A major obstacle in kidney transplantation for primary focal segmental glomerulosclerosis (FSGS) is the risk of disease recurrence. Recurrent FSGS affects up to 60% of first kidney grafts and exceeds 80% in patients who have lost their first graft due to recurrent FSGS. Clinical and experimental evidence support the hypothesis that a circulating permeability factor is the mediator in the pathogenesis of primary and recurrent disease. Despite all efforts, the causing agent has not yet been identified. Several treatment options for the management of recurrent FSGS have been proposed. In addition to plasma exchange, B-cell depleting antibodies are effective in recurrent FSGS. This indicates, that the secretion and/or activity of the postulated circulating permeability factor(s) may be B-cell related. This review summarizes the current knowledge on permeability factor(s) possibly related to the disease and discusses strategies for the management of recurrent FSGS. These include profound B-cell depletion prior to transplantation, as well as the salvage of an allograft affected by recurrent FSGS by transfer into a second recipient. Correct assigning of FSGS to its subclasses primary, genetic, and secondary is pivotal for therapeutic decisions and assessment of recurrence risk after renal transplantation.It is obvious that one or possibly more circulating permeability factors are causative in the pathogenesis of primary FSGS and its recurrence.This circulating permeability factor(s) has not yet been identified.Additionally, B cells may play a central role in the pathogenesis of FSGS and its recurrence. This hypothesis is supported by the success of plasma exchange and B-cell depleting antibodies  in the treatment and pretreatment of FSGS recurrence. However, CD20-directed antibodies might also exert a beneficial effect by stabilizing podocyte function after directly binding to podocyte-derived antigens.Allograft transfer of a kidney transplant that failed in the first recipient due to fulminant FSGS recurrence into a second recipient is an option to rescue the allograft and to avoid futility of organs.Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage renal disease worldwide. It is a histologic description of a glomerular lesion caused by a multitude of pathogenicities that are linked by podocyste injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms. Genetic  FSGS is linked to specific mutations in key podocyte molecules, whereas secondary FSGS is caused by a variety of injuries such as drugs , infections , or the mal-adaptive alterations that occur after any loss of kidney parenchyma  1–5). I. I5). InThe incidence of primary FSGS recurrence after kidney transplantation varies between 40 and 60% . DiagnosCompared to transplant for other causes, patients with FSGS have a significantly inferior graft survival with a 5-year graft survival of 81% in FSGS recipients vs. 88% in non-FSGS recipients. In pediatric patients, the difference in the transplant outcome is even more pronounced with 68% 5-year graft survival in FSGS recipients compared to 93% in non-FSGS recipients. FSGS recurrence may be fulminant with nephrotic-range proteinuria appearing hours to days after transplantation. Most commonly, recurrence occurs in the first 2 years following kidney transplantation . For patAn analysis of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) data revealed that the expected graft survival advantage of a live donor kidney transplant in patients with primary FSGS was lost due to the increased risk for FSGS recurrence . A more There is clinical and experimental evidence that a circulating permeability factor is involved in the pathogenesis of primary FSGS and its recurrence. The first clinical evidence for a causative circulating factor dates back to 1972 when Hoyer et al. reported 3 patients who experienced recurrence of FSGS after kidney transplantation despite profound immunosuppressive therapy . Additioin vitro model of isolated rat glomeruli presented by Savin et al. . Patients with FSGS were shown to have increased serum concentrations of suPAR . The proAnother candidate protein that has been proposed to play a role in FSGS is cardiotrophin-like cytokine factor 1 (CLCF-1) . CLCF-1 in vitro and in vivo, and be confirmed in validation studies. (2) The permeability factor must be identified in well-phenotyped patients but not in appropriate controls and validated in independent patient cohorts. (3) The temporal relation of the permeability factor with disease activity and remission has to be demonstrated. (4) Specific removal or inhibition of the permeability factor in vivo must block the biologic effect  The permeability factor must have biologic effects c effect .n = 78) in the non-recurrent group. The differing antibody profiles in sera of patients with recurrent vs. non-recurrent FSGS demonstrate that FSGS is associated with a signature of increased humoral response to a variety of non-HLA antigens. A biomarker panel of 7 antibodies targeting glomerular antigens can predict post-transplant FSGS recurrence with 92% accuracy. In this panel, the anti-CD40 antibody exerts the strongest correlation with FSGS recurrence prediction. Immunohistochemistry showed positive staining for CD40 in podocytes from FSGS whereas there was no CD40 protein expression in normal renal tissue. Furthermore, anti-CD40 antibodies isolated from recurrent FSGS patients induced podocyte depolarization and blocking CD40 relieved proteinuria , disease recurrence , and definition of remission. There is no established standard for the treatment of recurrent FSGS post-transplant. Instead, various therapeutic regimens are applied , as recurrence of FSGS post-transplant is associated with accelerated graft loss. Clinical decision making is often driven by the fear of loss of the allograft. The application of several treatments simultaneously is favored over establishing hypothesis-driven therapies and controlled trials.The therapeutic targets of the different treatments that are currently applied in recurrent FSGS are illustrated in Building on the assumption that a possible serum factor was responsible for FSGS disease and recurrence, Zimmermann was the first to report plasma exchange as a treatment option for FSGS recurrence in 1985 . Plasma A recent systematic review by Kashgary et al. identified 43 case series and 34 case reports of recurrent FSGS treated with plasma exchange . Of the In contrast to total plasma exchange, immunoadsorption (IA) is a selective apheretic procedure that does not induce loss of coagulation factors and therefore might be preferable with respect to postoperative bleeding risk. Immunoadsorption can either be performed with a protein A column or an IgG column. Immunoadsorption for the treatment of relapsing FSGS following kidney transplantation was originally described by Dantal et al. . In a reRituximab is a chimeric mouse/human monoclonal antibody that targets CD20 on B-cells thereby inducing selective and profound B-cell depletion for 6 months following antibody administration. Apart from this immunological effect, rituximab is thought to act as a direct modulator of podocyte function. Through binding to sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) on podocytes, rituximab exerts a protective effect on the podocyte actin cytoskeleton , 36.2). Five-year allograft survival was 100% in responding compared to 34.3% in the non-responding patients.The beneficial effect of rituximab in recurrent FSGS was first described by Pescovitz . RecurreOfatumumab is a human anti-CD20 monoclonal antibody that binds to an epitope of CD20 distinct from the rituximab binding site. It induces profound B-cell depletion for up to 6 to 10 months after therapy. With ofatumumab, complement dependent cytotoxicity (CDC) appears to be greater and occurs even at a lower density on the cell surface than with rituximab. The greater binding avidity to CD20 is thought