Phenylephrine is the most commonly used vasopressor for prophylaxis against maternal hypotension during cesarean delivery; however, the best regimen for its administration is not well established. Although variable infusion protocols had been suggested for phenylephrine infusion, evidence-based evaluation of variable infusion regimens are lacking. The aim of this work is to compare variable infusion, fixed on-and-off infusion, and intermittent boluses of phenylephrine for prophylaxis against maternal hypotension during cesarean delivery.A randomized controlled study was conducted, including full-term pregnant women scheduled for elective cesarean delivery. Participants were divided into three groups which received phenylephrine by either intermittent boluses (1.5 mcg/Kg phenylephrine), fixed on-and-off infusion (with a dose of 0.75 mcg/Kg/min), or variable infusion (with a starting dose of 0.75 mcg/Kg/min). The three groups were compared with regard to frequency of: maternal hypotension (primary outcome), second episode hypotension, reactive hypertension, and bradycardia. Other outcomes included heart rate, systolic blood pressure, physician interventions, and neonatal outcomes.Two-hundred and seventeen mothers were available for final analysis. The 2 infusion groups showed less incidence of maternal hypotension {26/70 (37%), 22/71 (31%), and (51/76 (67%)} and higher incidence of reactive hypertension compared to the intermittent boluses group without significant differences between the two former groups. The number of physician interventions was highest in the variable infusion group compared to the other two groups. The intermittent boluses group showed lower systolic blood pressure and higher heart rate compared to the two infusion groups; whilst the two later groups were comparable.Both phenylephrine infusion regimens equally prevented maternal hypotension during cesarean delivery compared to intermittent boluses regimen. Due to higher number of physician interventions in the variable infusion regimen, the current recommendations which favor this regimen over fixed infusion regimen might need re-evaluation. Subarachnoid block is the preferred route of anesthesia during cesarean delivery. Maternal hypotension is a frequent and deleterious complication after subarachnoid block in this population. Without prophylactic vasopressors, the post-spinal hypotension affects nearly 60% of mothers undergoing cesarean delivery , 2. UsinPhenylephrine (PE) is still the most commonly used vasopressor during cesarean delivery , 4; howewww.clinicaltrials.gov protocol registry system before enrolment of the first participant . Written informed consent was obtained from all participants prior to recruitment in the study. The study was conducted from October 2017 to October 2018. An online random number software was run by a statistician to generate computer-generated sequence of codes (in a ratio of 1:1:1) which were placed into sealed, opaque envelopes. Each envelope included the instructions of preparing the drug, calculating the starting infusion rate, and the management protocol. The envelope was opened by a research assistant who was responsible for preparation of the drugs. Included participants were: full term, singleton, ASA physical status I or II, pregnant women scheduled for elective cesarean delivery, aged between 18 and 40 years. We excluded patients with cardiac morbidities, hypertensive disorders of pregnancy, peripartum bleeding, baseline heart rate < 60 bpm, and body mass index > 35 kg/m2. Upon arrival to the operating room, an 18G intravenous catheter connected to a three-way stopcock was inserted, and monitors were applied (electrocardiography – pulse oximetry – non-invasive blood pressure monitor). Baseline systolic blood pressure (SBP) was calculated as the average of three consecutive measurements at 2-min intervals with a difference < 10%. Patients were pre-medicated with metoclopramide (10 mg intravenous) and ranitidine (50 mg intravenous). Subarachnoid block was performed in the sitting position with 500 mL rapid co-load of lactated Ringer’s solution. Ten milligrams hyperbaric bupivacaine (2 mL) in addition to 20 mcg fentanyl were injected at L3-L4 or L4-L5 interspace using 25G spinal needle. Maternal blood pressure and heart rate were obtained at the baseline; then at 2-min interval till delivery of the fetus; then at 5-min intervals till the end of the operation. Block success was confirmed using pinprick. The surgeon was allowed to start the surgery when the block level was at T4. Patients with failed block (defined as sensory level below T4) were excluded from the study. Lactated Ringer’s solution was infused until a maximum of 1.5 l. Participants were placed in supine position with left uterine displacement. After spinal block, patients received PE according to the group allocation: Intermittent boluses group (n = 75): received 1.5 mcg/Kg PE bolus after spinal block, then received additional vasopressor boluses whenever SBP decreased by 20% or more from the baseline reading. Fixed infusion group (n = 75): received PE infusion with a starting dose of 0.75 mcg/Kg/min. If the blood pressure decreased by 20% or more, a vasopressor bolus was given without changing the rate of PE infusion. The infusion stopped when SBP increased by 20% or more from the baseline reading; when the SBP return to ±20% of the baseline reading, PE infusion was resumed. Variable infusion group (n = 75): received PE infusion at a starting dose of 0.75 mcg/Kg/min. The infusion was titrated up and down according to blood pressure as follows: 1- If the blood pressure decreased by 20% or more, a vasopressor bolus was given in addition to increasing PE infusion rate by 20%. 2- The infusion was stopped if blood pressure increased by 20% or more from the baseline; and was resumed in 50% of the baseline rate when SBP returned within ±20% of the baseline reading. For the infusion groups, the study drug was prepared in a 50-mL syringe (50 mcg/mL) and was administrated in the same line with running fluids. Vasopressor infusion was initiated just before injection of the local anesthetic in cerebrospinal fluid. Vasopressor infusion was stopped 5 min after delivery of the fetus. An oxytocin bolus (0.5 IU) was slowly administered after fetal delivery followed by an infusion of 2.5 IU/hour. Maternal hypotension  was treated by PE bolus of 50 mcg. Severe maternal hypotension (defined as decreased SBP ≤ 60% of the baseline reading) was managed by PE bolus of 100 mcg. Bradycardia (defined as heart rate less than 55 bpm) was managed by IV bolus of ephedrine 9 mg (if accompanied with hypotension). If bradycardia was accompanied with hypertension, it was managed by stoppage of PE infusion. Atropine sulphate bolus (0.5 mg) was given if bradycardia was severe and persistent despite stoppage of the infusion.A randomized, controlled, trial was conducted in Cairo University hospital after approval of institutional research ethics committee approval (N-71-2107) on 16 September 2017. The study was registered at Incidence of maternal hypotension: percentage of mothers with SBP ≤ 80% of the baseline preoperative reading during the period from spinal block till fetal delivery.Incidence of severe maternal hypotension Incidence of second episode hypotension (SBP ≤ 80% of the baseline reading after a previously managed episode)Incidence of post-delivery hypotension Incidence of reactive hypertension (SBP ≥ 20% the baseline preoperative reading after PE administration)Hemodynamic variables: SBP and heart rate (baseline reading and subsequent 12 readings)Number of physician interventions: each of the following was considered intervention: vasopressor bolus plus increasing the vasopressor infusion rate = 1 intervention, atropine bolus = 1 intervention, cessation of the vasopressor infusion = 1 intervention, re-starting of the vasopressor infusion.Intraoperative requirements of PE, ephedrine, and atropine.Incidence of intraoperative nausea and vomitingNeonatal data: Apgar score at 1 and 5 min post-deliveryP (Bonferroni correction) of 0.025 was considered significant for the primary outcome; hence, the minimum sample size increased to 202 mothers (67 patients per group). The randomized number of participants was increased to 76 mothers per group for dropout compensation. Data analysis was performed using Statistical package for social science (SPSS) software, version 15 for Microsoft Windows . Categorical data were presented as percentage and were analyzed using chi-squared test. Continuous Data were evaluated for normality through inspection of the histogram and were presented as mean (standard deviation) , or median (quartiles) (for skewed data). Inter-group comparisons for continuous data with normal distribution were conducted using one-way analysis of variance (ANOVA) test with post-hoc Tukey modification; whilst, skewed data were analyzed using Kruskal-Wallis on ranks. For analysis of repeated measures, two-way ANOVA test was run to evaluate groups (between-groups factor) and time (repeated measures). Bonferroni test was used for Post-hoc pairwise comparison. A p value of ≤0.05 was considered statistically significant.Our primary outcome is the frequency of post-spinal hypotension. According to previous reports  the freqP < 0.001} , and 217 participants were available for final analysis Fig. . The twoP < 0.001} (Table P = 0.014} (Table The median (quartiles) number of physician interventions was higher in the variable infusion group compared to the other two groups {10,3), 10,2), and 1} , We reported that both PE infusion protocols maintained maternal blood pressure better than intermittent boluses. Neither of the two infusion regimens (variable infusion regimen and fixed on-and-off regimen) was superior to the other in terms of hemodynamic outcomes ; however, the variable infusion regimen demonstrated more physician interventions. Vasopressor management during cesarean delivery aims to maintain a balance between prevention of hypotension and avoidance of reactive hypertension. Another aim is to be feasible and simple for the attending physician without the need for excessive un-necessary interventions. Many authors had used fixed on-and-off vasopressor infusion regimens effectively during cesarean delivery , 8–10. N


