENKTCL and DLBCL were mostly descriptive analysis, and the results could not be obtained directly and conveniently. Different from previous studies, the current study established a simpler and more reliable score model for the diagnosis of ENKTCL by assigning values to the imaging features of ENKTCL with significant diagnostic values, following the principle that the higher the diagnostic value, the higher the score. Statistically significant variables identified from univariate analysis were included in multivariate logistic regression analysis, and it was found that site (nose), blurred edge, high-intense signal on T2WI, gyrus like changes, and positive EB virus nucleic acid were independent predictors for the diagnosis of ENKTCL, among which gyrus like changes has not yet been fully studied, while the rest were consistent with the results of several previous studies on the diagnosis of ENKTCL and DLBCL . Two stuBased on the weighted scores of the regression coefficients of the 5 independent predictors of ENKTCL: 2 points for site, 3 points each for blurred edge and gyrus like changes, and 4 points each for high-intense signal on T2WI and positive EB virus nucleic acid, this study constructed a reliable and easy-to-use points-scoring system that can successfully differentiate ENKTCL from DLBCL. The 0-16 points were further divided into 4 scoring intervals according to the score distribution, and the corresponding diagnostic accuracy of each interval were calculated. When the threshold was ≤ 6 points, all the 34 cases were non-ENKTCL; 7-9 points, about 33.33% were ENKTCL; 10-11 points, about 82.35% were ENKTCL; 12-16 points, 100% were ENKTCL. When the weighted score was ≤ 6 points, and less than two out of these five features could be observed, the score of the patient must be less than 6 points, indicating a greater chance of the patient being diagnosed as DLBCL rather than ENKTCL. In contrast, if the patient scored ≥ 12 points, at least four features could be identified. In this case, the patient should be assuredly diagnosed as ENKTCL rather than DLBCL.In addition, our study showed that the intra- and interobserver agreements of imaging features (Site、Edge、T2WI、Eyrus like changes) assessments were excellent with all ICC values greater than 0.80  (This study has the following limitations: (1) This is just a retrospective study without groups set for validation, which may lead to bias of the diagnostic efficacy of the score model. (2) The sample size of this study is relatively small, especially for ENKTCL, and inter-group comparison may affect the reliability of the model. Besides, not every score was observed in patients, which may lead to bias in the diagnostic accuracy of ENKTCL. (3) Selection bias may be caused when excluding patients who lacked enhanced CT scans, enhanced MR, or EB virus nucleic acid tests.In conclusion, we established a novel, simple, practical score model for the diagnosis of ENKTCL by differentiating the imaging features, EB virus nucleic acid, and clinical features of patients with ENKTCL and DLBCL. Five independent predictors were identified: site (nose), blurred edge, high-intense signal on T2WI, gyrus like changes, and positive EB virus nucleic acid. The regression coefficients of the above five independent predictors were weighted, and the weighted scores were 2, 3, 4, 3 and 4, respectively. The overall score of the model was 0-16 points. The score distribution was 0-6 points, 7-9 points, 10-11 points, and 12-16 points, and the corresponding diagnostic accuracy increased gradually, which were 0%, 33.33%, 82.35% and 100%, respectively.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Review Committee of The Second Affiliated Hospital of Zhejiang Chinese Medical University. The patients/participants provided their written informed consent to participate in this study.J-YX and J-XX contributed to data analysis and manuscript editing. X-SH and YC contributed to the supervision of the whole process. NF and X-ZZ carried out to collect the data of patients. L-MX and Q-PR helped in images analysis. L-YM were responsible for data analysis. All authors contributed to the article and approved the submitted version.


We also studied the mechanical effect of the heart and leg muscles contractions on blood pressure. We recorded electrocardiogram, blood pressure and electromyogram from 21 patients with Parkinson’s disease and 18 age-matched healthy controls during supine, head-up tilt at 70°, and standing positions with eyes open. The interaction and bidirectional causalities between the cardiovascular and musculoskeletal signals were studied using wavelet transform coherence and convergent cross mapping techniques, respectively. Parkinson’s patients displayed an impaired cardiac baroreflex and a reduced mechanical effect of the heart on blood pressure during supine, tilt and standing positions. However, the effectiveness of the cardiac baroreflex decreased in both Parkinson’s patients and healthy controls during standing as compared to supine. In addition, Parkinson’s patients demonstrated cardio-postural coupling impairment along with a mechanical muscle pump dysfunction which both could lead to dizziness and falls. Moreover, the cardiac baroreflex had a limited effect on blood pressure during standing while lower limb muscles continued to contract and maintain blood pressure via the muscle-pump mechanism. The study findings highlighted altered bidirectional coupling between heart rate and blood pressure, as well as between muscle activity and blood pressure in Parkinson’s disease. The outcomes of this study could assist in the development of appropriate physical exercise programs to reduce falls in Parkinson’s disease by monitoring the cardiac baroreflex and cardio-postural coupling effect on maintaining blood pressure.Cardiac baroreflex and leg muscles activation are two important mechanisms for blood pressure regulation, failure of which could result in syncope and falls. Parkinson’s disease is known to be associated with cardiac baroreflex impairment and skeletal muscle dysfunction contributing to falls. However, the mechanical effect of leg muscles contractions on blood pressure (muscle-pump) and the baroreflex-like responses of leg muscles to blood pressure changes is yet to be comprehensively investigated. In this study, we examined the involvement of the cardiac baroreflex and this hypothesized reflex muscle-pump function  to maintain blood pressure in Parkinson’s patients and healthy controls during an orthostatic challenge induced  We also studied the mechanical effect of the heart and leg muscles contractions on blood pressure.Parkinson’s disease (PD) is a neurodegenerative disorder characterized by tremors, bradykinesia, rigidity, and postural instability . When trvia efferent neural pathways causing an elevation in heart rate, systemic vascular resistance, and cardiac contractility  in maintaining blood pressure in Parkinson’s patients and healthy controls during an orthostatic challenge. The mechanical effect of the heart and leg muscles contractions on blood pressure was also examined. We recorded EMG activity from the medial and lateral gastrocnemius , tibialis anterior (TA), and soleus (SOL) muscles. Wavelet transform coherence (WTC) was utilized to study the interdependency between the respective signals of the cardiovascular and musculoskeletal systems . ConvergWe hypothesized that: 1) The cardio-postural coupling is impaired in Parkinson’s disease along with inefficient lower limb muscles contractions to maintain blood pressure. 