to be responsible for improved CDC .Basu et al. observed a dramatic improvement in renal function in a patient with rituximab-resistant FSGS following therapy of chronic lymphocytic leukemia with ofatumumab. Ofatumumab was shown to be effective in four more patients with rituximab-resistant nephrotic syndrome and led to a decline in the protein-creatinine ratio and a rise in estimated glomerular filtration rate at 6 months .Wang et al.  and Bernin vitro data from Yu et al. (Abatacept (cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein CTLA4-Ig) is an inhibitor of the T-cell costimulatory molecule B7-1 (CD80). B7-1 is not expressed in normal human kidney podocytes but is found in biopsy specimen from patients with recurrent FSGS. Clinical and u et al.  indicateThese promising results were refuted by the study of Delville et al. who prospectively administered abatacept or belatacept (a B7-1 blocker with a 2-fold higher affinity for B7-1) to nine consecutive patients with recurrent FSGS after transplant. Neither did abatacept/belatacept induce proteinuria remission, nor did the authors detect podocyte B7-1 expression in the biopsies performed at the time of FSGS recurrence . AccordiIn patients who have lost their first allograft due to recurrent FSGS, kidney retransplantation is associated with recurrence rates of 86%  before and after renal transplantation will ameliorate the course of FSGS, Ohta et al. were the first to describe preoperative plasmapheresis as a preconditioning regimen for transplant in FSGS patients . Prophyl2 per dose), and perioperative plasma exchange sessions were started between day 7 before transplant and postoperative day 2. Plasmapheresis was then continued for a total of 3 to 10 sessions. The authors concluded that there was no difference in recurrence rates between patients who received a preemptive therapy and those who did not receive a pretreatment . The major limitation of this study is that only patients with at least two risk factors for disease recurrence received preemptive treatment. The observed recurrence rates therefore need to be interpreted with caution. Nevertheless, the study stands out as one of the largest prospective trials with a highly selected study cohort of truly idiopathic FSGS patients including 36% of patients receiving a kidney retransplant  and involving both deceased and living donor kidney transplants.In a recent prospective observational cohort study, Alasfar et al. assessed the efficacy of perioperative rituximab and therapeutic plasma exchange for preventing post-transplant FSGS recurrence . Based oIn addition to plasma exchange, it has been postulated that LDL (low-density lipoprotein) apheresis eliminates humoral factors. Accordingly, Sannomiya et al. applied pretransplant LDL apheresis in 5 patients with FSGS to prevent disease recurrence . The pre2 during week 1, followed by 1,150 mg/m2 weekly for 5 weeks. Four months later, the boy received a deceased donor renal transplant from a 2-year old DCD (donation after circulatory death) donor (category III). Moreover, to prevent FSGS recurrence, daily plasma exchange was initiated immediately after transplant. Despite excellent allograft function with normal serum creatinine levels, severe proteinuria indicated FSGS recurrence within days after the transplant. A series of 15 plasma exchanges and administration of ofatumumab  on day 33 post-transplant reduced proteinuria to subnephrotic levels. In response to an increase in B lymphocytes with a concomitant rise in urinary protein levels at 6 months after transplantation, ofatumumab was administered at a dose of 1,150 mg/m2 every 6 months. This reduced proteinuria to subnephrotic levels. At 17 months after kidney retransplantation, the patient has excellent graft function with a serum creatinine of 0.4 mg/dl. We feel that ofatumumab represents a novel therapeutic option not only in the treatment of manifest recurrent FSGS but also as a preemptive therapy for FSGS recurrence after kidney (re)transplantation.Building on recent case reports about the successful use of ofatumumab in the treatment of post-transplant FSGS recurrence, our group hypothesized that pretreatment of the recipient with ofatumumab before a second kidney transplant could prevent FSGS recurrence through induction of profound B-cell depletion prior to the transplant . FollowiKK-W wrote the manuscript. SW and SS critically revised the manuscript. SS was responsible for the overall preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Assessment of fluid responsiveness is problematic in intensive care unit (ICU) patients, in particular for those undergoing modes of partial support, such as pressure support ventilation (PSV). We propose a new test, based on application of a ventilator-generated sigh, to predict fluid responsiveness in ICU patients undergoing PSV.This was a prospective bi-centric interventional study conducted in two general ICUs. In 40 critically ill patients with a stable ventilatory PSV pattern and requiring volume expansion (VE), we assessed the variations in arterial systolic pressure (SAP), pulse pressure (PP) and stroke volume index (SVI) consequent to random application of 4-s sighs at three different inspiratory pressures. A radial arterial signal was directed to the MOSTCARE™ pulse contour hemodynamic monitoring system for hemodynamic measurements. Data obtained during sigh tests were recorded beat by beat, while all the hemodynamic parameters were averaged over 30 s for the remaining period of the study protocol. VE consisted of 500 mL of crystalloids over 10 min. A patient was considered a responder if a VE-induced increase in cardiac index (CI) ≥ 15% was observed.p < 0.0001, p = 0.0004 and p < 0.0001, respectively). The AUC of the slope of SAP  and specificity 95.8% (78.8–99.9%) was significantly greater than the AUC for PP (0.91) and SVI (0.83) . The SAP slope best threshold value of the ROC curve was − 4.4° from baseline. The only parameter found to be independently associated with fluid responsiveness among those included in the logistic regression was the slope for SAP  0.10–0.70)). The effects produced by the sigh at 35 cmH20 (Sigh35) are significantly different between responders and non-responders. For a 35% reduction in PP from baseline, the AUC was 0.91 (CI95 0.82–0.99), with sensitivity 75.0% and specificity 91.6%.The slopes for SAP, SVI and PP of were all significantly different between responders and non-responders  contains supplementary material, which is available to authorized users. T), i.e., > 8 mL/kg body weight and non-severely impaired lung compliance ), while the reduction in SVI was not (p = 0.38). After Sigh35, reductions in SAP, SVI and PP were all significantly different between responders and non-responders . The AUCs of the ROC obtained after Sigh25 were not significantly different for any of the variables analyzed. The AUC for PP after Sigh35  was significantly greater than the AUCs for SAP . The PP nadir best threshold value of the ROC curve was − 35% from baseline.After Sighp < 0.0001 for all comparisons)]. The AUC of the slope for SAP  was significantly greater than the AUCs for PP . The SAP slope best threshold value of the ROC curve was − 4.4° from baseline  vs. − 1.5°(− 3.0/− 0.20); − 3.3°(− 3.8/− 2.2) vs. − 1.5°(− 2.5/− 0.9) and 7.6° (− 9.3/− 6.4) vs. − 3.7°(− 5.1/− 2.1), respectively; p = 0.009; odds ratio 0.27 (CI95 0.10–0.70)].The only parameter found to be independently associated with fluid responsiveness among those included in the logistic regression was the slope for SAP [(2O and of (2) the lowest PP valued obtained after one sigh at and 35 cmH2O reliably predict fluid responsiveness in a selected ICU population undergoing PSV.Our study shows that the functional hemodynamic assessment of (1) the lowest SAP values obtained after the consecutive application of sighs at 15, 25 and 35 cmHThe rate of the dynamic indexes of fluid responsiveness being