Purpose: Gender differences exist in the prevalence of asthma and allergic diseases, partially due to the effects of sex hormones on the development of allergic manifestations. Women, compared with men, are more prone to suffer allergic asthma, experience difficulties in controlling asthma symptoms, and show adverse responses to drugs. However, there are knowledge gaps on the effectiveness of anti-leukotrienes drugs on lung function, symptoms, and pulmonary and systemic inflammation in adult asthmatic women compared with men. We conducted a prospective cohort study to characterize the effectiveness of an anti-leukotrienes drug, montelukast (MS), in asthmatic adult women and men.Methods: Twenty-one asthmatic subjects (11 women and 10 men), who were on low-dose inhaled corticosteroids (ICS), were treated with MS. The optimal control of the symptoms was achieved in both groups according to the Global Initiative for Asthma guidelines. At enrollment, and after 13 weeks from the beginning of MS, pulmonary function tests and asthma control tests were performed, and the fraction of exhaled nitric oxide and blood eosinophils levels were measured.Results: From baseline until the end of the study, women treated with MS + ICS had better control of the asthmatic symptoms, defined as higher asthma control test (ACT) score , improved pulmonary function [with higher forced expiratory volume in 1 s ], and forced vital capacity  compared with men. Interestingly, MS + ICS-treated women had significantly lower levels of blood eosinophils  and exhaled nitric oxide  compared with men.Conclusion: The treatment with MS, added to ICS, in women leads to better control of symptoms, better management of lung function, and decreased inflammation levels compared with ICS + MS treatment in men. Asthma, a highly prevalent chronic inflammatory disease of the airways, is characterized by a variable degree of airflow obstruction  and bronTo overcome these gaps in knowledge, this study aimed at evaluating the gender differences in asthmatic symptoms, pulmonary function, and biomarkers between men and women patients with asthma who were treated with MS + inhaled corticosteroids (ICS).The patients were recruited from the outpatient clinics of the Pulmonary and Critical Care Medicine department of “Mauro Scarlato” Hospital in Scafati, Italy.Asthmatic patients with a history of atopy and documented presence of allergy (see later) were included. We excluded individuals with a history of lung diseases other than asthma, coronary artery disease, congestive heart failure, or any comorbidity such as gastroesophageal reflux or rhino-sinusitis, which could have had an effect on symptoms.1.0) of >12% and >200 ml from baseline in response to 400-mcg albuterol; or 2) excessive variability in twice-daily peak expiratory flow over 2 weeks ; or 3) positive bronchial challenge test (drop of ≥20% in FEV1.0 from baseline in response to standard doses of methacholine). The patients underwent intradermal skin testing for immunoglobulin E (IgE)-mediated hypersensitivity. The subjects did not use anti-histaminic drugs for at least 48 h before the skin testing. Allergy skin-prick tests were performed using 14 common aeroallergen extracts : Dermatophagoides farinae, D. pteronyssinus, cat, dog, ragweed mix, grass mix , ash, beech, birch, hickory, oak, poplar, and the molds Aspergillus and Alternaria tenuis; histamine (1 mg/ml) and saline (0.9%) solutions were used as positive and negative controls, respectively. Atopy was defined as a positive intradermal test to at least one allergen with a 2+ or greater wheal-and-flare response with or without pseudopods . Histamine reactivity was documented by an intradermal injection of 0.05 ml of a solution containing histamine at 1 mg/ml. Serum samples were screened for total and specific IgE. Total IgE were evaluated by Fluoro-Fast Test , and an IgE level above 100 IU/ml was considered to be indicative of high probability of atopy. The diagnosis of asthma was successively confirmed by a positive radioallergosorbent (RAST) test for IgE antibodies . The RAST results were classified as Class 1 (low level of specific IgE), Class 2 (moderate level), Class 3 (high level), and Class 4 (very high level). Only patients with both positive intradermal test and RAST were enrolled.Asthma was diagnosed based upon the presence of both: a) respiratory symptoms  usually triggered by exercise, laughter, allergens, or cold air and worsening at night or on waking or exacerbated by viral infections; and b) expiratory airflow limitation. The asthmatic airflow phenotype was confirmed by one or more of the following: 1) increase in forced expiratory volume in 1 s  in two females (https://ginasthma.org/): regular low dose of ICS plus as-needed short acting beta2-agonists (SABA). Since the asthma was non- or partially controlled based upon daytime asthma symptoms, night waking due to asthma, as-needed use of SABA, activity limitation due to the symptoms, a step-up approach  was required at baseline visit. According to the Step 3 approach, the subjects were switched to a low-dose maintenance therapy with ICS [100–200 mcg of beclomethasone dipropionate (HFA) per day] + MS (10 mg per day), plus as-needed SABA or low-dose ICS/LABA.Following enrollment, two women and two men were excluded from the analysis for no-show at the follow-up visit. The final study population included 10 males between 23 and 43 years old and 11 age-matched females; among the participants, there were two mild smokers  with a smoking history of 8.2 + 2.9 pack/years. No woman was taking oral or intrauterine contraceptives. Obesity, defined as a body mass index ≥30 kg/m females Table 1.1.0, FVC, fraction of FeNO, and eosinophils levels were recorded, together with the results of the asthma control test (ACT). Patients were seen by their assigned physician in an outpatient setting at enrollment and 13 weeks after the enrollment.At enrollment, prior to the MS addition to ICS therapy, the values for FEV1.0 and FVC values was used in subsequent analyses. Predicted normal values of FEV1.0 and FVC were derived from standard equations.Spirometry was performed according to the American Thoracic Society/European Respiratory Society guidelines. Spirometric maneuvers were conducted in triplicate, and the highest sum of FEVThe eosinophil count was performed by diluting whole blood with a phyloxine B staining solution that stains the eosinophil population in red. The diluted sample were charged onto a hemacytometer for counting using a low-power (10×) objective.The fraction of FeNO was measured by using a portable electrochemical analyzer  according to the manufacturer’s instructions. All patients were instructed to exhale with a constant expiration flow for 10 s, and the plateau value of NO was recorded. Maneuvers with irregular tracings were rejected. Participants repeated the test until three acceptable tests were performed. To avoid any influence of forced expiration on the NO measurements, spirometry was performed after FeNO measurement. Each FeNO measurement was repeated three times by two physicians who were blinded to the clinical information, and then the average levels of FeNO were calculated.The ACT is a five-point questionnaire assessing asthma symptoms , use of rescue medications, and the effect of asthma on daily activities. Each item includes five answers corresponding to a five-point Likert-type rating scale. At the end of the test, the answers for each of the five items are summed to yield a score ranging from 5 (poor control of asthma) to 25 (complete control of asthma).1.0, FVC, FeNO, circulating eosinophil number, and ACT test score) were assessed at the 13-week visit.The same parameters  was used. The results were expressed as mean ± S.E.M. P-values < 0.05 were considered as significant.Differences in ACT score, FeNO levels, FEVG-power 3.1.9.2  was used for power analyses . We compth) and all respondents provided informed consent before participation.The local Ethics Committee “ASL Salerno” approved the study  than men  Table 2.1.0 in asthmatic women, when compared with baseline FEV1.0 (from 77.25 ± 6.79% to 103.88 ± 6.24% p < 0.0077). In contrast, there were no differences in the values of FEV1.0 between baseline and follow-up visit in the asthmatic men group , a higher production of LTs has been demonstrated in women. In particular, the levels of LTs were inversely correlated with the levels of testosterone, and 5α-dihydrotestosterone repressed LT synthesis in women down to the levels observed in men. Moreover, during inflammatory reactions, androgens orchestrate the events preceding the LT biosinthesis, such as 5-LO subcellular localization, phospholipase D activity, and the 5-LO/FLAP complex assembly. As a result, there is a lower LT biosynthesis in men versus women  for asthma were included in the study, and thus, the effects of MS in other stages of asthma cannot be extrapolated. Second, we have only evaluated blood peripheal eosinophils. The evaluation of lung eosinophils could have been more informative of the levels of lung inflammation. However, bronchoalveolar lavage fluid analysis was not allowed in our study population for etichal reasons. Third, the sample size is limited due to the exclusion criteria we applied in order to select a population of age- and gender-matched asthmatic people without comorbidities that would have biased the interpretation of the asthmatic symptoms and clinical outcomes. On the other hand, this choice may have reduced the generalizability of results. Fourth, the limitations related to the observational nature of this study should be considered in the interpretation of the results. Last, we cannot exclude that the effects observed after the step-up therapeutic approach was initiated are due to the synergistic effect of MS + ICS. However, as no differences between females and males were observed with the ICS therapy alone , it is vOur results indicate that treatment with MS + ICS improves control of the asthma symptoms, lung function, and inflammation in women much more than in men. Future clinical studies are needed to clarify the beneficial effects of anti-LT in asthmatic women and men in order to set up a gender-tailored therapeutic approach to the disease.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee “ASL Salerno.” The patients/participants provided their written informed consent to participate in this study.Conceptualization: BD’A, RE, and MP. Data curation: GS, AL, and MS. Formal analysis: GS, AL, and MS. Funding acquisition: BD’A. Investigation: DG, FF, and MF. Methodology: AR and FR. Supervision: BD’A, MP, and FP. Validation: FP. Roles/writing—original draft: RE and GS. Writing—review and editing: BD’A, LB, and FP. All authors have approved the final article.This work was supported by PRIN 2015 no. 201532AHAE_004 from the Italian Ministry of Education, University and Research. MS’s postdoc is supported by a grant from the Novo Nordisk Foundation to the University of Copenhagen (NNF15SA0018404).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.