2) The cardiac baroreflex effect on blood pressure control is reduced during standing as leg muscles contractions also contribute to increased cardiac output and blood pressure.The study’s findings are expected to reveal the effect of Parkinson’s disease on cardiac baroreflex and cardio-postural coupling, both of which are important mechanisms to maintain blood pressure and ensure a stable upright stance.We recruited PD patients from the Movement Disorders Clinic at Sanford Health in Fargo, ND. All PD patients met at least two of the four diagnostic criteria for PD: bradykinesia, tremor, rigidity, and postural instability, and were DOPA responders. We also recruited healthy controls from the community. PD patients and healthy controls were excluded if they had severe neurological or medical conditions, such as multiple sclerosis, stroke, epilepsy, COPD, congestive heart failure, or renal failure. Participants were also excluded if they had any implanted devices . We excluded PD patients if they had a Montreal Cognitive Assessment [MOCA ] score <All PD patients were administered the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS–UPDRS) Part III  to assesThe protocol required participants to lie supine on a tilt table for 5 min of baseline recording. After 5 min, the table was tilted to 70° for 15 min to induce orthostatic challenge. After which, participants were asked to step off the tilt table into a force platform, where they stood upright with eyes open for 6 min. The procedure was conducted in a reduced sensory environment. The experiment was terminated immediately if the participant showed signs of dizziness, nausea, discomfort, risk of syncope (rapid and drastic drop in BP), or upon request. No participants requested early termination nor demonstrated adverse symptoms requiring withdrawal from the study.We recorded electrocardiogram (ECG) in the lead I electrode configuration from BIOPAC systems, continuous non-invasive blood pressure (BP) using a finger photoplethysmography cuff , and electromyogram (BIOPAC EMG system) from 21 PD patients  and 18 healthy controls  in supine, head-up tilt at 70° and standing positions with eyes open. The electromyogram (EMG) of four different leg muscles on each leg, bilateral tibialis anterior (TA), lateral and medial gastrocnemius , and soleus (SOL) were acquired following the SENIAM recommendations for sensor placement . Data weDue to the presence of movement artifacts during the transition phase between tilt and standing, the first minute of data was not included in the analyses. Therefore, minutes two through six of supine, tilt, and standing data were analyzed. RR intervals were obtained from the ECG signal. Beat-to-beat systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated as the maximum and the minimum value in the blood pressure waveform within a heartbeat. Mean arterial pressure (MAP) was obtained from SBP and DBP as: In this study, we were interested in investigating blood pressure control through lower limb muscles contraction, thus EMG signals from all individual muscles were added to represent the overall muscle activity . EMG dat1) Fraction time active (FTA) was calculated as the portion of time during which the squared cross-wavelet coherence mulation . FTA ref2) The gain reflects the relative amplitude between the signals of each pair over a specified frequency range and it was calculated as the mean value of gain at each time scale over the periods where hreshold .3) The active gain was calculated as (FTA × Gain) to study the effectiveness of the cardiac baroreflex and cardio-postural coupling .In this work, we used wavelet transform coherence  to studyConvergent cross-mapping (CCM)  techniqu work of . Mean va work of . Please Since data were recorded on supine, tilt, and standing positions and not all response variables were normally distributed, we used a nonparametric Anova-type statistic  suggested by . The F1- using R .Parkinson’s patients varied in disease severity . All patients were on either Carbidopa/Levodopa alone or Carbidopa/Levodopa with dopamine agonists or Monoamine Oxidase Type B (MAO-B) inhibitors. Averaged values (over 5 min period) of cardiovascular and musculoskeletal variables are shown in SBP coefficient of variation was lower No difference in the cardiac baroreflex position .Cardiac baroreflex fraction time active was lower in PD during supine  during supine, head-up tilt at 70°, and standing. In addition to cardiac baroreflex dysfunction, we found that Parkinson’s disease patients experience reduced mechanical muscle pump  and cardio-postural coupling (reflex activity). Impairments in these orthostatic reflexes could result in dizziness and an unexpected fall. We found that adjustments of blood pressure through leg muscles contractions during standing may compensate for, or limit the effect of, the cardiac baroreflex on blood pressure since the muscle-pump had already counteracted changes in blood pressure.Parkinson’s disease is known to be associated with cardiac baroreflex dysfunction, however, the effect of Parkinson’s disease on cardio-postural coupling has not been previously investigated. Upon standing, 500–1,000 ml of blood shift from the central body compartments to the lower extremities and splanchnic circulation , leadingMuscle strength deficits and impaired cardiac baroreflex control are responsible for postural instability and contribute to falls in Parkinson’s disease . As a reParkinson’s disease patients displayed impaired cardiac baroreflex as shown by the reduced active gain, fraction time active, and RR interval spectral power in the low-frequency band which is thought to be mediated by both sympathetic and parasympathetic activities with a parasympathetic dominance . In addiPatients with Parkinson’s disease exhibit varying degrees of autonomic dysfunction, which can occur in the early stages of the disease, and symptoms worsen as the Hoehn and Yahr PD stage progresses . The effvia the muscle pump mechanism, and thus the effect of the cardiac baroreflex on blood pressure control was lessened in Parkinson’s patients and healthy controls during standing. This is supported by the increased leg muscle activity, muscle-pump gain, and muscle-pump active gain during standing in both groups as compared to supine position.The cardiac baroreflex gain and active gain were reduced from supine to standing in both groups. Upon standing, lower leg muscles contract and maintain blood pressure Research have shown that the cerebellar fastigial nucleus (FN) which innervates antigravity muscles to maintain postural balance has heavy branches to the nucleus tractus solitarius (NTS), the primary integrative center for respiration and cardiovascular control . NTS recBased on the above information, we suggest that the neurophysiological pathways of the hypothesized blood pressure reflex  could be as follows: In the supine position, gravitational forces are similar on the thorax, abdomen, and legs as these compartments lie in the same horizontal axis. Consequently, arterial and venous pressures are distributed evenly throughout the body. Upon tilting, gravity acts on the vascular volume causing blood to pool in the lower extremities leading to greater postural variations in blood pressure as compared to the supine position . These cvia other mechanisms, could lead to dizziness and falls in Parkinson’s patients. In addition to blood pressure control, lower limb muscle activation plays an important role in maintaining balance during standing, forming a closed-loop between the cardiovascular and postural systems   . Therefoositions .Parkinson’s patients exhibited higher cardio-postural coupling , gain, and active gain for quantitative evaluation of blood pressure control in Parkinson’s disease indicate a potential to use this methodology for the development of effective interventions to reduce falls in Parkinson’s disease by monitoring the cardiac baroreflex and cardio-postural coupling and their role in maintaining blood pressure and postural stability.In this study, we investigated the involvement of the cardiac baroreflex and cardio-postural coupling—a hypothesized blood pressure reflex involving the skeletal muscle-pump–in maintaining blood pressure in Parkinson’s disease patients and healthy controls. We also studied the mechanical effect of the heart and leg muscles contractions on blood pressure. The results support the previous research suggesting that the cardiac baroreflex is impaired in PD patients and is likely driven by sympathetic and parasympathetic dysfunction. Furthermore, our study demonstrated novel findings that Parkinson’s disease patients exhibited higher cardio-postural coupling gain but lower cardio-postural coupling active time during supine, tilt, and standing. In addition, the effect of leg muscle activation to maintain blood pressure was lower in Parkinson’s patients during supine, tilt, and standing. We argue that PD-related rigidity, muscle weakness, and delayed muscle responses contribute to PD patients engaging dyssynchronous and ineffective leg muscles contractions without seeing an impactful benefit on blood pressure control. This would suggest PD patients experience a mechanical muscle pump impairment and cardio-postural coupling dysfunction which both could lead to dizziness resulting in an unexpected fall. We have also found that the cardiac baroreflex has a limited effect on blood pressure during standing as lower limb muscles contract to pump blood back to the venous circulation, increasing cardiac output and blood pressure