used in ICU patients to assess fluid responsiveness is rather small . ReliablT magnitude [34 [11 [For the increasing number of ICU patients retaining, to some extent, a spontaneous breathing activity , 31, 32,agnitude , increastude [34  and caus [34 [11 . In factT by adding a sigh to predict fluid responsiveness in ICU patients with residual spontaneous breathing activity and undergoing PSV. In fact, a similar approach has been already successfully used in patients undergoing forms of controlled ventilation to enhance the reliability of stroke volume variation and PP variation. Freitas et al. increased the VT from 6 to mL to 8 mL/kg body weight for 5 min [T [T-challenge”, increasing the VT from 6 up to 8 mL/kg [This is the first study demonstrating the feasibility of applying a transient increase in Vor 5 min ; Reuter 5 min [T  and, mor 8 mL/kg . Finally 8 mL/kg –42.T and in intrathoracic pressure, which reduces the stroke volume by increasing RV afterload and, to some extent, by reducing RV preload. The RV is extremely sensitive to an acute increase in afterload and is unable to maintain the systolic function in this condition and reduces RV stroke volume through a beat-to-beat adaptive response [In a similar manner, the application of a sigh is a test aimed at revealing fluid responsiveness by inducing increases in Vresponse . The com2O for 30 s has been recently successfully applied in patients undergoing general anesthesia, to predict fluid responsiveness [After a few heartbeats, the reduced RV stroke volume affects left ventricle preload and SV, and, consequently, SAP and PP. The PP nadir occurred within the first 10 heartbeats after sigh application in 80% of our patients , 4. For siveness .15 on PP and SVI were negligible, while those induced by Sigh25, though statistically significant, were small and overall were insufficient for clinical use . The variable transmission of the applied inspiratory pressure may explain the lack of reliability of Sigh35 in some patients. Lansdorp et al. demonstrated that the amount of Paw distributed to the pericardium and vena cava is about one third of the overall applied pressure, with ± 17% and ± 11% variability for pericardium and vena cava, respectively [35 identifies those patients who should not receive fluids to correct hemodynamic instability, i.e., displaying a drop in PP ≤ 35% during Sigh35, on the other hand, it fails to recognize some responders, which makes an adjunctive form of functional hemodynamic assessment such as the PLR advisable before administering fluids.The hemodynamic variations induced by Sighse Table . After Sectively . If, on 20, demonstrating moderate reliability of the nadir SAP analysis in predicting fluid responsiveness (AUC 0.77) [The analysis of the slope for SAP variations after sigh application is a post-hoc mathematical elaboration, which predicts fluid responsiveness. The evaluation only of the nadir values avoids the inclusion of early inspiratory increases in the stroke volume, which are more prominent in patients with hypervolemia and congestive heart failure and not related to volume responsiveness , 46. TheUC 0.77) . Though 2O, though for a few seconds. In 13 ICU patients with early ARDS, Patroniti et al. increased Paw once a minute during PSV for 3–5 s at a minimum of 35 cm H2O and observed an improvement in oxygenation without adverse effects [Some may argue about the safety of raising Paw to 35 cmH effects . As confOur study has some limitations. First of all, our criteria for patient selection are very strict, as it is commonly the case for “proof of concept” studies, which often include relatively few and highly selected patients in order to control potential confounding factors, limiting the external validity of the study. The inclusion and exclusion criteria have been specifically requested by the local ethical committees to guarantee the safety of the study protocol application. Unfortunately, this led to a selection of less severely ill ICU patients. Second, the reliability of MOSTCARE™ is still debated. Despite the positive results of a large multicenter study performing a head-to-head comparison with transthoracic echocardiography along five consecutive heartbeats , the abiFor all these reasons, the promising results of this pilot investigation need to be confirmed in studies with less selective inclusion criteria.The slope of the line defined by SAP and airway pressure after the application of three successive sighs and the nadir of PP after a sigh with 35 mmHg can predict fluid responsiveness in patients mechanically ventilated with spontaneous breathing. Assessments of applicability and effectiveness in larger patient populations and comparisons with other functional tests of fluid responsiveness are deemed necessary to ascertain the clinical importance of these findings.Additional file 1:Figures S1 and S2. Slope calculation of pulse pressure (PP) and stroke volume index (SVI) in responders and non-responders. Red triangles and green circles represent the mean values of PP the two populations  at each step of the protocol. Purple triangles and yellow circles represent the mean values of SVI the two populations  at each step of the protocol. For slope computations, please refer to Table Additional file 2:Table S1. Hemodynamic baseline values at each step of the protocol. (DOCX 15 kb)


Kidneys are organs having a biological clock, and it is well known that the disruption of the circadian rhythm increases the risk of chronic kidney disease (CKD), including the decline of renal and proteinuria. Because shift work causes circadian disruption, it can directly or indirectly affect the incidence of chronic kidney disease. Therefore, the purpose of this study was to investigate the association between shift work and chronic kidney disease using a Korean representative survey dataset.2. The cross-tabulation analysis and multivariate logistic regression analysis were performed to confirm the association between shift work and chronic kidney disease stratified by gender.This study was comprised of 3504 manual labor workers over 20 years of age from data from the fifth and sixth Korea National Health and Nutrition Examination Survey (2011–2014). The work schedules were classified into two types: day work and shift work. The estimated glomerular filtration rate, which is the ideal marker of renal function, was estimated according to the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, and chronic kidney disease was defined as urinary albumin to a creatinine ratio equal to or high than 30 mg/g and/or estimated glomerular filtration rate lower than 60 mL/min/1.73 mThe risk of CKD showed a significant increase  in the female worker group. The same results were obtained after all confounding variables were adjusted . However, the results of the male worker group were not significant.In this study using nationally representative surveys, we found that the risk of CKD was higher female workers and shift work. Future prospective cohort studies will be needed to clarify the causal relationship between shift work and CKD. Since the beginning of the second industrial revolution, people have been able to illuminate the night as bright as the day from the advent of electricity and technology. This phenomenon led to an environment in which employees were allowed to work at night, and the systematization and efficiency of the work has increased . In addiAlthough there are some differences in literature, shift work is defined as all types of work other than those at the regular working time 7 a.m.