Kuwait has one of the highest obesity rates in the world. This study examined the associations between sedentary behaviour (objectively measured and self-reported), adiposity and systolic blood pressure in a sample of adolescents residing in Kuwait. Data was obtained from the Study of Health and Activity among adolescents in Kuwait (2012–2013). The sample included a total of 435 adolescents (201 boys). Outcomes were age- and sex specific body mass index Z-scores and systolic blood pressure. Exposures were total sedentary behaviour measured by accelerometry and time spent in some sedentary behaviours . We used multiple linear regression analyses, adjusted for age, governorate, maternal education and physical activity, to examine associations between sedentary behaviour and adiposity and systolic blood pressure.Only 2 statistically significant associations were found between sedentary behaviour and the study outcomes: body mass in boys was directly associated with higher sedentary time [β (95% CIs) 0.003 (0.00 to 0.06)]; body mass index was inversely associated with videogames in both sexes . In this sample of Kuwaiti adolescents, sedentary behaviour showed limited deleterious associations with adiposity and systolic blood pressure. The epidemic of overweight and obesity affects almost all nations and age groups. In 2013, 36.9% of men and 38.0% of women had a body mass index (BMI) ≥ 25 .In both sexes, there was no evidence of associations between measures of SB  and systolic blood pressure Table .Table 3AFinally, we performed sensitivity analyses including both sexes to increase the statistical power of our analyses  and there was no difference in the direction of our results  0.001 (0.00 to 0.003) p = 0.07; or for total sedentary time and BP: β (95% CIs) 0.01 (− 0.001 to 0.025) p = 0.08).MVPA was not associated with BMI or blood pressure when boys and girls were analysed separately. When the two sexes were combined, MVPA was associated with systolic blood pressure in the fully adjusted model : β (95% CIs) 0.017 (0.05 to 0.23) p = 0.002).This study is the first to examine associations between objectively measured SB and cardio-metabolic risk markers in a sample of adolescents from Kuwait. We found limited evidence of an association between objectively measured SB and adiposity or blood pressure. With the exception of adiposity in boys, our findings are consistent with several major accelerometry studies that did not find associations of accelerometry based sedentary time and clusters of cardiometabolic outcomes , 22. SelOn the other hand, we found an inverse association between time spent playing videogames and adiposity, where 1 h/day playing videogames was associated with a lower BMI-Z score in girls and boys. This finding contradicts literature from some Western countries, that has reported non-significant associations, , 12, 24 Our findings indicate that there were limited associations between SB and adiposity and systolic blood pressure in a sample of Kuwaiti adolescents, a findings that is relatively consistent with several large recent observational studies conducted in Western countries.The study has several important limitations that must be noted. Firstly, our sample only covered three of the six governorates of Kuwait and as such, may not be representative of the broader population. Secondly, the reliability and validity of our SB questionnaire has not been established. However, it remains a challenge to draw robust conclusions about the reliability of self-reported sedentary behaviours due to the use of unstandardized methods in the literature  . Materna


Diabetes was associated with albuminuria . In 85% of all CKD cases at least one of the four most common factors  was associated with CKD. A singular associated factor was found in 61%, two in 14%, and ≥3 in 10% of all CKD cases. We observed a high prevalence estimate for CKD and found that both classical cardiovascular and neglected infectious diseases might be associated with CKD in a semi-rural population of SSA. Our finding provides further evidence for the hypothesis that the “double burden” of non-communicable and endemic infectious diseases might affect kidney health in SSA.In sub-Saharan Africa (SSA), epidemiological data for chronic kidney disease (CKD) are scarce. We conducted a prospective cross-sectional study including 952 patients in an outpatient clinic in Tanzania to explore CKD prevalence estimates and the association with cardiovascular and infectious disorders. According to KDIGO, we measured albumin-to-creatinine ratio and calculated eGFR using CKD-EPI formula. Factors associated with CKD were calculated by logistic regression. Venn diagrams were modelled to visualize interaction between associated factors and CKD. Overall, the estimated CKD prevalence was 13.6% (95% CI 11–16%). Ninety-eight patients (11.2%) (95% CI 9–14%) were categorized as moderate, 12 (1.4%) (95% CI 0–4%) as high, and 9 (1%) (95% CI 0–3%) as very high risk according to KDIGO. History of tuberculosis  and schistosomiasis  were associated with CKD. A trend was seen for increasing systolic blood pressure . Increasing BMI (OR 0.92 per 1kg/m Chronic kidney disease (CKD) is increasingly recognized as a global public health problem with major impact on health, health-care costs and productivity , 2. HoweHowever, up to now, the impact of the double burden of communicable and non-communicable diseases on the development of CKD has been poorly studied , 15. In Treatment of early CKD can slow or prevent progression to end-stage renal disease (ESRD) and reduce cardiovascular mortality , 18, 19.We conducted a single centre cross-sectional study at the outpatient clinic (OPC) of the Bagamoyo District Hospital (BDH) in Tanzania. The BDH is located in the Bagamoyo township on the coast of the Indian Ocean, 65 km north of Dar es Salaam. The hospital provides care for a semi-rural population of the Bagamoyo district in the Pwani region, with a total population of about 300`000 inhabitants counted in the 2012 nationwide census . The natAfter informed consent, all patients ≥ 18 years, irrespective of the reason of consultation, were included. Pregnant women and patients who were not able or willing to provide an informed signed consent were excluded. The study  was performed from 08.12.2010 to 30.05.2011.All data were collected in a case report form, translated from English to Swahili. In all participants body weight and height, blood pressure, heart rate and temperature were recorded. After informed consent, a blood sample was taken for complete blood count and serum creatinine. Complete blood count was performed by a Sysmex Xs 800i analyser. Serum creatinine was measured using Creatinine Jaffe Gen2 reagent on a Cobas Integra 400 plus analyser and calibrated to IDMS standards by the Ifakara Health Institute (IHI) laboratory at the Bagamoyo site center. HbA1c was measured from capillary blood by using a bed-side DCA 2000+ Analyzer . After informed consent, HIV-screening was done with an immunochromatographic test for antibodies to HIV-1 and HIV-2 . All participants were instructed to void a clean-urine specimen. Urine samples were prepared for microscopic analysis. Albumin-to-creatinine ratio (ACR) was measured using a DCA 2000+ analyser  .2 and/or an ACR of ≥30mg/g (≥3 mg/mmol) and categorized according to KDIGO risk stages [CKD was defined as the presence of either impaired kidney function and/or albuminuria based on a one-time measurement. When one-time measurements are used, prevalence of reduced GFR and albuminuria might be overestimated due to physiological variation and temporarily elevated values after physical activity and during acute illness or dehydration . Neverthk stages , 34. Thek stages , 34, 35.Office blood pressure (BP) was assessed by a single measurement using a manual sphygmomanometer in a sitting position after 5 minutes at rest. BP was regarded as “elevated BP” if BP was ≥140/90 mmHg. Anaemia was defined as Hb <13.0 g/dl in male and <12.0 g/dl in female patients . DiabetePrimary outcome of the study were prevalence estimates of CKD risk groups and the association of non-communicable and communicable disorders with CKD. Secondary outcome was the frequency and the magnitude of the overlap between the most frequent associated factors in patients with CKD and vice versa.All participants signed an informed consent form in Swahili. For illiterate patients, the informed consent was read, and fingerprint of the index finger was used instead of a signature. The study was approved by the Ethical Committee of the Cantons Basel-Stadt and Basel-Land (University of Basel) in Switzerland (No. 220/10), the Institutional Review Board of the IHI in Tanzania (IHI/IRB/No.20-2010), and approved by the Tanzanian National Institute for Medical Research (NIMR). ClinicalTrials.gov Identiver: NCT03458338.http://apps.bioinforx.com) to analyse the relationship between associated factors and CKD [Statistical analyses were performed using STATA version 14  and R (version 3.2.3) . Discret and CKD . For visOverall, 1006 patients were recruited . Twenty-2 and was significantly higher in women (26 kg/m2) than in men (23 kg/m2) (p<0.001). Seventy-six (8%) patients had a BMI <18.5 kg/m2 and 419 (44%) a BMI ≥ 25 kg/m2. Overall, 257 (27%) patients had a BP ≥ 140/90 mmHg, with more female (30%) than male (21%) affected (p = 0.002). More females had a positive history of hypertension ). Anaemia was detected in 312 (33%) patients and the percentage was significantly higher in women (41%) than in men (16%) (p<0.001).Patient characteristics are summarized in . The stuSymptoms of acute infection were recorded in 55 (6%) patients, with fever ≥ 38.5°C in 12 (1%), acute malaria in 17 (2%), acute UTI in 24 (3%), and TB in 2 (0.2%) cases. Sixty-four (7%) patients were HIV positive, including 43 (4%) newly diagnosed cases. History of Malaria was reported by 856 (90%) patients, history of schistosomiasis and TB by 73 (8%) and 45 (5%), respectively.2 and an ACR <30 mg/g (3mg/mmol) and therefore, in the absence of other markers of kidney injury, a low-risk prognosis  was 13.6% (n = 119) (95% CI 11–16%). Ninety-eight patients (11.2%) (95% CI 9–14%) were assigned to the moderate, 12 (1.4%) (95% CI 0–4%) to the high, and 9 (1%) (95% CI 0–3%) to the very high CKD risk group according to KDIGO . Seven hrognosis .The distribution of albuminuria, reduced eGFR, and CKD, are depicted in In univariate logistic regression older age , higher systolic BP levels , higher diastolic BP levels , a history of hypertension , diabetes mellitus , and a history of TB  were associated with albuminuria. Increasing haemoglobin levels were associated with a risk reduction  .2, 95%CI 0.88–0.97; p = 0.002) were associated with risk reduction.  , a history of TB , and a history of schistosomiasis  were associated factors for albuminuria . A stronduction. .In univariate logistic regression older age , increasing systolic BP , diastolic BP levels , a history of hypertension , and history of TB  were associated with impaired kidney function. Increasing haemoglobin levels were associated with risk reduction  .In multivariate logistic regression analysis, older age  and a history of TB  were associated with impaired kidney function . Female In univariate logistic regression older age , increasing systolic BP , increasing diastolic BP , a history of hypertension , diabetes mellitus , and a history of tuberculosis  were associated with CKD .2, 95%CI 0.88–0.96; p<0.001) and increasing haemoglobin levels were associated with risk reduction  , and history of schistosomiasis  were associated with CKD . A stron= 0.004) .The relationship of associated factors and CKD and vice versa is depicted in The main finding of our study was a high overall prevalence estimate 13.6%) for CKD. Interestingly, we found an association of both classical cardiovascular disorders and endemic infectious diseases with CKD. Reports from epidemiological studies pointed out, that the “double burden” could account for an increased CKD prevalence in populations from SSA , 22, 24..6% for CAt least one of the following factors,—elevated BP, diabetes, anaemia, or a history of TB or schistosomiasis—, was present in most of all CKD cases. In contrast, in two similar studies 50%  and 80% Due to the large number of unexplained CKD cases, Peck et al hypothesized, that schistosomiasis could be an important cause of CKD in SSA . A histoA history of TB was recorded in 5% of the patients. The cases reported were distributed over a long period of time, i.e. from 1962 until the year of enrolment. However, a quarter of all reported TB cases (24.4%) has occurred within the past three years. This unequal distribution across the time might be a consequence of recall bias or of an increased awareness of TB in recent years , 52. OurAs seen in other studies, elevated BP and diabetes were also very common in our population , 54, 55.2. In our population, only 10 out of 119 CKD cases have had an eGFR equal to or below 45ml/min/1.73m2. Overall, 90.5% of patients with CKD and anaemia had an eGFR >45 ml/min/1.73m2 and only 9.5% an eGFR ≤ 45ml/min/1.73m2 and importantly, the rate of patients with anaemia was equally distributed between cases with eGFR ≥ 60 (37.8%), eGFR 59–46 (58.3%), and eGFR ≤ 45 ml/min/1.73m2 (57.1%) (p = 0.293). These data suggest that anaemia is not explainable by CKD and reduced eGFR in all cases. Further investigations are needed to explore the question, whether anaemia is only a surrogate for chronic disorders, which in turn are risk factors for CKD or whether there is a role of anaemia as an independent causative factor for CKD.As far as we know, this is the first study, which included anaemia as a factor associated with CKD in SSA , 58–60. 2. The absence of significant impaired kidney function in the excluded sub-population, indicates that the study population overall consisted of not seriously acute ill patients. Therefore, selection bias by including acute ill people with AKI and by miss-classifying those as CKD cases should be low.Importantly, we performed our study in an outpatient clinic (OPC) clientele in a semirural area in Tanzania. Arogundade et al. suggested that a practical approach and a first step for prevention programs in SSA would be to engage in a general screening of all inhabitants attending hospitals for any reason . This apEpidemiological studies in diverse populations have shown a strong association between the degree of albuminuria and the kidney outcome independently of the eGFR , 65–67. Epidemiological studies also differ in the application of different formula to calculate eGFR –22. The In our study, we face several limitations. The estimated CKD prevalence data we are reporting are based on a single-point measurements of ACR and serum-creatinine. Therefore, prevalence of reduced eGFR and albuminuria might be overestimated. To the best of our knowledge there are no CKD prevalence studies in SSA without limitation of a single-point measurement. However, in our study the exclusion of patients with possible acute infection/inflammation and consecutively possible AKI and the exclusion of patients with suspected UTI and menstruation which could alter albuminuria should minimize selection bias by miss-classifying those cases as CKD cases. Nevertheless, there are multiple causes of AKI in the absence of acute infection/inflammation such as the ingestion of herbal remedies. Therefore, overestimation of our prevalence estimates cannot be fully excluded.Further, due the fact of single-point measurements and a cross-sectional design, our data do not allow to draw any conclusion about causality and effect of the analysed variables in regard of impaired kidney function or albuminuria. A major limitation is that office BP was assessed by a single measurement only. Therefore, conclusions about BP have to be cautiously drawn, and statements about BP categories/stages and prevalence rates of hypertension are not possible. A further limitation of our study is that certain conditions, especially the history of infectious diseases, were assessed mainly based on a history of recall and not on objectifiable data. Therefore, in future studies further assessments and longitudinal observations have to be carried out to determine their role in kidney disease.Finally, there was no screen log implemented to record systematically the rate of participants in the study. However, due to the setting of the study, the response rate was high and almost all patients were willing to participate in the study. The reasons for the high response rate were, that the frame of the regular consultation hour was not disturbed, but the quality increased by a standardized questionnaire, the investigation of basic vital parameters  and by additional blood and urine examinations without any expenditure for the participants. Further, because of the nature of the study with a cross-sectional design, there were no follow-up visits or other inconveniences for the participants.Our study conducted in a semi-rural population extends the existing epidemiological data set for CKD and provides further evidence for high CKD prevalence in SSA. Particularly, our findings support the hypothesis that people living in SSA are affected by a “double burden” of non-communicable and endemic infectious disorders which both might contribute to a steady rise of CKD in SSA , 43. In


We investigated whether the lower perfusion index (PI) measured with a pulse oximeter, which reflects finger perfusion, would affect the agreement between arterial pressures measured with ClearSight Paired arterial pressure data  and PI values were prospectively obtained from 30 patients undergoing major abdominal surgery. The primary outcome was standard deviation (SD) of the bias (precision) of blood pressure between ClearSight and arterial catheter. The ratio of the adjusted SD of the bias between PI≤1 and PI>1 was calculated using the linear mixed-effects model. The secondary outcomes were the bias and the limits of agreement (LOA) between the two devices .We analyzed 6312 paired data points. The adjusted SD of bias in PI ≤1 compared with those in PI >1 was 1.4-fold  for systolic arterial pressure, 1.5-fold  for diastolic arterial pressure, and 1.3-fold  for mean arterial pressure. The bias (LOA) were as follows: systolic arterial pressure in the PI ≤1 and PI >1 groups, -3.5 (-35.4 to 28.4) mmHg and 2.2 (-19.9 to 24.3) mmHg, respectively; diastolic arterial pressure in the PI ≤1 and PI >1 groups, 13.1 (-5.1 to 31.3) mmHg and 9.0, (-2.6 to 20.6) mmHg, respectively; and mean arterial pressure in the PI ≤1 and PI >1 groups, 8.7 (-11.3 to 28.7) mmHg and 7.6 (-6.2 to 21.3) mmHg, respectively.PI ≤1 was associated with a large SD of the bias between the devices. The PI value could be a real-time indicator of ClearSight precision. Invasive arterial blood pressure measurement with an arterial catheter (IAP) is the gold standard for continuous and accurate monitoring of arterial blood pressure, but this technique carries the risk of complications such as arterial occlusion, pseudoaneurysm, local infection, or hematoma . ClearSiThe agreement between the arterial pressure values measured by ClearSight (APcs) and the arterial catheter-based blood pressures has been examined by several studies –6. In paWe hypothesized that a lower peripheral perfusion would affect the agreement between the APcs and the IAP. As an indicator of peripheral perfusion, we chose the perfusion index (PI) measured by pulse oximetry, which is calculated as the ratio of the pulsatile infrared signal to the nonpulsatile infrared signal in the peripheral tissue ,10. The The objective of this study was to assess whether PI affects the agreement between APcs and IAP.This prospective observational study  was conducted according to the Declaration of Helsinki and was approved by the institutional ethics committee of the Yokohama City University Hospital, Yokohama, Japan on October 19, 2016. All patients gave written informed consent before inclusion. Our