To determine graft and patient survival and adverse events in patients who undergo orthotopic kidney transplantation.We performed a systematic review and meta-analysis. We search in Medline, Embase, and Central from inception to nowadays. We included observational studies with patients who undergo orthotopic kidney transplantation. The primary outcomes were overall patient and graft survival. We pooled the information in a frequency meta-analysis with a 95% CI. We analyzed bias with the STROBE statement.Of the 106 papers initially retrieved, four met the inclusion criteria. Vascular and urinary tract complications were reported in 19% and 15%, respectively. The overall patient survival was 92% 95%CI (88% to 95%), I2 = 0%, and the overall graft survival was 88% 95 CI (83% to 91%), I2 = 0%.Our analysis showed a high survival rate in patients and kidney grafts after orthotopic kidney transplantation, with a similar complication rate compared to a heterotopic kidney transplant. Currently, End-Stage Renal Disease (ESRD) is a worldwide highly prevalent condition, especially for those patients with comorbid conditions such as diabetes, obesity, and hypertension ,2. In thKidney transplants had played an important and relevant role in the past few decades, since 1954 when Joseph Murray performed the first successful [Sometimes, heterotopic kidney transplantation is not possible because of retained bilateral iliac fossa for a previous kidney transplant, urinary diversion, or vascular alterations. Accordingly, an orthotopic kidney transplant (OKT) might be an excellent alternative .The orthotopic kidney transplant was first described by Gil-Vernet et al. in 1989 and consisted of implanting the kidney graft through a retroperitoneal approach, mainly using the left renal vein, the left renal pelvis-ureter, and the splenic artery ,8. This Nevertheless, controversy exists about managing a patient with a contraindication for using the iliac fossa for the implantation because there are only a few publications about orthotopic kidney transplants. Accordingly, the long-term results are not well known, and the technique requires a highly skilled surgeon.In the literature there are few series of OKT, the largest has 216 cases. Therefore, this study aimed to determine the adverse events and graft and patient survival in patients who undergo orthotopic kidney transplantation.We performed this review according to the recommendations of the Cochrane Collaboration  and follStudy designs: We included observational studies.Participants: Studies including patients who undergo orthotopic kidney transplantation.Primary outcome: Overall survival and graft survivalSecondary outcome: Adverse effectsTiming: For all outcomes, studies should have at least a one-month follow-up.Exclusion criteria: We excluded case series with less than four patients and a single case report. No language restrictions were applied.We searched MEDLINE (OVID), EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to nowadays . To ensuTwo researchers reviewed each reference by title and abstract. Then they scanned full texts of relevant studies, applied pre-specified inclusion criteria, and extracted the data. Disagreements were resolved by consensus, and when the disagreement could not be solved, a third reviewer dissolved the conflict.Using a standardized form, two trained reviewers independently extracted the following information from each article: study design, geographic location, authors’ names, objectives, inclusion and exclusion criteria, sample size, losses to follow up, timing, outcomes, and association measures.We used the STROBE statement to assess the risk of bias.2 test. For the interpretation, we determined that the values of <50% and >50% in the I2 test corresponded to low and high levels of heterogeneity, respectively.The statistical analysis was executed in R. We performed a meta-analysis of proportions with the command metaprop and the method inverse (logit transformed proportions). Information was pooled with a random effect meta-analysis according to the heterogeneity expected. A priori, We considered a high clinical heterogeneity and a wide proportion of variation among studies. In addition, the results were reported in forest plots of the estimated effects of the included studies with a 95% confidence interval (CI). Finally, heterogeneity was evaluated using the IWe performed sensitivity analysis, extracting weighted studies and running the estimated effect to find differences.NoneWe found 106 studies with search strategies described previously. After duplicate exclusion and full-text evaluation, four studies met inclusion criteria ,6,11,12 We included four studies, which comprised 243 patients. Three of them were from Spain, one from the United States of America. Male was the predominant patient’s gender, with a mean age of 47.5 years (Range 4.2 to 73.6). The terminology used for ESRD etiology was not the same in these studies. The orthotopic kidney transplant indications were primarily severe iliac atherosclerosis; nonetheless, Musquera et al. presented a comparison between two periods, where during the first period 84.8% of the cases were performed in an elective indication [There was an unclear risk of bias for the objective, participants, and study design since there was no information regarding these items. Two studies  reported the patient’s information; however, there was not an appropriate description of the statistical analysis ,12. The Postoperative follow-up varied according to the author, Hevia, et al. presented a mean follow-up of 91.8 months, Paduch, et al. from six months to five years, De Gracia et al., 24 months, while Musquera et al., with the longest follow-up of 20 years.The four included papers described overall patient and graft survival. We found a pooled frequency of 92% 95% CI (88% to 95%); I2 = 0% for patient survival  and a poWe found 19% and 15% of vascular and urinary complications, respectively. Kidney transplant outcomes are described in Although the more weighted study was Musquera et al. 2010, results did not significatively changed when performing the sensitivity analysis.Orthotopic kidney transplantation has been reserved for those patients with contraindication for heterotopic one, due to atheromatosis, vascular abnormalities, or even urinary tract problems, becoming an excellent and safe alternative to heterotopic transplantation. The current systematic review and meta-analysis show a high survival rate in patients who underwent orthotopic kidney transplantation with a 92% overall patient survival, with an overall graft survival rate of 88%. This rate is considerably high, especially in a setting of patients with increased mortality risk due to multiple comorbidities [Delayed graft function (DGF) was found in 20% of cases, similar results obtained by other authors, such as Seth et al. who conducted a retrospective study of 95 transplant patients, where they found 21% DGF ,14. RiskOn the other hand, the rate of vascular complications in heterotopic kidney transplants is around 3–15% according to some published series ,14,16, wThe most frequent cause of vascular stenosis in the literature is due to technical failure, generally located at the level of the anastomosis. Other associated causes are vascular injury during preservation or due to the use of clamps, and torsion, kinking or angulation of the artery and possibly atherosclerosis . Being tIn addition, we found a similar rate of urinary complications in both groups, being 15% in orthotopic kidney transplantation and 1–15% in heterotopic transplantation, according to some published series. Urinary fistula and obstruction are the two most frequent categories ,19. UretAlthough case reports were not included, we also wanted to describe a few characteristics from them. Three manuscripts reported cases from young people with specific conditions indicating the orthotopic transplant, such as multiple pelvic arteriovenous malformations, congenital abnormalities, multiple pelvic and abdominal surgeries, and twin pregnancy ,21,22. IIn the first place, all patients who undergo a renal transplantation must have their vascular anatomy evaluated by Angio CT scan, to confirm the possibility of performing a heterotopic transplant. Furthermore, if it is contraindicated, to assess the feasibility of an orthotopic transplant, before excluding from the transplant list.Secondly, since orthotopic renal transplantation is an option for patients with a contraindication for heterotopic transplantation, because of atheromatosis, vascular abnormalities, or even urinary tract problems, it is technically complex, so it is recommended with a previously detailed technique study, and, accordingly, perform them in high-volume centers.Our main limitations were that we only found four studies that met the eligibility criteria, mostly Spanish papers. Furthermore, the two longest series reported are from the same center.Secondly, there was a high clinical heterogeneity due to the complexity and specificity of the procedure, requiring a certain level of expertise. Subsequently, these results should not be extrapolated to every team implementing this procedure.Orthotopic kidney transplantation is a feasible, safe, and reproducible alternative in patients with contraindication for heterotopic transplantation, with low rate of complications, and a high rate of recipient and graft survival. Nonetheless, we need more studies to accomplish these critical outcomes.