- 6 p.m.), according to the National Institute for Occupational Safety and Health (NIOSH) . In indu p.m., acAlmost all organisms, including humans, have a biological clock . NumerouChronic kidney disease (CKD) is on the rise worldwide, and is an important public health issue because it increases patient mortality and burdens those affected with medical expenses . The kidSome previous studies suggested a relationship between shift work and CKD. However, these studies were conducted on workers at specific workplaces, and there are few large-scale population-based epidemiological studies. Therefore, this study was conducted to analyze the association between shift work and CKD using the nationwide population-based survey, the Korean National Health and Nutrition Examination Survey (KNHANES).n = 7257), armed forces (n = 13), and skilled agricultural, forestry and fishery workers (n = 1421). Among these, a total of 3504 participants were finally selected as the subjects of this study after excluding the pregnant workers (n = 4), and female workers during their menstrual cycle (n = 76), since their urine albuminuria levels could be measured incorrectly, and those with missing data (n = 612) in sequence  and the third year (2012) data of the fifth Korean National Health and Nutrients Examination Survey (KNHANES) (2010–2012), and the first (2013) and the second year (2014) data of the sixth KNHANES (2013–2015) were used in this study. KNHANES is a national cross-sectional survey collected annually by the governmental organization, Korea Centers for Disease Control and Prevention (KCDC), and is provided as secondary data designed according to multistage stratified and cluster sampling. The data, which was used to assess the health and nutritional status of the Korean population, included variables such as age, gender, serum and urinary creatinine levels, and urinary albumin levels required to identify the association between shift work and CKD. It also included several demographic variables and clinical characteristics known to affect renal function and proteinuria. The occupations of the subjects in KNHANES were classified into ten occupational categories according to the KSCO standard, which was based on the International Standard Classification of Occupations (ISCO-08) of International Labor Organization (ILO), and which presented the criteria of classification for job related study by classifying and collecting job information consistently through statistical survey or census [11 and thThe National Institute for Occupational Safety and Health (NIOSH) defined shift work as all types of work conditions except for regular day work hours [7 a.m. to 6 p.m.] . In this2  and/or urinary albumin to creatinine ratio (UACR) 30 mg/g or more according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. [α x max-1.209 × 0.993age × 1.018 [if female] × 1.159 (if black), and the abbreviation and unit of variables included in the equation are eGFR , Scr , age (years), κ = 0.7  or 0.9 , α = − 0.329  or − 0.411 , min = the minimum of Scr/κ or 1, and max = the maximum of Scr/κ or 1. Since KNHANES only targets the Korean population, variables related to the race were not considered in this equation. The urinary albumin to creatinine ratio  was obtained by dividing the urinary albumin concentration by the urinary creatinine concentration. Blood sampling was performed in subjects that fasted for at least 8 h to obtain serum creatinine levels, and each sample was measured by a Jaffe rate-blanked and compensated method  in a professional blood test laboratory. Urinary albumin levels and urinary creatinine levels were collected from random urine in the first urine of the morning and measured by a turbidimetric assay  and Jaffe rate-blanked and compensated method , respectively.Since the glomerular filtration rate (GFR) is known as the ideal marker that best reflects renal function, it was set as an indicator of renal function levels in this study , 22. CKDriteria. . GFR was2). Then, BMI was categorized as underweight if lower than 18.5 kg/m2, normal if between 18.5 kg/m2 and 24.99 kg/m2, overweight if between 25 kg/m2 and 29.99 kg/m2, and obese if higher than 30 kg/m2 according to the obesity criteria of Centers for Disease Control and Prevention (CDC) [Factors known to affect CKD from previous studies were included as potential covariates in the study , 25. Demon (CDC) . Blood pon (CDC) . Blood st-tests were performed to compare means of continuous variables. Subsequently, both male and female subjects were classified into day worker group and shift worker group respectively to perform Student’s t-tests for continuous variables and chi-squared tests for categorical variables to confirm differences in general characteristics by work schedule. To determine if there was a significant association between CKD and various variables including work schedule, complex samples chi-squared tests were performed, and odds ratios (OR) were calculated by complex samples logistic regression analysis. To reflect the impact of each variable, age, BMI, SBP, total cholesterol, fasting glucose, diabetes mellitus and hypertension were adjusted in model 1, and work hours per week, household income, education level, smoking, and alcohol intake were additionally adjusted in model 2. Statistical significance was defined as p < 0.05 and SPSS version 18.0  was used for the statistical analysis.A weighted complex sample analysis was used for data analysis of 3504 subjects taking account of the characteristics of the data used in the study. After the data were stratified by gender, chi-square tests were performed to examine the distributions of categorical variables, and Student’s The detailed demographic and clinical characteristics of the subjects are presented in Tables In terms of work schedule, the proportion of regular day workers was higher than that of shift workers in both males and females, and the proportion of day workers in females was significantly higher than that in males. BMI was not significantly different between males and females, and there was no significant gender difference in the incidence of diabetes mellitus and hypertension. SBP, DBP, total cholesterol, and fasting glucose were significantly higher in males, while CKD prevalence was significantly higher in females Table . Age, edThe subjects were classified into two groups (the non-CKD and the CKD) according to the 2012 KDIGO guideline for CKD evaluation, and the prevalence of CKD according to each factor was investigated. The prevalence of CKD tended to increase with age in males, which tended to be similar in females except for females in their 20s. As to socioeconomic factors, the prevalence of CKD tended to be significantly increased with lower levels of education in both sexes. In addition, the prevalence of CKD tended to increase as the household income level decreased in males, and it showed a similar tendency in females, except in high-levels of a household level. For work conditions, the prevalence of CKD was significantly higher in males who worked less than 48 h per week than in males who have worked more than 48 h per week, but there was no significant difference in females. There was no significant difference in the prevalence between shift workers and day workers in males, whereas the prevalence was significantly higher in shift workers than in day workers in females. For clinical characteristics, the prevalence of CKD was significantly higher in subjects with diabetes mellitus and hypertension than in subjects without the diseases regardless of gender. There were no statistically significant differences in the prevalence of CKD according to smoking status, alcohol intake and BMI in both sexes Table .Table 3PTable The goal of this study was to investigate the association between CKD and shift work in the growing workforce, and the results showed gender disparities in the association. Specifically, shift work was associated with CKD in the female worker group, whereas no significant association was found between shift work and CKD in the male worker group.There is some evidence suggesting that shift work is associated with CKD. Boogaard et al. studied the relationship between albumin excretion and shift work . The subThe core pathophysiological mechanism among theoretical backgrounds