study was registered in the UMIN-CTR  prior to patient enrollment. We prospectively enrolled consecutive patients aged ≥20 years who were scheduled to undergo an elective major hepatectomy (defined as liver resection ≥ 3 segments), pancreatoduodenectomy, or both under general anesthesia at the Yokohama City University Hospital, Yokohama, Japan, between April 2 and October 6, 2017. Radial artery catheter placement was planned for every patient because of clinical necessity. The exclusion criteria included pronounced disturbance of peripheral perfusion , a known history of upper arm vascular surgery, and the presence or a known history of arterial fibrillation.The finger cuff of the ClearSight system was placed over the left middle phalanx of the third finger, ipsilateral to the radial artery catheter. The ‘Heart Reference System’ provided with the ClearSight device compensates for the hydrostatic difference between the finger and the heart. The Heart Reference System and the IAP transducer were zeroed at the midpoint of the right atrium as the reference level. IAP was monitored via a radial artery catheter  and pressure transducer  with standard low compliant tubing. The damping coefficient and natural frequency of the transducer were checked by the fast flush test at 1 minute before each measurement period. If inadequate damping was identified, we adjusted the condition of the arterial line . In cases where adjustment was not effective, we planned to exclude the data from the final analysis. The PI values were measured using a pulse oximeter . The pulse oximeter probe was attached to an ipsilateral finger not competing with the finger cuff of ClearSight. The bladder temperature measured by the urinary catheterization  was recorded as the body temperature.CS, DAPCS, and MAPcs, respectively) were recorded at 20-second intervals, and a set of three consecutive data points (obtained over 1 minute) were averaged to yield one datum. All APcs data were obtained at Physiocal intervals >30 beats that were considered to indicate stable and reliable pressure measurements . The PE was calculated as [1.96 SD of bias /  * 100] to evaluate the interchangeability between the two methods . In the All statistical analyses were performed using Microsoft Excel 2010 and R software version 3.3.2 . Data normality was assessed by the Kolmogorov-Smirnov test. All parametric data were presented as mean ± SD, and nonparametric data were presented as median  or number (percentage), as appropriate. The significance of the outcome was defined as a P value of less than 0.05 (two-tailed).We collected 6448 paired data points from 30 patients. After excluding the missing data for IAP or APcs, and artefacts, 6312 valid, paired arterial pressure readings were compared. The number of data points for PI ≤1 was 1685. The median of paired data readings per subject was 211 [170–228] pairs. The ICU data could not be collected in 15 patients because of technical problems  or operational problems (too large motion artefacts or the patients were not admitted to the ICU after surgery) .The patients’ characteristics, comorbidities, and anesthetic data are summarized in In the linear mixed-effect regression model, the adjusted SD of bias in the PI ≤1 group for SAP, DAP, and MAP were significantly larger than those in the PI >1 group . The absThe PEs of SAPcs, DAPcs, and MAPcs in the PI ≤1 group were significantly higher than those in all the data or the PI >1 group . In the We demonstrated that the PI ≤1 was associated with (1) reduced precision of APcs, indicated by a larger SD of bias, (2) increased biases between the two devices in SAP and DAP measurements, and (3) decreased interchangeability between the two devices. In the PI >1 group, the unadjusted mean difference of the biases between two devices and the LOAs were relatively better than those in the PI ≤1 group.Our study suggests that the PI value could be used as a real-time indicator of the precision of the APcs. Specifically, we demonstrated that the precision of SAPcs, DAPcs, and MAPcs were reduced  by 30% to 50% with PI ≤1 when compared to PI >1. In contrast, the changes in the bias between PI ≤1 and >1 were statistically significant but clinically marginal. We believe it is unlikely that our results were influenced by information bias, because PI values were blinded during the measuring period. In the clinical setting, lower precision is more difficult to compensate for than the larger bias. Therefore, our results may suggest the importance of maintaining PI >1 when using ClearSight.The mechanism underlying the association between PI and precision or bias is unclear; however, it may be explained by the ClearSight algorithm, which converts the finger pressure signal to the brachial arterial pressure. The algorithm was constructed based on the data of the 53 subjects , includiThe bias, or LOAs in our results tended to be worse than those in previous reports ,19, evenThe PEs for APcs in the PI ≤1 group were significantly larger than those in the PI >1 group. The interchangeable threshold of the PE for APcs has not been reported. The interchangeable threshold of the PEs for CNAP , which is a noninvasive arterial blood pressure monitor similar to ClearSight, were reported as 14.7% in SAP, 17.5% in DAP, and 18.7% in MAP . The PEsOur study has several limitations. First, our study was performed at a single center, and the type of surgery was also limited. Therefore, our results may not apply to other conditions such as cardiac or emergency surgery, other age groups, or high-risk patients. Second, this is an observational study, so we could not conclude whether various interventions to change the PI  similarly affect the precision of APcs. Third, we have only focused on blood pressure monitoring when discussing the exchangeability between ClearSight and the arterial catheter. However, the arterial catheter has many functions other than blood pressure monitoring . These aspects should be taken into consideration when clinicians decide whether the ClearSight can replace the arterial catheter in each individual clinical case.We found that PI ≤1 was associated with (1) decreasing the precision  of APcs, (2) increasing the biases between two devices in SAP and DAP, and (3) decreasing interchangeability between the two devices. The PI value could be used as a real-time indicator of the precision of the APcs. Further studies will be needed as to whether PI >1 is the best cutoff value for agreement between the two devices.S1 File(XLSX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.S4 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Hypertension is a well-known chronic disease that causes complications such as cardiovascular diseases or stroke, and thus needs to be continuously managed by using a simple system for measuring blood pressure. The existing method for measuring blood pressure uses a wrapping cuff, which makes measuring difficult for patients. To address this problem, cuffless blood pressure measurement methods that detect the peak pressure via signals measured using photoplethysmogram (PPG) and electrocardiogram (ECG) sensors and use it to calculate the pulse transit time (PTT) or pulse wave velocity (PWV) have been studied. However, a drawback of these methods is that a user must be able to recognize and establish contact with the sensor. Furthermore, the peak of the PPG or ECG cannot be detected if the signal quality drops, leading to a decrease in accuracy. In this study, a chair-type system that can monitor blood pressure using polyvinylidene fluoride (PVDF) films in a nonintrusive manner to users was developed. The proposed method also uses instantaneous phase difference (IPD) instead of PTT as the feature value for estimating blood pressure. Experiments were conducted using a blood pressure estimation model created via an artificial neural network (ANN), which showed that IPD could estimate more accurate readings of blood pressure compared to PTT, thus demonstrating the possibility of a nonintrusive blood pressure monitoring system. Hypertension is a well-known chronic disease, which affects approximately 25% of all adults in the world according to the World Health Organization (WHO) . UnfortuSince hypertension is a fatal disease that can result in death or disabilities due to cardiovascular diseases or stroke, it requires an accurate diagnosis and response. A system that can continuously measure blood pressure to alert patients to the dangers of hypertension is required. However, the existing method to measure blood pressure uses a cuff wrapped around the arm, making it cumbersome, and hence, most patients do not measure their blood pressure regularly. Recently, cuffless blood pressure measurement techniques have been continuously researched to improve the convenience of measurement ,4,5. TheThe PTT has a significantly high correlation with blood pressure , and regHowever, while estimating blood pressure using PTT, users must consciously make measurements using ECG and PPG sensors to obtain their blood pressure. To address this issue, techniques for non-intrusive measuring of biometric signals have been developed, thus improving the convenience of measurement ,12,13. OTo solve this problem, this study developed a fully nonintrusive/unrestricted chair-type cuffless blood pressure monitoring system that utilizes two PVDF films. After measuring two BCG signals from the two PVDF films, the phase difference between the two signals was calculated using the Hilbert transform. Blood pressure was estimated via an artificial neural network (ANN) using this phase difference as a feature value. The applicability of the developed system was verified by comparing the estimated blood pressure with the results from the existing PTT calculation method.In this study, a sofa-type experimental apparatus was fabricated to ensure the measurement of a stable biometric signal. The weight was supported by a steel plate on an aluminum frame, and PVDF films were attached to a urethane foam back and a cushion on the seat, which were then covered with natural leather to create a structure similar to a sofa. The BCG signals were measured in real time using the PVDF films attached to the experimental apparatus. To confirm that the BCG signals were measured accurately, the PPG signals were simultaneously measured as a reference by using a PPG sensor . The Atmega256 chip  was used as a microcontroller and the sampling frequency was set at 100 Hz. The raw BCG signals were sent to a computer system  via Bluetooth . The software developed in this study provides features such as noise processing extraction, as well as modeling and functions of blood pressure estimation. The software was developed on a MATLAB base. After the training stage, it can estimate blood pressure at intervals of 10 s through the signals measured via the chair. The concept of the system is illustrated in This study conducted experiments on 30 adults aged 20–50 years  with wide ranging attributes . The subjects were selected from a group of people with no hypertension. The study was approved by the Public Institution Bioethics Committee designated by the Ministry of Health and Welfare of South Korea (IRB P01-201812-12-001).In the experiments, the stable blood pressures of the subjects were measured simultaneously using the experimental sofa and a cuff-type blood pressure monitor  after the subjects were given a sufficient rest. The blood pressure was measured five times at intervals of 1 min.