No cephalometric predictors of efficacy were found that were predictive of MAD treatment success. Conclusions: The presence of a mandibular torus practically triples the probability of MAD success. This is the simplest examination with the greatest benefits in terms of the efficacy of MAD treatment for OSA.Background: In obstructive sleep apnoea (OSA), treatment with mandibular advancement devices (MADs) reduces patients’ Apnoea–Hypopnoea index (AHI) scores and improves their sleepiness and quality of life. MADs are non-invasive alternatives for patients who cannot tolerate traditional continuous positive airway pressure (CPAP) therapy. The variability of responses to these devices makes it necessary to search for predictors of success. The aim of our study was to evaluate the presence of mandibular torus as a predictor of MAD efficacy in OSA and to identify other potential cephalometric factors that could influence the response to treatment. Methods: This was a retrospective cohort study. The study included 103 patients diagnosed of OSA who met the criteria for initiation of treatment with MAD. Structural variables were collected . Statistical analysis was performed to evaluate the existence of predictive factors for the efficacy of MADs. Results: A total of 103 patients who were consecutively referred for treatment with MAD were included (89.3% men); the mean age of the participants was 46.3 years, and the mean AHI before MAD was 31.4 (SD 16.2) and post- MAD 11.3 (SD 9.2). Thirty-three percent of patients had mandibular torus. Torus was associated with a better response (odds ratio (OR) = 2.854 ( Continuous positive airway pressure is the most widely used treatment and an efficacious option for patients with obstructive sleep apnoea (OSA) . On the The variability of the responses to these devices reported in the scientific literature makes it necessary to search for predictors of success that allow us to choose the best candidates. Two systematic reviews ,6 that aThe mandibular torus is an exostosis located inside the mandible under the lingual surface   ≥ 15 and <30) with relevant symptomatology such as presence of snoring, witnessed apnoea, excessive daytime sleepiness, and asthenia not explained by other causes.A diagnosis of severe OSA (AHI ≥ 30) with CPAP rejected as the first therapeutic option.Patients with OSA undergoing CPAP treatment with a lack of adherence and/or intolerance or refusal of therapy.This was a cohort study performed with a prospective collection of variables . PatientPatients with severe somnolence while driving, for whom a delay in treatment with MAD represented a danger, were excluded. Other exclusion criteria included patients who would be intolerant of MADs from an orthodontic standpoint following an assessment by the prescribing pulmonologist of the Sleep Unit; lack of teeth (>8) preventing the correct anchorage of the MAD or poor mandibular advancement. We also excluded patients with serious concomitant pathologies or situations of clinical instability that, in the opinion of the prescribing physician, did not require treatment with MADs. Patients with central apnoea syndrome were excluded from this study.®), and its design features and effectiveness have been previously published [According to the characteristics of each patient and following the action protocol of the Sleep and Ventilation Unit, respiratory polygraphy from the Philips Respironics Alice PDx was requested for each patient. Events were scored according to the American Academy of Sleep Medicine criteria (AASM) . All patublished . TitratiThe dimensional and dentofacial parameters of the airway were measured using a digital cephalometric analysis program . 2), smoking history , and sleepiness (excessive somnolence measured using the Epworth score (ES)). The polygraphic variables were total recording time in minutes, respiratory events measured by the apnoea/hypopnea index (AHI), mean oxyhemoglobin arterial saturation (SaO2), percentage of recording time with SaO2 <90% (CT90: <30), and desaturation index values (ODI: number of desaturations per hour of recording). Data on the following variables were collected: age (years), sex, BMI  of Cantabria (Reference 2013.171). Written informed consent was obtained from all the patients. All data were obtained in compliance with Spanish laws and the guidelines of the Declaration of Helsinki.Effective: defined as an AHI < 10 with decrease of more than 50% from baseline ,15.Partially effective: defined as an AHI ≥ 10 with a decrease of more than 50% from baseline.Not effective: defined as an AHI decrease lower than 50% from baseline, regardless of the current AHI.To consider the efficacy of the MAD, we defined the patients’ responses to the MAD treatment as:Descriptive analysis of the sample was performed using absolute and relative frequency distributions for qualitative variables. For quantitative variables, the fit of the data to a normal distribution was checked using the Kolmogorov–Smirnov test by using the mean and standard deviation or the median and interquartile range, depending on the case.t-test was used to compare paired samples, and non-parametric tests were used if these conditions were not met. If the variables were normally distributed, the non-parametric Mann–Whitney U test was used for independent samples, and the Wilcoxon test was used if two variables were related. When three or more variables were analysed, we used the non-parametric Kruskal–Wallis test for independent samples. A value of p < 0.05 was considered significant. Chi-square tests were used to examine the relationships between the qualitative variables. Student’s A logistic regression analysis was performed. For the selection of variables for the multivariate analysis, a univariate analysis was performed with each of the variables, following the model proposed by Hosmer and Lemeshow : variablTo search for efficacy factors and construct a predictive model, the three response categories  were simplified to a dichotomous model (effective and non-effective), with partially effective responses grouped with the non-effective responses.All calculations were performed using the SPSS statistical package .A total of 123 patients started the protocol, of which 103 completed the study. Twenty patients (16%) were excluded after the radiological tests were performed and following examinations by dentists. The main reasons for exclusion were dental problems and the risk of occlusal changes (see patient flow chart 2 and torus was detected in 34 patients (33%). The average age of the patients was 46.3 years, the majority were male (89.3%), and approximately 30% were smokers. The average body mass index was 28.6 kg/mThe mean mandibular advancement was 68% (SD: 6.1) of maximum breakthrough and mean device compliance was 5.87 (SD 1.36) hours/night. The overall changes in respiratory variables pre and post-MAD, depending on the presence or absence of torus, are shown in The effectiveness of MAD was approximately 58%, but when grouped with the partially effective responses, the effectiveness reached up to 70% see . While tp = 0.007). Among the cephalometric variables, those that obtained p < 0.25 were OCC, overjet, BMI grade, smoking, age, and the existence of mandibular torus. These six variables and sex were selected for the multivariate analysis.In the univariate analysis , only thNo collinearity was found between the variables.p < 0.25 were OCC, overjet, BMI, smoking, age, and the existence of mandibular torus. These six variables and sex were selected for the multivariate analysis.Among the variables, those that obtained p = 0.0.35; OR = 2.85).With this model, an area under the curve of 0.706 was obtained .We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to be 41.8%, 80.0%, 74.2%, and 50.0% respectively. p = 0.055 .The relationship between the presence of a mandibular torus and different cephalometric variables was also analysed . The exiThe effectiveness of mandibular advancement devices has been previously demonstrated. Traditionally, they have been recommended for mild or moderate OSA or for those who do not tolerate CPAP treatment . In adulHistorically, the best responders to MAD have been young patients ,25,26, fOn the other hand, given this problem of classification into responders and non-responders to MAD, some authors propose the introduction of an easy-to-make and low-cost trial device into the therapeutic pathway of OSA patients can circumvent the problem of individual responses to treatment by allowing effective classification of patients .Regarding cephalometric measurements in the upper airway, there is no established protocol, which makes it difficult to compare data between different studies.The cephalometric variables reported in the literature in responders are decreased mandibular plane angles, reduced hyoid to mandibular plane distances, short soft pal-ates, increased parapharyngeal spaces, and increased inferior intercanine widths . In a prThirty-three percent of the 103 patients in this study had a mandibular torus, which coincides with the prevalence reported in other studies . ClinicaMandibular tori have been postulated to be anatomical features with two different meanings in patients with OSA. On the one hand, when they are large , they map = 0.055); in other words, the lower the value of the C3-hyoid distance, the greater the frequency of the presence of mandibular tori and the better the response to treatment with MADs. In our study, the presence of a mandibular lingual torus was associated with greater hyoid retroposition (A potential hypothesis underpinning our results to explain the role of torus could be the theory that the mandibular torus is a protective factor in anatomically unfavourable situations, although it is an explanation that does not refute the literature and would require studies directed at the function of the hypoglossus muscle. Thus, patients with a more distal hyoid position would require greater traction on the genioglossus muscle. This would lead to hypertrophy of the mandibular torus, which would act both as a compensation system against the effort that the genioglossus muscle must develop and as a predictive factor for the success of treatment with MADs by providing more favourable traction to the mandibular advancement itself.In the present study, we also found that current smokers were less likely to have MAD success. Smoking is responsible for chronic gum inflammation, and thus, weakening of the supporting tissue of the teeth . SmokingBased on our results, the assessment of the mandibular torus seems to be an indispensable variable in patients undergoing treatment with MADs as a predictor of therapy success. We could not find a variable that was easier to obtain, cheaper, and more predictive of the efficacy of MADs. Revealing the impact of the torus in MAD treatment responses should be the priority of future studies with larger numbers of patients.The mandibular torus is an anatomical variable associated with the success of MAD treatment. Its presence practically triples the probability of MAD success. This is the simplest examination with the greatest benefits in terms of the efficacy. In the present study, we did not identify any cephalometric variables that were predictive of treatment success.


Autosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1–4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed.We evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment.No formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min.The evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.The online version contains supplementary material available at 10.1007/s40620-022-01286-0. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy, causing about 10% of cases with end stage renal disease (ESRD) . The disMany factors are involved in the progression towards ESRD in patients with ADPKD: male gender, early appearance of urologic events, hypertension and PKD1 truncated mutations, among the most relevant . ImportaRenal function can be assessed either by the indirect estimation of glomerular filtration rate (GFR) using formulas or direct measurement by gold-standard techniques. More than 70 equations have been described, based on creatinine and/or cystatin-c  ml/min in the whole group, 75 (32%) of the cases had mGFR > 90 ml/min, 70 (30%) had values between 60 and 90 ml/min, 55 (24%) between 30 and 60 ml/min and 34 (14%) below 30 ml/min. Mean eGFR according to the most used equations ranged from 66 to 75 ml/min for the MDRD and the CKD-EPI group of formulas. The assessment of TKV concomitant to the measurement of GFR was available in 159 cases (68%) and averaged 1008 ml (IQR: 635–1941) and 1639 (IQR: 866–2742) by high performance ultrasound and MRI, respectively.Creatinine-based formulas: TDI averaged 55% for all formulas Table . For exaCystatin-C-based formulas: TDI averaged 64% Table . As an eCreatinine and cystatin-C-based formulas: TDI averaged 40%, CCC 0.93 and cp35 Table .Single values of mGFR were associated with an ample range of estimations Fig. . For exaThe correlation between creatinine or cystatin-c and mGFR was poor Fig. . A singl(a) Examples of eGFR in cases with comparable mGFR: patients were selected in pairs with comparable mGFR covering values from 16 to 95 ml/min Table . The samn = 14) and the estimations of 4 equations: MDRD and the 3 CKD-EPI equations. Estimations were quite scattered, showing either over- or underestimations of real GFR. Extreme variations were frequent with values around 50 and 70 ml/min.(b) Random variations of eGFR around a similar value of mGFR: Fig. A total of 38 cases had mGFR < 30 ml/min. In 10 26%), the MDRD or the CKD-EPI-creatinine equations provided estimations above this threshold .The main finding of our study was that the error of eGFR formulas in patients with ADPKD was wide, frequent and unpredictable. The average error of any formula was about ± 50% of real renal function. This wide variability was found for every tested equation: either based on creatinine and/or on cystatin-c.n = 61), in particular those that have been used frequently in the last decades, i.e. MDRD, CKD-EPI, FAS, etc. Thus, we evaluated differences in precision and accuracy between formulas that use creatinine or cystatin-c and the added value of cystatin, if any, in the estimation of GFR. Renal function was measured with a gold standard, the plasma clearance of iohexol. Finally, the agreement between eGFR and mGFR was evaluated with specific statistical tests [We evaluated a homogeneous group of patients with ADPKD, covering a broad range of renal function, from predialysis care to moderately decreased kidney function to glomerular hyperfiltration. So, the population studied reflects the patients that are seen in day-to-day clinical practice. We evaluated a large group of equations  to 80–85 ml/min (+ 40%). Similar results were observed for the remaining equations. Moreover, in one out of every 10 patients, the error could be even larger. Therefore, formulas have wide and frequent variability in reflecting real renal function in this population. This error is comparable or in some cases larger than the error previously observed in other CKD groups like diabetes, CKD of different origins, renal transplant patients, etc. (see reference 7 for review) [The causes of this error are not completely clear. Formulas depend mostly on the relationship between serum creatinine or cystatin-c values and mGFR. However, both markers proved to have a weak correlation with mGFR. A recent analysis showed that a single value of serum creatinine or cystatin-c, i.e. 1.5 mg/dL or mg/L can be associated with a value of mGFR ranging from 30 to 90 ml/min, showing a 200% variability . The sam2). As a consequence, some payers still limit reimbursement of the drug based on eGFR values. AEMPS still lists an eGFR value above 45 ml/min/1.73m2 to support reimbursement for tolvaptan for ADPKD [The consequences of the variability of eGFR in patients with ADPKD are multiple. Proper evaluation of the degree of renal dysfunction is crucial in the clinics. The large variability of eGFR may determine that patients can be incorrectly classified in higher or lower CKD stages, as shown previously by our group . Tolvaptor ADPKD , followior ADPKD . More reor ADPKD . When eGor ADPKD . Given tFew studies evaluated the error of formulas in ADPKD. Orskov et al. in 101 patients found large p30 values, i.e. the number of estimations included in a range of ± 30% of mGFR, for commonly used formulas: Cockroft-Gault, MDRD and CKD-EPI-cr . A p30 oOur study has limitations. It is a cross sectional study, which does not allow the analysis of the error of eGFR on the evaluation of real GFR changes over time. A prospective evaluation of this cohort will be the matter of a future study.In conclusion, the evaluation of renal function with formulas in patients with ADPKD is unreliable. Extreme variations from real renal function are quite frequent. The consequences of this error deserve attention as they may preclude reimbursement or initiation of specific therapy for ADPKD. Whenever possible, in particular, to help identify rapid progressors towards CKD or to check the evolution of renal function in patients on Tolvaptan, mGFR is recommended. More research in the field of the consequences of the error of eGFR in this population is clearly needed.Supplementary file1 (DOCX 26 KB)Below is the link to the electronic supplementary material.