that explain this association is the disruption of the circadian rhythm. Circadian rhythm, which is coordinated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is one of the fundamental characteristics of most organisms , and it The kidney is an organ with a peripheral circadian clock; hence most of the renal physiologic processes, such as the regulation of the renin-angiotensin-aldosterone system (RAAS), follow the circadian rhythm. RAAS is well known to regulate the balance of fluids and electrolytes, and thus blood pressure in the body . The cirMeanwhile, shift work is known to induce oxidative stress . ReactivThe link between shift work and CKD was partly explained by previous studies on sleep disturbance. McMullan et al. conducted an 11-year follow-up study with 4238 female participants, which showed that shorter sleep duration was independently associated with decreased renal function. . SimilarAccording to the adjusted odds ratio for CKD, a significant relationship was found between shift work and CKD in the female worker, but not in the male worker group. The theoretical background of this gender disparity is not understood, but it can be explained by some hypotheses. In general, the load of domestic work, such as childcare and household chores is heavier in women than in men. This workload results in stress and decreased rest time, which may exert a synergistic effect on the development of CKD . FurtherMoreover, shift work is known to be associated with low socioeconomic status and lifestyle, as evidenced by dietary patterns and smoking , 44. SmoThe global mean prevalence of CKD was found to be 13.4% in a meta-analysis of 42 CKD-related literature by Hill et al. . On the The blood pressure, fasting glucose, and total cholesterol were significantly lower in the shift group than in the normal group. There are two possible explanations, however, in regards to these results. First, on account of its statistic nature that the larger the study population, the smaller the standard deviation, a relatively small difference in the level of continuous variables can be interpreted as a significant difference in the level of these variables in a large population size. In this study, the number of the weighted study population is 6,469,033, which is relatively a large sample size. Thus, although the differences in the mean value of the blood pressure, fasting glucose, and total cholesterol level were less than 1 between day work group and shift work group, the results showed statistically significant differences between the two groups. Since the indices are very sensitive, the difference of 1 or less in these indices is not considered clinically significant. Therefore, although the values of these indices were significantly different statistically, they were not considered clinically different. Second, it is difficult to explain clearly how the adverse outcome between the CKD prevalence and the blood pressure occurred. However, because the blood pressure is affected by several factors  besides overactivation of RAAS by circadian rhythm disruption, hypertension can be caused by various factors. Moreover, the most common type of hypertension is primary hypertension, which comprises 95% of hypertension and has no identifiable cause. If a patient with hypertension took an antihypertensive medication a few hours before measuring the blood pressure, his or her blood pressure could be lowered, and this might alter the mean value. We believe that there is a limit to the nature of the survey items to see if there is a clinically meaningful difference in blood pressure between the two groups after adjusting all these factors.Some limitations hampered determination of the relatedness of shift work and CKD. First, the causal relationship between shift work and CKD was unclear because of the inborn limitation of the cross-sectional study. Second, because the demographic factors were collected based on the self-reported report by subjects, recall bias might have occurred. Third, the renal functional abnormalities and kidney damage should last more than 3 months in order to define CKD . Since KNevertheless, this study had several strengths that overcome these limitations. First, using the nationwide survey that represents the Korean population, we found an association between shift work and CKD. In addition, when estimating the renal function, a more accurate value of GFR could be obtained by applying the CKD-EPI creatinine equation, which is known to be more accurate than the MDRD equation. Finally, the diagnostic criteria for CKD were revised to define CKD based on not only the reduction of GFR, but also kidney damage, such as albuminuria, since 2012. . This stBecause CKD increases mortality and has social and economic burdens, effort should be made at the public health level to lower the prevalence of CKD. This cross-sectional study using the nationally representative survey found that the risk of CKD was significantly higher in female shift workers than in female day workers. A well-designed cohort study should be undertaken to identify the causal relationship between shift work and CKD and to contribute to establishing a policy to improve the health and welfare of shift workers.


The healthcare-related functions of wearable devices are very useful for continuous monitoring of biological information. Wearable devices equipped with communication function can be used for additional healthcare services. Among the wearable devices, the wristband type is most suitable for acquiring biological signals, and the wear preference of the user is high, so it is highly likely to be used more in the future. In this paper, the health-related functions of wristband were investigated and the technical limitations and prospects were also reviewed. Most current wristband-type devices are equipped with the combination of accelerometer, optical sensor, and electrodes for their health functions, and continuously measured data are expanding the possibility of discovering new medical meanings. The blood pressure measurement function without using cuff is the most useful and expected function among the health-related functions expected to be mounted on the wrist wearable device, in spite of its technical limits and difficulties. It is a common human desire to live long and healthy regardless of age or area. Recently, as the development of genetic analysis technology has enabled us to recognize and prevent the risk of genetic diseases in advance, this hope has become more realistic. With the development of continuous medical technology and new drug development, diseases that were previously regarded as incurable diseases can now be seen as chronic diseases that can be managed through continuous management. In addition, as the ongoing research and achievement of stem cell technology continues, there is growing hope that human tissue can be regenerated, and thus the possibility of extending the life span of human beings, which is considered to be about the limit of around 100 years, is getting stronger.So, if we cope with these diseases properly, can anyone live long and healthy? The answer should be considered in two respects. If the best unlimited healthcare services are offered to an individual, the chances of a long and healthy life are high, but considering the high costs involved, it is difficult to imagine that the social medical system will be established where the best medical services are provided to every individual. In other words, if it is not possible to provide unlimited medical services to all members of society, it is imperative to have a sustainable healthcare system that will keep the population as healthy as possible at a minimum cost, in parallel with the development of effective medical technology for treating the disease. Especially as aging has accelerated, the increase in the number of chronic illnesses and consequent increase in the cost of disease