(1)Identify the local maxima and local minima of the given time-series signals.(2)Use interpolation to estimate the upper and lower envelopes by connecting the local maxima and minima values, respectively.(3)Calculate the mean envelope by averaging the upper and lower envelopes determined in the above point.(4)Extract new time-series signals by subtracting the mean envelope determined in the above point from the original signals. These extracted signals are defined as IMF.(5)Set the time-series signals from which the extracted IMF is removed as new original signals and repeat steps (1) to (4). Define the new IMF until the newly designated original signals are expressed as a monotone function or have only one extreme value and no more new time-series signals can be extracted.BCG signals consist of various other signals such as breathing signals and motion noises, particularly many motion noises that occur at low frequencies. Since heartbeat signals can be measured in the bandwidth of 0.5–6 Hz, BCG signals without motion noises were obtained in this study by applying a third-order Butterworth band-pass filter with cut-off frequencies of 0.5–6 Hz. The estimation of blood pressure using PTT is greatly affected by the accuracy of finding the peak i.e., the blood pressure cannot be estimated correctly if the peak is missed from signals. Hence, while the peak was not sought, the same features as PTT were extracted from the BCG signals by using the instantaneous phase difference (IPD) method. Many researchers have used this method to estimate blood pressure from PPG signals, demonstrating its significant correlation with PTT ,19. The To create a blood pressure estimation model, a regression analysis model was created using an ANN. An ANN is a mathematical model consisting of numerous processing elements with a hierarchical structure in which the relationships between inputs and outputs are studied by adjusting the weighted values repeatedly across previous input data and the corresponding output data. It can be used to estimate a very complex nonlinear function. In fact, a multilayer feed-forward back propagation ANN with one hidden layer is sufficient for fitting a continuous function. The median of the IPD value of two BCG signals and personal information  was entered in the ANN input layer as the feature values, and 25 neurons of the hidden layer were used. The SBP and DBP values were estimated from the two output neurons in the output layer. The ANN was trained using the Levenberg–Marquardt algorithm with 70% of the sample data as training set, 15% as validation set, and the remaining 15% as testing set. The model was then trained and evaluated via 10-fold cross validation to obtain the optimum model.To examine the relationship between IPD and blood pressure, the relationship between the median of the IPD and the systolic blood pressure was observed . As showIn this study, a chair-type system that can measure blood pressure in a nonintrusive manner using PVDF films and two BCG sensors was developed. While chair-type blood pressure monitoring systems have been developed in the past ,15, mostThe experimental results of this study showed the possibility of a nonintrusive/unrestricted blood pressure estimation system, which utilizes IPD. This system can continuously monitor blood pressure in a nonintrusive manner while the user is simply sitting on a chair. Since this study only estimated blood pressure in a state of rest, further research is needed in the future to determine whether the proposed system can accurately measure blood pressure for varying situations, such as a blood pressure that has returned to a normal level after having been increased during exercise. It should also be verified for applicability to use for both home and hospital living.


To analyze pre-transplantation and early postoperative factors affecting post-transplantation urine output and develop a predictive nomogram.st (UO1) and 8th (UO8) postoperative days (POD). Predictors for both UO1 and UO8 were cold ischemia time (CIT), patient and donor age and sex, HLA I and II compatibility, pre-transplantation duration of renal replacement therapy (RRT), cause of ESRD (ESRD) and immunosuppressive regimen. UO8 predictors also included UO1, 1st/0th POD plasma creatinine concentration ratio (Cr1/0), and occurrence of acute cellular rejection (AR). Multivariable linear regression was employed to produce nomograms for UO1 and UO8.Retrospective analysis of non-preemptive first transplanted adult patients between 2001-2016. The outcomes were hourly diuresis in mL/Kg in the 11 and UO8 (Spearman's p=-0.43 and −0.37). CR1/0 inversely correlated with UO8 (p=-0.47). On multivariable analysis UO1 was mainly influenced by CIT, with additional influences of donor age and sex, HLA II matching and ESRD. UO1 was the strongest predictor of UO8, with significant influences of AR and ESRD.Four hundred and seventy-three patients were included, mostly deceased donor kidneys’ recipients . CIT inversely correlated with UO1 rapidly wanes and is replaced by indicators of functional recovery (mainly UO1) and allograft's immunologic acceptance (AR absence). Mean absolute errors for nomograms were 0.08 mL/Kg h (UO1) and 0.05 mL/Kg h (UO8).The predominant influence of CIT on UO Many transplanted kidneys will not immediately function. One-fifth to one-third of deceased donor –4 and 3 Allograft functional recovery is customarily assessed with serial plasma creatinine measurements . Yet, thOne should be reminded, however, that predictors’ effects can be nonlinear, and interpreting non-linear effects from complex multi-variable models through coefficients’ tables is no easy task. Such results are better digested when presented graphically; with, for instance, nomograms , 21. NotAfter Institutional Board Review, we retrospectively retrieved medical records from all consecutive patients older than 18 years who underwent non-preemptive deceased and living-related first kidney transplantation in our unit from January 2001 to January 2016. We excluded patients that died before the second postoperative day, those with severe urinary leakage - thus lacking a quantifiable urine output - as well as those with missing values for the outcome variables.Continuous predictors included patient and donor age (years), duration of pre-transplantation renal replacement therapy , cold ischemia time , last donor plasma creatinine concentration  and panel of reactive antibodies score . Ordinal predictors were Human Leucocyte Antigen mismatches in the A, B (HLA I) and DR (HLA II) loci. Categorical predictors included patient and donor sex, and End-Stage Renal Disease (ESRD) etiology, segregated into renal, systemic, urologic, autossomic dominant polycystic kidney disease (ADPKD) and undetermined causes. Additional categorical predictors were organ origin: whether the kidney came from live-related or from a deceased donor, whether due to vascular or non-vascular causes of brain death; initial immunosuppressive regimen: cycloporine and azathioprine (CSA+AZA), cyclosporine and mycophenolate (CSA+MMF), tacrolimus and azathioprine (FK+AZA), tacrolimus and mycophenolate (FK+MMF) and no use of calcineurin inhibitors either without  or with thymoglobulin (Thymo); and use of anti-interleucin 2 antibodies (anti-IL2: basiliximab or daclizumab) in initial immunossupression.st to 6 a.m. of the 2rd postoperative day (UO1), where the day of the operation was considered postoperative day 0 (th to 6 a.m. of the 9th postoperative day (UO8). Regarding the latter outcome we added predictors from the initial postoperative course: Occurrence of biopsy-proven rejection episodes during the first postoperative week (AR), a categorical predictor; the ratio between 1st and 0th postoperative day plasma creatinine concentration (Cr1/0); and UO1, both the latter continuous predictors.Our outcome variables were hourly urine output in milliliters per patients's dry weight (mL/ Kg h), measured from 6 a.m. of the 1ve day 0 , and houp) were computed between continuous predictors and urine output.We summarized continuous variables with medians and interquartile ranges (IQR), and proportions between categorical variables were displayed in frequency tables. Differences in urine output between categorical variables were assessed with Wilcoxon's and Kruskal-Wallis’ tests, the latter followed by Dunn's tests when appropriate. Spearman's rank correlation coefficients . Missing values were imputed with predictive mean matching , and 1 and UO8. Most remaining 473 