Atherosclerotic renovascular disease (ARVD) often follows an asymptomatic chronic course which may be undetected for many years. However, there are certain critical acute presentations associated with ARVD and these require a high index of suspicion for underlying high-grade RAS  to improve patient outcomes. These acute presentations, which include decompensated heart failure syndromes, accelerated hypertension, rapidly declining renal function, and acute kidney injury (AKI), are usually associated with bilateral high-grade RAS (> 70% stenosis), or high-grade RAS in a solitary functioning kidney in which case the contralateral kidney is supplied by a vessel demonstrating renal artery occlusion (RAO). These presentations are typically underrepresented in large, randomized control trials which to date have been largely negative in terms of the conferred benefit of revascularization.Here we describe 9 individual patients with 3 classical presentations including accelerated phase hypertension, heart failure syndromes, AKI and a fourth category of patients who suffered recurrent presentations. We describe their response to renal revascularization. The predominant presentation was that consistent with ischaemic nephropathy all of whom had a positive outcome with revascularization.A high index of suspicion is required for the diagnosis of RAS in these instances so that timely revascularization can be undertaken to restore or preserve renal function and reduce the incidence of hospital admissions for heart failure syndromes. Atherosclerotic renovascular disease (ARVD) often follows an asymptomatic chronic course which may be undetected for many years. The prevalence of ARVD ranges depending on the population studied. In the general asymptomatic population, it is estimated that 6.8% of the population over the age of 65 years have evidence of 50% or greater renal artery stenosis (RAS) on duplex ultrasound . In thosHowever, there are certain critical acute presentations associated with ARVD and these require a high index of suspicion for underlying high-grade RAS to improve patient outcomes. These acute presentations, which include decompensated heart failure syndromes, accelerated hypertension, rapidly declining renal function, and acute kidney injury (AKI), are usually associated with bilateral high-grade RAS (> 70% stenosis), or high-grade RAS in a solitary functioning kidney in which case the contralateral kidney is supplied by a vessel demonstrating renal artery occlusion (RAO). As the latter presentations are rarely associated with flank pain or haematuria, the consensus is that these RAO are usually chronic.In contrast, acute RAO is a rare and organ threatening condition with varied presentations. The potential causes include thromboembolic disease, renal artery thrombosis, dissection and iatrogenic during endovascular procedure. One of the leading causes of acute occlusion is atherosclerosis. The majority of patients with acute RAO present with flank pain or with features such as fever, nausea, uncontrolled hypertension, haematuria or acute renal injury . NonspecFunctional MRI studies measuring tissue oxygenation by blood oxygenation level dependant (BOLD) MRI have shown that when increasing severity of RAS occurs beyond 70% there is risk of progressive reduction in perfusion leading to cortical ischaemia . This inOur centre has specialised in the management of patients with ARVD for over 3 decades, treating over 1000 patients with the condition during this time. The vast majority of patients have a sub-acute or chronic presentation. These are the patient phenotypes highly represented in the large scale randomised control trials (RCT) of stenting and medical care versus medical care alone in ARVD, namely ASTRAL and CORAL, that failed to show a benefit of revascularization to outcomes of renal function, cardiovascular events and death. Acute presentations in patients with ARVD are much less common and such patient phenotypes only had minority representation in the RCTs. Expert opinion suggests that these patients are more likely to derive a positive benefit from renal revascularization procedures, and we wish to draw attention to the classical phenotypes which should not be overlooked by describing our experience of acute ARVD presentations over the last 15 years.In this review we have described all patients referred to our institution with acute presentations of atheromatous RAS and have characterised their presentation, imaging, treatment, and long-term outcome. We describe 9 individual patients with 3 classic presentations including accelerated phase hypertension, heart failure syndromes, anuric AKI and a fourth category of patients who suffered recurrent presentations.2 to avoid risk of nephrogenic systemic fibrosis; contrast free MRA or CTA was performed in such patients. If CTA was indicated in those with eGFR of < 30 ml/min/1.73m2 a standard protocol of pre-hydration with normal saline given at a rate of 250 ml/hour for one hour pre-procedure and continued until one hour post CTA was employed to reduce the risk of contrast induced injury. Patients with ARVD without symptoms or features consistent with RAS were excluded. Data collected included demographics, co-morbidities, presentation, method of diagnosis, intervention, immediate outcomes, and long terms outcomes where available.The electronic health records of patients referred to Salford Royal for renal artery intervention between 2005 and 2020 were reviewed for diagnosis of “critical renal artery stenosis” or “renal artery occlusion”. Patients were included if they had complete occlusion of the renal artery or if they had an acute presentation with clinical features consistent with high-risk clinical phenotypes. This initially yielded 14 patients; 5 were excluded based on presence of trauma or other conditions such as vasculitis or fibromuscular dysplasia. In addition, their imaging in terms of CT or MR angiography was reviewed and patients were included if this confirmed the clinical suspicion of RAS which was deemed suitable for intervention. No MRA with gadolinium was performed in those with an eGFR of < 30 ml/min/1.73mIn the 15 years from Jan 2005 to Jan 2020 there were a total of 156 percutaneous renal artery revascularisation procedures undertaken in 132 patients with atherosclerotic RAS within our unit. In this case series we reviewed those acute presentations treated with renal artery stenting; there were 16 such presentations in 9 individual patients.Accelerated hypertension is a hypertensive emergency characterised by systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 120 mmHg with evidence of acute target organ damage . RAS is 8HERCULES , a prospective multicentre trial of 202 patients with ARVD undergoing intervention for uncontrolled hypertension, found a significant reduction in systolic blood pressure (SBP) in stent-treated patients with uncontrolled hypertension. The absolute reduction was related to severity of hypertension pre intervention, those with a starting SBP > 180 mmHg experiencing a mean fall of 48 mmHg while those with a starting SBP of 140–160 mmHg experiencing a mean reduction of 23 mmHg at 9 months . This trA group in Lyon with a similar MDT approach to those diagnosed with atherosclerotic renal artery disease between 2013 and 2015 who primarily focused on blood pressure control found better control in those assigned to intervention. Those in the revascularisation group had a decrease in systolic blood pressure of -23 ± 34 mmHg ( p = 0.007) and diastolic blood pressure of 12 ± 18 mmHg ( p = 0.007). There was also a reduction of antihypertensive agents and the number of cases of resistant hypertension at one year follow up. There was no change in those assigned to medical treatment .Our unit is a dedicated renal centre and it is possible that accelerated phase hypertension treated by other specialities such as cardiology may be under represented in this case series. There were 3 patients whose initial presentation was that of accelerated phase hypertension Table . All 3 pSustained hypertension and the salt and water volume retaining state of atherosclerotic RAS play a role in the decompensation of patients with ARVD and heart failure. The hallmark ‘flash pulmonary oedema’ is a well-recognised manifestation of renal artery disease. Flash pulmonary oedema (or Pickering syndrome) is a general term used to describe a hyper-acute presentation of decompensated heart failure due to an acute rise of left ventricular end diastolic pressure.Although it has become synonymous with bilateral severe RAS or severe RAS affecting a solitary kidney, prompting the physician to consider screening for this underlying arterial pathology , it can Previous reports from this unit have illustrated that patients presenting with heart failure syndromes, such as flash pulmonary oedema, if managed medically, have an increased risk for death and cardiovascular events but not for progression to end stage kidney disease. Revascularisation in these patients was associated with reduced risk of death but not CV events or ESKD .Below Table  is a desIschaemic nephropathy is a term which describes a loss in renal mass with replacement fibrosis as indicated by a size discrepancy  and/or significant proteinuria, and most patients have CKD. Previous non-randomised studies have indicated that those with rapidly progressive renal impairment are most likely to benefit from prompt revascularisation due to a degree of reversibility of renal function . The patIn patients with known atherosclerotic renovascular disease or those with evidence of generalised atheroma ( such as carotid bruit etc.) who present with AKI and no evidence of obstruction on imaging clinicians should have a high suspicion for this diagnosis. Early confirmation and intervention is indication which can transform outcomes for the affected individual.Acute kidney injury is the most common acute presentation in the experience of our unit. Four of our 9 acutely presenting patients had this initial presentation, and it accounted for 5 of the recurrent presentations. All 4 patients presented with severe AKI requiring renal replacement therapy who recovered significant function post intervention and remained independent of dialysis. Table .Table 3Several case series exist describing revascularisation for the management of occlusive renal artery disease. Lawrie, Morris and DeBakey described their experience of 40 patients with renovascular hypertension and totally occluded renal arteries in the 1980s, before widespread application of percutaneous revascularization techniques. 