management, the increase in waiting time due to lack of medical personnel, and the decrease in actual hours of treatment further strengthen the demand for a new medical system.In this respect, according to a previous study , health Environmental factors can be controlled and quantitatively measured and monitored by national and governmental regulations and efforts; however, the individual's lifestyle and behavior will need to be reviewed to determine what to measure and monitor. In order to measure health-related habits in daily life rather than patients in a hospital, a wearable device capable of measuring a biosignal attached to an individual's body is required. Recently, wrist-type smart devices have been widely used, and the healthcare-related technologies that utilize them are increasing. Therefore, not only wellness services that help individuals to manage their own health but also services for remotely managing chronic diseases using measured data are being tried by governments and insurance companies. An example is the use of a wristband to monitor exercise and heart rate after coaching appropriate levels of exercise in patients treated with heart failure, thereby preventing readmission and reducing medical costs accordingly.In this review, healthcare-related technologies applied to personal wearable devices have been examined which are widely used in recent years, and the sensing technology and related technical issues required for health management in the future are discussed.In this review, health-related functions included in wearable devices are surveyed and summarized. Technical problems related to the cuffless blood pressure measurement function which is not mounted on wrist wearable devices up to now are discussed.First, the functions of patient monitoring system in hospitals and biosignal measurement items that can be measured in daily life were compared to predict the technology status and development direction of wearable devices. It was also examined that which of the various wearable devices are suitable for biosignal measurement, and the measurable functions were listed accordingly. The biomedical measurement items using sensors included in a wristband, which is a typical wearable device, are summarized.Secondly, an overview diagram of blood pressure measurement methods has been made to review the possibility and current status of cuffless blood pressure measurement techniques, and the technical limitations of the pulse wave velocity (PWV) method, which has been widely tried, were investigated.2, respiration rate, and body temperature are now all possible with small-size handheld devices or wearable devices as shown in the figure. However, the miniaturization of blood pressure measurement function is still ongoing, which will be discussed later.The current development of medical devices shows that it is a big trend to monitor and monitor at any time in home and everyday life, not in a specific place of hospital. In accordance with this trend, medical technology is moving from the field of doctors and specialists to the general public, from the hospital to the home, and also to the mobile environment, and wearable devices and related services will play an increasingly important role. For example, biomedical measurements such as electrocardiograms and oxygen saturation that have been measured using equipment in hospitals can now be easily measured by wearable devices that are small and inexpensive. As a result, new healthcare services using the measurement data can also be introduced. In In addition to technological advances, expectations and requirements of consumers who purchase and use wearable devices are also meeting new remote healthcare services. According to a recent report , the widFrom Fitbit's product portfolio , which iThe wristband-type devices currently available are almost all combinations of the above three sensors and functions. In particular, in the case of the optical sensor for measuring the heart rate –29, the Blood pressure is one of the fundamental and important vital signs  and is closely related to arterial health, which is considered to be an important indicator of health. Therefore, blood pressure is a kind of health indicator that needs to be managed with great importance. In particular, in the case of hypertension, the blood pressure trend for 24 hours is more important than the blood pressure value measured from time to time. Therefore, it is necessary to continuously monitor and manage it. Because hypertension is the most common cause of death among developed and developing countries , the neeThe methods of blood pressure measurement are classified and summarized in There also have been numerous attempts to develop ABPM devices; however, personal blood pressure monitors without cuffs have not yet been proven to be accurate. Although the BPro device  showed good accuracy in previous studies –38, the The most popular method among the various methods shown in st derivative, etc.) of electrocardiogram (ECG), photoplethysmogram (PPG) [The PWV can be calculated by dividing the artery length with the pulse transit time (PTT) or pulse arrival time (PAT), which can be derived combining the feature points  –46, phonam (PPG) , seismocam (PPG) , and balam (PPG) , 50. Somam (PPG) .  Figuream (PPG) .Because the elasticity of an artery changes not only by blood pressure but also by other factors such as the environment, temperature, and emotion, it is difficult to estimate the accurate blood pressure when the arterial characteristics change with time. In addition, when the pulse arrival time including PEP is used for PWV calculation, the PEP fluctuation is expected to reduce the accuracy of the blood pressure estimation –66.Calibration using a conventional sphygmomanometer with cuff is always necessary since the PWV method does not measure the blood pressure values directly.Since systolic and diastolic blood pressures are independent of each other, additional information other than the PWV measurement is needed to obtain the two blood pressure values . Therefore, accurate estimation of systolic and diastolic blood pressure requires efforts to find new and effective features besides PWV, as shown in a recent work .The difficulties or problems of conventional blood pressure estimation techniques using PWV can be summarized as follows:In conclusion, the cuffless blood pressure estimation technology using PWV for wearable devices should be designed and developed to overcome such shortcomings.An increase in the cost of healthcare due to aging necessitates the establishment of a more effective healthcare system. The healthcare function of the wearable device can be very useful for efficient preventive/postmanagement services in that the user's body information can be monitored, and communication with healthcare professionals is always possible. Among various wearable devices, the wristband is most suitable for acquiring biomedical signals, so it is highly likely to be useful in a new medical system. The sensors of wristband for health-related functions are mainly composed of accelerometer, optical sensor, and electrodes. Using the combinations of these sensors, wristband measures most functions of the patient monitoring system in hospital except blood pressure measurement.Therefore, the biggest leap in health-related functions of wristband-type devices is expected to be blood pressure measurement technology without cuff, and it is expected to have a ripple effect as the technical difficulty is very high. However, even if a new blood pressure sensing technology is not developed early, the 24-hour continuous biosignal measurement function of the wearable device, which has been developed so far, provides biosignals in daily life in various environments. Unlike patient data measured in hospitals, it will provide new medical implications and possibilities for healthcare services, and these efforts are expected to continue.