patients were middle-aged (median 40 years), male , and received deceased donors’ allografts , and CR1/0 inversely correlated with UO8. Patient age inversely correlated with UO1 and UO8 . Urine output was greater in patients receiving kidneys from living-related versus deceased donors . UO1 and UO8 were significantly less in patients that received versus those that did not receive thymoglobulin , and UO1 was significantly less in patients that used compared to those that did not use anti-IL2 . Urine output progressively decreased with increasing HLA I and II mismatches. Patients with systemic causes of ESRD had significant less UO8 than patients with ESRD due to undetermined causes .CIT inversely correlated with both UO1 model, we removed organ origin and PRA scores from the predictors’ set as their values were determined from the other predictors   followed by model comparisons via likelihood ratio tests produced our final model, which admitted nonlinear effects only for CIT.Multiple multivariable linear regressions for both response variables were undertaken with 100 imputed datasets . Missingctively) , 26. The1 . Initial immunosuppressive regimen, RRT, donor age, patient sex and HLA II compatibility were also able to explain more than 0.5% of UO1's variance  with AR, ESRD etiology and patient sex also presenting partial R2≥0.05. This model's mean absolute error was 0.05 mL/Kg hour, and its 0.53 initial R2 was corrected to 0.47 after validation. Besides UO1, AR, ESRD etiology and patient sex we included Cr1/0 and CIT in a second nomogram for illustrative purposes  and immunologic acceptance of the allograft (AR), almost completely dissipated CIT's ability to predict urine output one week after transplantation. With our regression models we constructed and internally validated nomograms to predict post-transplantation diuresis.This study indicated CIT as the dominant predictor of early post-transplantation diuresis. Inclusion of early predictors associated with reestablishment of allograft function . This rise in predictive power led us to conjecture that early urine output was most likely influenced by unmeasured variables, and that the aggregate effect of these unmeasured variables was effected through early diuresis (UO1), by far the most important predictor of urine output one week after transplantation. Indeed, UO1 alone accounted for 35% of the total variance of the UO8 model. Corrobatory evidence to this conjecture lies in the fact that CIT, after exerting its key effect on early diuresis, became a remarkably weaker predictor in the UO8 model , for we fail to reason why the effects of these unmeasured variables should not follow an analogous path. Although a large predictors’ set inhibits the clinical use of a predictive tool, one should concede that predicting a continuous variable with truly multivariate causative factors may, ultimately and unavoidably, demand more predictors.We observed this limitation in predictive ability through the steep increase in optimism-corrected R1 model's predictive power brought about by these and probably other predictors.This study has many drawbacks. We are quite aware that urine output is a necessary but not sufficient condition of allograft functional recovery, as metabolic waste products, ions and other molecules must be also be eliminated. We thus acknowledge that our study addresses only one - however fundamental - aspect of kidney function. Also, we did not have access to other potentially important predictors, such as type of harvesting procedure (single versus multiple organ) and preservation solution, patient pre-transplantation diuresis and occurrence of intraoperative hypotension, to name a few. As discussed above, one cannot lightly dismiss the possibility of a significant rise in UO1 model. Furthermore, we also recognize that one can read our grouping of ESRD causes as arbitrary and therefore a source of classification bias. Still, we consider that any such classification scheme will have some built-in arbitrariness, so that bias may be difficult to avoid. Lastly, we fully acknowledge that our results are conditioned to the peculiarities of our dataset, and advise caution on the part of the reader in the clinical application of our results.In addition, one may oppose the presence in the dataset of patients receiving both living-related and deceased allografts, considering that brain death has severe autonomic and hemodynamic repercussions that are not wholly encapsulated by CIT. We wanted, however, to assess the widest possible range of CITs, and we hope to have mitigated differences between deceased and living-related allografts by admitting nonlinear CIT effects in the UO1), with donor age, RRT and choice of initial immunosuppressive regimen playing a secondary - albeit important - role. Urine output one week after transplantation (UO8) was mainly determined by early diuresis, and penalized by acute rejection episodes. From these results we developed and internally validated nomograms to predict urine output in the 1st and 8th days after transplantation. The sharp increase in explanatory power between models, however, suggests the existence of preoperative and intraoperative unmeasured variables exerting their effects through early urine output (UO1).This study indicated the preponderant role of CIT in determining early post-transplantation diuresis (UOWe hope that this study inspires other investigators to further explore and improve these predictive models. In particular, which variables may be added in predictive models for early urine output to increase their predictive power. In that we acknowledge that our investigation is but a first attempt to provide the urologic and nephrologic community with what we deem to be an useful predictive tool for the postoperative course of these patients in order to better manage patients’ expectations.


Hypertension is one of the most frequent cardiovascular risk factors. The population of hypertensive patients includes some phenotypes whose blood pressure levels are particularly difficult to control, thus putting them at greater cardiovascular risk. This is especially true of so-called resistant hypertension (RH) and refractory hypertension (RfH). Recent findings suggest that the former may be due to an alteration in the renin–angiotensin–aldosterone axis, while the latter seems to be more closely related to sympathetic hyper-activation. Both these pathophysiological mechanisms are also activated in patients with obstructive sleep apnoea (OSA). It is not surprising, therefore, that the prevalence of OSA in RH and RfH patients is very high  and that treatment with continuous positive airway pressure (CPAP) manages to reduce blood pressure levels in a clinically significant way in both these groups of hypertensive patients. It is therefore necessary to incorporate into the multidimensional treatment of patients with RH and RfH  a study of the possible existence of OSA, as this is a potentially treatable disease. There are many questions that remain to be answered, especially regarding the ideal combination of treatment in patients with RH/RfH and OSA  and patients’ varying response to CPAP treatment. Hypertension is one of the most common modifiable risk factors for the development of cardiovascular disease and mortality. The global prevalence of hypertension, based on office blood pressure (BP) measurements, has been estimated at 1.13 billion individuals worldwide in 2015, with a prevalence in adults of 30–45% [RH and RfH are characterized by an incomplete response to antihypertensive therapy, which makes it particularly challenging to identify potentially modifiable associated factors that could help to reduce BP levels. This identification is essential, however, in the light of the high cardiovascular impact of RH and RfH, as they are associated with a 50% higher probability of developing a cardiovascular event or damage to target organs than controlled hypertensive patients [Obstructive sleep apnoea (OSA) is a common sleep disorder characterised by recurrent episodes of upper airway obstruction that provoke intrathoracic pressure changes, sleep fragmentation, intermittent hypoxia and increased sympathetic activity, triggering a variety of intermediate mechanisms that mediate various clinical outcomes, including hypertension and a propensity to a non-dipper circadian BP pattern . Recent OSA and hypertension are closely related. OSA triggers direct and intermediate mechanisms associated with the development and maintenance of hypertension, such as sympathetic hyperactivity . The preIn this review, we will cover the different aspects of the relationship between RH and OSA, including the epidemiology of RH and RfH, the clinical association with OSA, the pathophysiological links between the two disorders and the different therapies for RH and RfH , as well as potential future challenges in the interactions between OSA and RH. RH was defined in the first American Heart Association (AHA) statement as those forms of hypertension with no identifiable cause in which BP levels remain uncontrolled despite the use of at least three antihypertensive drugs (including a diuretic) prescribed at optimal doses or are controlled only by treatment with four or more antihypertensive drugs . Based oA more recent statement that took into account new evidence reported in the latest clinical studies adapted the thresholds of clinical BP and provided greater details of the type, dose and frequency of the drugs that patients should usually be taking to fulfil the definition of RH. This statement also points out the importance of performing 24 h ambulatory blood pressure monitoring (ABPM) in the assessment process for this type of patient . One of the most important contributions in recent years has been the definition of a particular subgroup within RH patients. Acelajado et al. , after aHowever, the first definition of RfH proposed by Acelajado et al.  has beenTherefore, the key point for the fulfilment of the definition