21 of these patients underwent surgical renal artery reconstruction, 15 of which were successful which was defined by long term patency (mean of 223 months). This study assessed potential factors predictive of a good outcome including sex, age, renal function, contralateral reconstruction, technical factors and physical attributes of affected kidney and only size and weight of kidney were consistent predictors of outcome . WhitehoA large case series of 363 patients undergoing renal artery stenting for either hypertension or renal insufficiency included follow up in which re-stenosis was found in 21% of 102 patients overall; this was less common in large calibre vessels ie > 4.5 mm . The majFour of our 9 patients had recurrent presentations, with 11 presentations between them Table . Their sThe 16 acute presentations of atherosclerotic RAS, treated by renal stenting, which are described in this report equated to 10% of all revascularisation procedures performed in our patients, highlighting that acute presentations are relatively uncommon  and that they necessitate a high index of suspicion and timely intervention.All of the RAS lesions were detected by CTA or MRA, techniques which have high sensitivity and specificity for detecting significant RAS. Doppler ultrasound is also an important diagnostic and screening tool for evaluating RAS with a sensitivity and specificity for diagnosing significant RAS up to 90% and 95% respectively . It is aAll our patients were revascularized using percutaneous techniques involving RAS dilatation and stent placement. Prior to availability of angioplasty surgical repair was the only option for correction of atherosclerotic renal artery disease. In modern practice percutaneous intervention has replaced surgical intervention for the management of most cases of RAS due to the associated morbidity and mortality risk of surgery. Surgery is now reserved for more complex anatomical cases, such as those with multiple small renal arteries or where aortic reconstruction is required at the origin of the renal arteries in association with aneurysm repair, where severe aortoiliac disease co-exists, and in patients in whom stenting procedures have failed .The predominant acute presentation was that of acute ischaemic nephropathy as manifest by AKI or deteriorating renal function, accounting for 56% (9/16) of the presentations. Accelerated hypertension accounted for 25% (4/16) of cases with heart failure accounting for 19% (3/16) of cases. Although the characteristic presentation of acute RAO is a patient presenting with loin pain and anuric AKI this classic presentation was seen on just 2 occasions and in only one individual patient, and only in subsequent presentations rather than the original one.Severe hypertension accounted for 25% of our acute presentation cases. Hypertension is a common co-morbidity worldwide and a leading cause of mortality. Prevention and control of hypertension decreases mortality and incidence of heart failure. The prevalence in the past two decades has been increasing possibly due to increased consumption of processed food and changes in lifestyle . Up to 12 to 33.4% in those with eGFR < 45 ml/min/1.73m2 [24In the general population there is a high prevalence of resistant hypertension amongst those with CKD with increasing prevalence seen with reducing renal function, ranging from 15% in those with eGFR ≥ 60 ml/min/1.73mn/1.73m2 . Previoun/1.73m2 , 2425 haOther smaller studies of patients with high grade RAS that was managed medically without revascularisation found that more anti-hypertensive medications were required to effectively control blood pressure and that 5.8% of patients eventually required revascularisation . In our Previous studies have highlighted the benefit of revascularisation in those with heart failure with a substantial reduction in all-cause mortality and hospital admission . The preWe believe that three important considerations are necessary when contemplating renal revascularization for patients with atherosclerotic RAS. The clinical presentation is key but so too is the severity of the RAS lesion and the extent of parenchymal damage within the kidney . Our case series highlighted cases compatible with the recommendations of the ACC/AHA 2018 guidelines that suggest revascularisation should be reserved for those patients with “high risk” presentations such as recurrent flash pulmonary oedema, rapidly declining renal function and refractory hypertension  Fig. 3)3).Fig. 3Acute presentations of atheromatous RAS are relatively uncommon but should be considered in patients presenting with severe hypertension, acute heart failure syndromes or with rapidly deteriorating renal function, especially AKI, particularly if there is evidence of widespread atheromatous disease. A high index of suspicion is required for the diagnosis of RAS in these instances so that timely revascularization can be undertaken to restore or preserve renal function and reduce the incidence of hospital admissions for heart failure syndromes. These are situations in which targeted early renal revascularization has a genuine chance of improving survival.


Lower urinary tract symptoms significantly worsen quality of life. The hypothesis that they might lead to serious systolic blood pressure alterations through inducing sympathetic nervous activity has not been studied so far. To investigate the relationship between benign prostate enlargement-related storage and voiding symptoms and systolic blood pressure. Cross-sectional single-center study on data from a hospital patient record system. We evaluated the medical records of all consecutive patients with benign prostate enlargement-related lower urinary tract symptoms admitted between January 2012 and December 2017. Storage and voiding symptoms were assessed separately. International Prostate Symptom Score, uroflowmetry, postvoiding residual urine volume and systolic blood pressure were recorded. Pearson correlation and linear regression analysis were used. Positive correlations were found between systolic blood pressure and all of the storage symptoms. Among these, urgency had the most significant effect. There were 166 patients (41.4%) with urgency for urination, which increased mean systolic blood pressure from 124.88 mmHg  to 132.28 mmHg . Hesitancy in urinating and feeling of incomplete bladder emptying had weak positive correlations with systolic blood pressure. There was a negative correlation between systolic blood pressure and intermittency of urination. With increasing numbers of urine storage symptoms, systolic blood pressure also increases, while the opposite occurs for voiding symptoms in patients with benign prostate enlargement. We conjecture that storage symptoms may lead to this increase through inducing sympathetic hyperactivity. Further prospective studies with larger groups are needed to confirm these findings. The detrimental effects of storage symptoms on patients’ quality of life, which have been recognized as a major burden on healthcare resources, are more significant than voiding symptoms.,,,,,Since blood pressure elevation indicates sympathetic hyperactivity, this subject has become a focus of interest over recent years.,So far, published studies have mainly focused on the International Prostate Symptom Score or, specifically, on the effects of nocturia on the blood pressure. Our aim was to investigate the association between SBP  and each benign prostate enlargement-related storage or voiding symptom, separately.Our study was designed as a cross-sectional evaluation of data extracted from our hospital’s patient record system. It was conducted after obtaining approval from the local ethics committee at our hospital , and in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Checklists compiled using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) recommendations were also used.The data of all 732 patients aged 50 years and over who presented benign prostate enlargement-related lower urinary tract symptoms and were admitted to our urology clinic between January 2012 and December 2017 were assessed.Patients who presented stage-2 hypertension, diabetes, hyperlipidemia, uncontrolled hypothyroidism, obesity or metabolic syndrome; renal, cardiac, pulmonary, vascular, hepatic or psychiatric diseases; or sleep disorders or active urinary tract infections were excluded in order to eliminate other etiologies that might trigger sympathetic activity. Except for benign prostate enlargement, patients with histories of other urinary diseases, urethral manipulations and strictures or pelvic or cardiovascular surgery were excluded. Patients who were using antihypertensive drugs or alpha-blocker medications that might affect the autonomic nervous system were also excluded from the study in order to avoid the presence of misleading lower urinary tract symptoms and blood pressure measurements.,We used the 2017 guidelines of the American College of Cardiology/American Heart Association for blood pressure classification.The patients thus selected were divided into three groups with regard to their SBP values. Patients with SBP of 110-119 mmHg (normotension), SBP of 120-129 mmHg (elevated blood pressure) and SBP of 130-139 mmHg (stage-1 hypertension). These were named the first, second and third group, respectively.Basic vital signs and blood pressure measurements were part of our routine for every patient and these values were systematically recorded. During each visit, measurements were made after the patient had rested for at least five minutes in a warm room while sitting in a back-supported position.Following the International Continence Society’s classification scheme, patients who