Congestive heart failure (CHF) is associated with high mortality and a heavy financial and healthcare burden in the dialysis population. Determining which dialysis modality is associated with a higher risk of developing CHF might facilitate clinical decision making and surveillance programs in the dialysis population.Using the Taiwan National Health Insurance Database, we recruited all incident dialysis patients during the period from January 1, 1998 to December 31, 2010. The propensity score matching method was applied to establish the matched hemodialysis (HD) and peritoneal dialysis (PD) cohort. Incidence rates and cumulative incidence rates of CHF-related hospitalization were first compared for the HD and PD patients. Multivariable subdistribution hazards models were then constructed to control for potential confounders.Among a total of 65,899 enrolled dialysis patients, 4,754 matched pairs of HD and PD patients were identified. The incidence rates of CHF in the matched HD and PD patients were 25.98 and 19.71 per 1000 patient-years, respectively (P = 0.001). The cumulative incidence rate of CHF was also higher in the matched HD patients (0.12–0.21)] than in the corresponding PD patients (P<0.0001). HD was consistently associated with an increased subdistribution hazard ratio (HR) of CHF compared with PD in the matched cohort . Similar phenomenons were observed in either the subgroup analysis stratified by selected confounders or in the HD and PD group without matching.HD is associated with a higher risk of developing CHF-related hospitalization than PD. The surveillance program for CHF should differ in patients receiving different dialysis modalities. Pa. Pa19]. In order to balance the distribution of potential confounders and to minimize the potential indication bias between HD and PD patients, a 1:1 matching of incident HD and PD patients from the national dialysis cohort was performed according to their corresponding propensity scores. The propensity score for a PD prescription was estimated using a logistic regression model , 21, whilog) versus log of survival time graph, according to each of the covariates. A forest plot was used to present the hazard ratios of the subgroup population stratified using the selected potential confounders. Tests for interaction between dialysis modalities and selected covariates were assessed in the Cox regression models. All statistical analyses were performed with SAS version 9.4 . Two-sided p values < 0.05 were defined as statistically significant in this study.The continuous variables were summarized as means and standard deviations, and the categorical variables were listed as the number of cases and percentages. The comparison of continuous between-group variables was done through the use of a Student’s t-test, and the categorical variables were assessed with either a Chi-square test or a Fisher’s exact test. The estimation of incidence rate was calculated under the Poisson assumption. After matching based on the propensity score, the standardized differences were used to assess the differences in the baseline covariates between the study groups. Because of the high mortality rate of dialysis patients and a long follow-up period adopted in our study, the estimation of cumulative incidence rates was based on the cumulative incidence competing risk analysis, and the difference between the HD and PD groups was compared by using the modified Gray’s test , 24. FurWe first identified 65,899 incident dialysis patients from 1998 to 2010, of which 61,126 patients received HD, and 4,773 patients received PD . Among tp value < 0.0001)  .Pinteraction<0.0001). Age-specific analyses showed that HD was associated with significantly higher HR of CHF in patients aged ≥ 60 years (adjusted HR: 2.04 [95% CI: 1.50–2.79]) as compared to those aged under 60 years (adjusted HR: 1.22 [95% CI: 1.01–1.49]).The results concerning the risk of CHF between different dialysis modalities based on the multivariate subdistribution hazard models are also presented in In this retrospective cohort study of dialysis patients, we compared the incidence of newly-diagnosed CHF requiring hospitalization after the initiation of maintenance dialysis therapy between matched pairs of patients receiving HD and PD. Our study results suggested that patients receiving HD had a higher risk of developing CHF than those receiving PD after adjustment for potential confounders and after taking the competing risk event  into consideration. The elevated risk of CHF associated with HD was even more evident in elderly patients aged ≥ 60 years as compared to younger patients, but it was quite homogeneous in patients characterized by various comorbidities and medication use. Therefore, our study results indicated that HD patients are at a higher risk of developing CHF and warrant more intensive surveillance programs and management for the prevention of CHF among dialysis patients. The K/DOQI guideline has suggested that all dialysis patients should receive echocardiogram study at a three-year interval, after the initiation of dialysis therapy . So a shde novo cardiovascular disease rather than CHF. This would further bias the estimation of propensity scores in logistic regression models and the HRs in Cox models if the primary outcome were to be changed to CHF. Therefore, we believe that the estimations from our study might be closer to the true risk of CHF induced by different dialysis modalities.Several studies have been conducted to evaluate the risk of CHF related to both HD and PD, but the findings from these previous studies have been inconsistent. Foley et al. reported that dialysis modality is not associated with increased risk of CHF , which wp-cresol, which are risk factors for development of CHF, are lower in patients receiving PD than in those receiving HD [Several explanations might support the premise that HD is associated with higher CHF risk than PD. First, accumulated evidence suggests that HD can induce repeated myocardial ischemia and stunning, which might ultimately progress over time into fixed systolic dysfunction with distinct systemic hemodynamic consequences, including elevated cardiac troponin T levels, intra-dialytic hypotension, fatal arrhythmia, and even sudden cardiac death , 28. Oneiving HD , 31. Thiiving HD .Practitioners need to be aware of various degrees of risk for developing CHF with known vascular comorbidity. Nevertheless, given the unfavorable impact of HD on the risk of CHF presented in this study, different time intervals for surveillance programs should be suggested to patients receiving different dialysis modalities. In addition, receipt of PD therapy for ESRD patients with higher risk of developing CHF should be considered, including those comorbid with diabetes , coronary artery disease (CAD) , hyperlipidemia , and chronic obstructive pulmonary disease . Furthermore, PD therapy is characterized with gentle removal of water and solutes, a lack of neurohumoral activation and stable hemodynamic status during treatment, as well as better removal of cytokine/chemokine, which would be beneficial for the cardiovascular system .Dialysis patients are characterized with inadequate capacity of free water excretion and they are usually comorbid with fluid overload if they are not compliant with suggestions for fluid restriction or dialysis protocols. Although fluid overload is one of the risk factors for CHF, we would suggest that diagnosis of fluid overload is not equivalent to that of CHF, including mild CHF. The diagnostic criteria for heart failure suggested by either the NYHA/ACC/AHA should be mainly based on clinical symptoms related to heart failure . The incOur study has several limitations. First, NHIRD does not collect all detailed information of potential risk factors for CHF, such as residual renal function, anthropometric parameters, nutritional status, dialysis adequacy, inflammatory markers, or cardiac function. Therefore, we were unable to control for these risk factors for CHF in the analyses. However, we first applied the propensity score matching method to minimize potential indication bias and to balance the potential confounders at baseline between the HD and PD patients. The Cox regression models were then constructed to adjust for these baseline confounders to reduce the residual confounding as much as possible. In addition, the quality control program for dialysis patients in the NHI system ensures that most dialysis patients maintain satisfactory levels of nutrition and dialysis adequacy. Since CAD, AMI, valvular heart disease, and cardioprotective medications can directly modify cardiac function, they could serve as surrogate markers of cardiac function and, at least partially adjust the effect of cardiac function in our Cox models. Nevertheless, we should highlight that the residual confounding caused by these unmeasured variables could still be present even though the two-step approach was employed in the current study. Second, the application of propensity score matching in the analysis may have helped improve the internal validity of our study results, but this might have been at the cost of compromising external validity. Less than 10% of the ESRD patients were selected in the final analysis after matching. To investigate whether our study results can be generalized to the entire dialysis population, we constructed another multivariate Cox model based on the unmatched HD and PD cohorts , and theIn conclusion, our study demonstrated an increased risk of newly-diagnosed CHF requiring hospitalization in HD patients as compared to their propensity score-matched pairs of PD patients. Since a certain number of dialysis patients present risk factors for CHF, strategies for dialysis modality selection and intervals for active surveillance programs should be individualized for patients with different degrees of risk for CHF.S1 Table(DOCX)Click here for additional data file.