of RfH that satisfies all these requirements is the failure to achieve BP control, despite adding more drugs and maximising the most effective drugs while also reducing the volume overload.Consequently, some significant differences have been reported in the clinical profiles of subjects with RH and those with RfH. RfH patients seem to be younger ,25,26, wHigh-quality evidence has shown that OSA and hypertension are closely related. It has been established that about 50% of OSA patients suffer from hypertension and that roughly 30–50% of hypertensive patients have OSA ,27,28. SCross-sectional studies have reported a high prevalence of OSA among patients with RH, ranging from 60–90%, depending on the AHI threshold used to define OSA ,32,33,34p < 0.001) [p = 0.03) [Other studies have shown that the prevalence of OSA is significantly increased in patients with RH compared to those with controlled hypertension. In a case control study of 63 patients with RT and 63 with controlled hypertension, OSA was present in 71% of the patients in the first group, compared to only 38% in the second (< 0.001) . Ruttana = 0.03) . In both = 0.03) . It is well known that there are significant racial and ethnic disparities in hypertension prevalence, with higher rates of RH in non-Hispanic blacks. In this respect, two studies have investigated the association between OSA and RH in the black population ,37. The Abdel-Kader et al. have addressed the association between OSA, RH and chronic kidney disease in a cohort composed of 224 community-based subjects without chronic kidney disease, 88 patients with non-dialysis-dependent chronic kidney disease and 95 with end-stage renal disease by means of unattended home polysomnography and home BP measurements . The autIt is notable that OSA patients with RH do not usually present typical OSA symptoms, particularly excessive daytime somnolence (EDS). In this respect, one study observed that only 70% of patients with OSA and RH were snorers and very few had witnessed apnoeas , whereasSeventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure included OSA as a common identifiable cause of hypertension [All the aforementioned evidence has led the scientific community to consider OSA as an important contributing factor to hypertension and RH. In 2003, the rtension , and in rtension . Moreovep < 0.05 for both comparisons). Although it is unclear whether RfH is simply the most severe extreme of the RH spectrum or whether it really constitutes a different clinical phenotype, it undoubtedly carries the greatest cardiovascular risk. So far, however, only one study has investigated the association between OSA and RfH . In thisAs there appear to be crucial differences between the pathophysiology of RH and RfH , there mDespite the different pathophysiological mechanisms behind RH, fluid overload is considered to be the main one . SympathThe high prevalence of OSA in resistant hypertensive patients could be explained by fluid retention, mainly as a result of hyperaldosteronism. The negative thoracic pressure associated with sleep apnoea causes fluid to move from the legs to the neck area when the patient is lying down , resultiAs mentioned above, RfH is defined as BP that remains uncontrolled despite therapy with at least five drugs, including an intensive diuretic treatment that maximizes volume depletion, a long-acting thiazide-like diuretic and a mineral-corticoid receptor antagonist . It is nAs in the case of RfH, sympathetic over-activity in OSA patients seems to be the main pathophysiological mechanism explaining the syndrome’s pressor effect ,15,50. IDespite the significant progress made in recent years with respect to the treatment of RH, several aspects remain unclear. The situation is even worse as regards RfH, as there is nothing to test beyond hypothesis .The same recommendations about lifestyle changes given to the general hypertensive population could also be considered suitable for RH patients, and so the need for weight reduction, sodium restriction (2 gr/day), moderation of alcohol consumption and regular physical exercise (3–5 sessions of 30–40 min weekly) should be advocated.Nevertheless, some specific points still need to be clarified. Although weight loss does have a significant effect on BP reduction, and might improve OSA when it is present , no triaThe initial studies testing renal denervation treatment for RH patients raised expectations for this procedure as a possible definitive therapy for both RH and RfH ,61. FurtPharmacological therapy has constituted the primary approach to the treatment of RH to date and it has provided the main advances made in recent years, although some RfH patients never achieve BP control. There is no longer any doubt about the efficacy of spironolactone in improving BP control and it should be added to the baseline treatment, if possible, as a fourth drug  . SpironoIn addition to pharmacological treatment, the treatment of OSA with continuous positive airway pressure (CPAP) might be an alternative means of achieving BP control in RH subjects with OSA, due to its additional effect of lowering blood pressure in these patients ,72,73,74n = 20) showed a decrease in 24 h diastolic BP  compared with the control group without CPAP. Moreover, the number of patients with a dipping pattern significantly increased in the CPAP group . Patients who used CPAP > 5.8 h showed a greater reduction in 24h BP (6.98 mmHg in diastolic blood pressure (DBP) and 9.71 mmHg in systolic blood pressure (SBP)). The largest RCT on the effect of CPAP on BP levels in RH patients was the HIPARCO study (NTC00616265) undertaken by the Spanish Sleep Network [n = 98) or no CPAP (n = 96) over 3 months. The CPAP group achieved a greater decrease in 24 h mean BP  and 24 h DBP , but not in 24 h SBP , compared with the control group (P = 0.02). Finally, as seen in previous studies, there was a significant positive correlation between hours of CPAP use and the decrease in 24 h mean BP , SBP  and DBP , respectively. After this meta-analysis, an additional RCT was published by a French group (RHOOSAS study) [The last published meta-analysis was performed by Lei et al.  and inclS study)  in 2018.p = 0.021) and 24 h DBP , especially at night . The adjusted difference between groups was statistically significant in 24 h SBP levels  [Some interesting additional data on the effect of CPAP in patients with RH or RfH hypertension can be found in some other studies: Campos-Rodríguez et al.  reported= 0.021) . Moreove= 0.021) . Recentl= 0.021)  publishep < 0.041) in patients with white-coat RH. After adjustment, a weak but significant association was found between cumulative time spent with SaO2 below 90% and baseline aldosterone concentration (p < 0.047), and between changes in aldosterone concentration and changes in office DBP (p < 0.020).Beyond the known effect on the reduction in the sympathetic activity of CPAP, this treatment has also been shown to affect aldosterone concentration. De Souza et al.  demonstrp = 0.01). CPAP treatment also significantly altered a total of 47 plasma miRNAs and decreased aldosterone-to-renin ratios in the responder group (p = 0.016) but not in the non-responder group. Moreover, Sanchez de la Torre et al.  observedFinally, another study analysed the additional effect of CPAP on renal denervation. Linz et al.  publisheThe reduction in BP levels is greater in RH patients  than in normotensive or well-controlled hypertensive patients (approximately 2 mmHg)The degree of reduction in BP levels is similar to those achieved by some antihypertensive drugs, especially in patients with RfH.There is a positive and linear correlation between the hours of use of CPAP and the reduction in BP levels.CPAP treatment produces an increase in the percentage of the normal nocturnal BP dipper pattern.CPAP decreases both the sympathetic activity and the level of aldosterone concentration in both RfH and RH patients, and these could constitute some of the pathophysiological action mechanisms involved in this treatment.The effect on RH of CPAP treatment combined with other pharmacological or non-pharmacological interventions such as renal denervation and antihypertensive drugs is still not known.In conclusion, and taking into account all these published findings on the effect of CPAP on BP levels and other characteristics in patients with RH or RfH, it seems that:The relationship between RH  and OSA has been detected recently and so many future challenges still await us, and they need to be tackled urgently for several reasons. On the one hand, there are few therapeutic options available for patients with RH/RfH, despite their ominous prognosis, while on the other hand, the prevalence of OSA among these patients is significantly high, and the treatment with CPAP has proved effective in reducing BP levels, being established as a new therapeutic way. To the date, beyond the magnitude of the effect of CPAP on BP in RH patients that might be even more important in RfH subjects, there is the need to set agreed criteria regarding how to fit in the multidimensional management of RH/RfH  the potePatients with RH/RfH have a high cardiovascular risk and few therapeutic options. Recently, a close relationship between these phenotypes of hypertensive patients and OSA has been discovered. Both diseases seem to alter similar pathophysiological mechanisms. This has meant that in clinical studies, the prevalence of OSA in patients with RH/RfH is very high and that treatment with CPAP, which eliminates nocturnal respiratory events, is able to decrease BP levels in a clinically significant way. There are still many unanswered questions that pose future challenges such as the ideal combined treatment in these patients, or the role that long-term CPAP can play in the incidence of cardiovascular events. However, given the great cardiovascular risk of these patients and their scarce therapeutic options, ruling out the presence of an OSA is important since this is a potentially treatable disorder.