experienced urgency for urination, nocturia and high frequency of urination were classified as those with storage symptoms and patients who experienced intermittency of urination, hesitancy in urinating, feeling of incomplete bladder emptying and straining to urinate were classified as those with voiding symptoms. A validated Turkish-language version of the seven-item International Prostate Symptom Score was applied to assess subjective urinary symptoms. Each question was scored from 0 to 5. Total scores in the ranges of 0-7, 8-19 and 20-35 were classified as mild, moderate and severe, respectively.Uroflowmetric analysis, including peak urinary flow rate, was recorded for every patient, followed by physical examination, digital rectal examination, urinalysis and prostate-specific antigen (PSA) measurement. Uroflowmetric measurements were performed using the Flowmaster Wireless Uroflowmeter . Prostate volume and postvoiding residual volume were measured using a 3.5-MHz transabdominal ultrasound probe . This was positioned suprapubically in accordance with the ellipsoid formula, which consisted of multiplication together of the largest anteroposterior diameter , transverse diameter  and cephalocaudal diameter  with 0.524 (H × W × L × π/6).In order to achieve a power of 80.4% with 92.5% confidence interval for the statistical analysis, the sample size was designed to include at least 83 individuals in each of the three groups of SBP. The calculation yielded a total of 249 individuals.Statistical analyses were performed using the IBM Statistical Package for the Social Sciences (SPSS), version 21 . Continuous variables were presented as the mean ± standard deviation. The normality of continuous variables was evaluated using the Shapiro-Wilks test. Comparisons of continuous variables were performed using the independent-sample t test and one-way analysis of variance (ANOVA). Comparisons between pairs of categorical variables were made using chi-square analysis. The Pearson correlation coefficient was used to analyze associations between pairs of continuous variables. Multiple linear regression analysis was used to assess multivariate relationships between SBP and other variables. Candidate independent variables for multiple linear regression analysis were identified using univariate analysis. All tests were two-tailed and P-values of less than 0.05 were considered to be statistically significant.It was determined that 401 patients were eligible for inclusion in this study. The mean age of all the patients was 57.26 ± 9.36 years. In the presence of urgency of urination, nocturia and high frequency of urination, the SBP values increased and the classification of the patients changed from “elevated blood pressure” to “stage-1 hypertension”. However, voiding symptoms did not lead to a similar effect on the systolic blood pressure .When the cutoff value was set at 40 g, the increase in prostate volume did not lead to a significant change in SBP P = 0.305). Similarly, no statistically significant relationship between postvoiding residual volume and SBP was found (P = 0.174) . Among t05. SimilIn a subgroup analysis that was composed of 33 patients who only had storage symptoms and 27 patients who only had voiding symptoms, SBP was found to be significantly higher in the patients who only had storage symptoms (135.21 ± 6.10 versus 128.04 ± 7.62 mmHg) (P < 0.001).,,,,,,,,,,,Many studies have investigated factors such as age and health-related, physical, psychiatric, lifestyle, socioeconomic and metabolic factors that might show associations with storage and voiding symptoms.,,Some studies have demonstrated that pathophysiological similarities and common pathways exist between lower urinary tract symptoms and autonomic nervous system hyperactivity.Systolic or diastolic blood pressure has been presented as a determinant of nocturia.Martin et al. evaluated many factors associated with uncomplicated storage and voiding symptoms. None of the storage and voiding symptoms were found to be significant in terms of SBP and DBP.According to a rodent model, chronic intermittent hypoxia causes increased HIF-1 alpha synthesis. This alerts the sympathetic neurons and stimulates the release of epinephrine, norepinephrine and other catecholamines. As a result, blood pressure increases.According to Jang et al., in patients with sympathetic hyperactivity, alpha blockers were less effective.Our study differs from the previous studies because we investigated each voiding and storage symptom separately, in terms of their association with SBP. We found that storage symptoms were more significant determinants than voiding symptoms, in terms of stage-1 systolic hypertension. Even if these patients have blood pressure values that do not require any medication, they still could experience cardiac problems in their future lives.,According to the 2007 guidelines of the European Society of Cardiology/European Society of Hypertension, and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, prehypertension was classified as 130 ≤ SBP < 140 mmHg and/or 80 ≤ DBP < 90 mmHg.The 2017 guidelines of the American College of Cardiology/American Heart Association changed the definition of prehypertension, to create two different stages: elevated blood pressure (120 ≤ SBP < 130 mmHg and DBP > 80 mmHg) and stage-1 hypertension (130 ≤ SBP < 140 mmHg or 80 ≤ DBP < 90 mmHg).Patients with benign prostate enlargement experiencing lower urinary tract symptoms, who did not need antihypertensive medication, were included in our study. We divided them into subgroups in terms of SBP. Although we did not detect any statistically significant correlation between the International Prostate Symptom score, peak urinary flow rate and SBP when lower urinary tract symptoms were examined individually, the other six symptoms except for straining to urinate were found to have significant effects on SBP. Among these six symptoms, urgency of urination, nocturia and high frequency of urination had the strongest effects on SBP and shifted the blood pressure stage from “elevated blood pressure” to “stage-1 hypertension”. The contributions of these symptoms to increased SBP were 6.55, 4.63 and 3.33 mmHg, respectively and these increases were statistically significant. Considering that, according to the new American College of Cardiology/American Heart Association classification, the differences between the groups are only 10 mmHg, and that such differences in SBP  change the therapeutic approach that physicians take, we believe that these results are clinically significant as well.Hypertension and benign prostatic hyperplasia (BPH) are common age-related diseases. These two pathophysiological conditions coincide in about 25-30% of men over 60 years old.,,,We demonstrated that as the number of storage symptoms increased, the SBP value also increased. As the number of voiding symptoms increased, the SBP value decreased. Sympathetic activity was not directly measured in this study, but our findings were compatible with those of other studies that measured sympathetic activity and suggested that sympathetic activity could be triggered via storage symptoms.When the cutoff value was set at 40 g, we observed that the increase in prostate volume did not lead to a significant change in SBP. This was expected, because there is no direct correlation between prostate volume and the severity of lower urinary tract symptoms. Prostatic hyperplasia is a histological phenomenon and does not always have to cause obstruction, whereas lower urinary tract symptoms are a mixture of neuromuscular changes that are assumed to interact with the autonomic nervous system. Prostate enlargement of solely non-obstructive nature has no direct connection with the neuronal changes that play a major role in lower urinary tract symptoms. It is assumed that prostate enlargement alone does not have an impact on the autonomic nervous system unless it is symptomatic.,We did not find any relationship between postvoiding residual volume and SBP. This may be explained by the low residual urine volumes. Most of the patients were within the normal range and hardly any were above the generally well-accepted limit of 50 ml. At values under 50 ml, there are no SBP-related changes, possibly because there is no irritation effect on the bladder. At values above 50 ml, compensation due to continuous sympathetic stimulation develops and there is inhibition of nerve conduction.,Because heart rate variability can be assessed as a non-invasive indicator of sympathetic nervous system function, some researchers have used it to analyze sympathetic activity., the power of our study would have become higher, but this was not possible because of our study design. Another limitation of our study was the small number of patients.One limitation of our study was that we did not measure the variability of sympathetic activity via heart rate variability or a stress tilt test. We defend our hypothesis based on the findings in the literature. If we had been able to prove that variability in sympathetic activity was presentTo our knowledge, this was the first study to evaluate voiding and storage symptoms separately in terms of their associations with SBP, in patients with benign prostate enlargement-related lower urinary tract symptoms.We presume that storage symptoms are directly related to systolic blood pressure levels. When each symptom was analyzed individually, urgency of urination, nocturia and high frequency of urination were found to be correlated with the most significant rises in systolic blood pressure. We also found that the combination of urgency of urination and nocturia had an adjuvant effect and together increased the systolic blood pressure more than each symptom did alone. In accordance with previous studies, we hypothesize that storage symptoms provoke sympathetic system activity and may manifest as stage-1 hypertension, which is an important precursor for cardiovascular diseases. Further prospective studies with larger patient groups are needed to prove this relationship and to show whether treatment of storage symptoms may help in treating stage-1 systolic hypertension.