To determine the prevalence of hypertension treatment and control among hypertensive patients in the Cuban municipalities of Cardenas and Santiago and to explore the main associated predictors.Cross-sectional study, with multistage cluster sampling, conducted between February 2012 and January 2013 in two Cuban municipalities. We interviewed and measured blood pressure in 1333 hypertensive patients aged 18 years or older. Hypertension control was defined as blood pressure lower than 140/90 mmHg.The mean age ± standard deviation (SD) of participants was 59.8 ± 14 years, the mean systolic and diastolic blood pressure ± SD was 130.0 ± 14.4 and 83.1 ± 9.0 mmHg respectively. The majority of patients  were on pharmacological treatment, 49% with a combination of 2 or more classes of drugs. Among diagnosed hypertensive patients 58% (95%CI 55–61) had controlled hypertension. There was no association between hypertension control and gender, age and socio-economic condition. Levels of hypertension control depended on health area and control furthermore was positively associated with post-primary education, not being obese and white ethnicity: adjusted Odds Ratio (95% CI) 1.71 (1.26–2.34), 1.43 (1.09–1.88) and 1.41 (1.09–1.81) respectively.The observed figures are outstanding at the international level and illustrate that hypertension treatment and control are achievable in a resource-constrained setting such as Cuba. The country’s primary health care approach and social equity in access to health care can be seen as key determinants of this success. Nevertheless, there is still room for improvement, as over a third of patients did not have controlled hypertension. Non-communicable diseases (NCDs) account for 63% of global mortality nowadays and it is predicted that they will account for 69% of global deaths by 2030 . They arCardiovascular diseases (CVD) are the leading cause of death around the world and uncontrolled hypertension is a related cause of 7.6 million deaths each year . FurtherNotwithstanding, the majority of health systems provide inadequate chronic diseases management, with health services mainly designed to provide acute curative care. This global trend has been termed “the tyranny of the urgent” . ChronicCuba went through an epidemiological transition from the mid-twentieth century onwards. Today, chronic diseases account for 86% of total deaths in the country and CVD are responsible for 39% of the overall mortality , while iCuba is internationally recognized for having a well-organized national health system based on a primary health care (PHC) approach and it can be considered an excellent setting to study the potential of low-resource health systems to develop comprehensive programs for chronic care. The Cuban health system not only has achieved excellent control of communicable diseases but also presented one of the best hypertension control figures in the world . NeverthThe present study primarily aims at determining the current proportion of treated and controlled hypertensive patients in two different geographical areas of the country . Moreover, predictors associated with achieving hypertension control were explored.This cross-sectional study was conducted between February 2012 and January 2013 in the Cuban municipalities of Cardenas and Santiago  . They arThe study municipalities and the health areas within each municipality were purposively selected on the basis of feasibility and the commitment of local health authorities to carry out the study and to implement subsequently interventions for quality improvement of the hypertension management program. In each municipality, two urban health areas were selected: “Julio Antonio Echeverria (JAE)” and “Moncada” in Cardenas and “Grimau” and “Finlay” in Santiago. In each health area, 14 FDNP were randomly selected. In each of these FDNP, 25 hypertensive patients were selected by simple random sampling from the family doctor register. Patients were included if they were aged 18 years or older, had a confirmed diagnosis of hypertension documented in their medical records and provided their written informed consent. Thus, a total of 1400 hypertensive patients were sampled , allowing to estimate the proportion of patients with controlled hypertension (anticipated to be at least 50%) with a confidence level of 95%, a precision of 5% and a cluster effect of 2.5.Data collection was done by a group of junior researchers of the Cuban National Institute of Hygiene and Epidemiology (INHEM). In order to guarantee reliability and consistency, they received a 3 days training at INHEM and had to pass a standardized test on blood pressure measurement. Door to door visits in the homes of the selected patients, during which blood pressure measurement and interviews were carried out, were made by research staff. In case the person was not found at home, two further visits were made before another patient was selected. Blood pressure was measured three times, from the right arm in a sitting posture, using a mercury manometer, following international standardized recommendations for blood pressure measurement in population surveys , 17. TheParticipants’ weight and height were also measured. Body weight was measured to ±0.1 kg using electronic scales, standing height was measured to ± 0.01 m using a wall mounted stadiometer and body-mass index (BMI) was calculated as weight/height2 (kg/m2). Based on Word Health Organization criteria , 20 nutrP values less than 0.05 were considered significant. Potential predictors for controlled hypertension were included in a multivariate logistic regression model if they were statically significant in bivariate analysis (conservatively taking p < 0.1 as threshold) or a priori considered of relevance. Unadjusted and adjusted Odds Ratios (ORs) and their 95%CI were calculated, taking into account the clustered/multistage study design.Data were double-entered in a Microsoft Access 2000 database and analysed using the Statistical Package for Social Sciences (SPSS) V.23 . Means and standard deviations and proportions with 95% confidence intervals (95%CI) were calculated for continuous and categorical variables respectively. The association between hypertension control and socio-demographic and clinical factors was explored using the Chi-squared and the t test for categorical and continuous variables respectively. p < 0.001). Based on self-report, 43% of the sample was white, 29% mestizo and 28% black. High levels of health care utilization were observed: 42% of patients had a contact during the 3 months before the survey; 71%  of these contacts were with first-line health services. The mean blood pressure in the study population was 130.0/83.0 mmHg. Controlled hypertension was found in 773 patients  (Table Sixty-seven sampled patients (5%), mostly from JAE health area, were not found at home after 3 visits but were not replaced due to operational constraints. Hence, the total number of respondents was 1333 (Table p = 0.44) but levels of hypertension control depended on health area. Gender, age, civil status, labour activity, receiving anti-hypertensive drugs, compliance with pharmacological treatment and personal history of coronary heart disease or diabetes were not significantly associated with hypertension control. Among the 115 not receiving treatment 55%  had controlled hypertension. In multivariate analysis, the variables which exerted significant influence on hypertension control were: post-primary education, obesity and white ethnicity  was 22.4% vs 20.4% found in the Ministry of Health registers . In ordeThe high prevalence of hypertension treatment and control among diagnosed patients found in this study is consistent with a previous study carried out in the Cuban province of Cienfuegos in 2001–2002 , suggestHypertension control at population level has been forwarded as a correlate measure of how well a health system functions, given that this condition is entirely dependent on the health system for its care and control . ConstraAppropriate drug titration and combination therapies are also key elements for achieving hypertension control. According to international guidelines, more than two-thirds of hypertensive patients require treatment with more than one antihypertensive drug to achieve blood pressure control , 36, 37.Being on pharmacological treatment was not significantly associated with hypertension control, but the vast majority of patients were on pharmacological treatment and control in other hypertensive may have been achieved by lifestyle modifications, which were not explored in depth in the present study. International literature widely describes the positive effects that sustained lifestyle modifications such as weight loss, diets rich in fruits/vegetables, and sodium (Na+) reduction have on blood pressure (BP) control . Other nThe lack of association of hypertension control with age, gender and socio-economic conditions could be explained by the equity in access to health care services in Cuba irrespective of gender or social condition, where all adults receive at least one home visit of their family doctor/nurse per year, a frequency that increases according to specific risk profiles or disabilities . The assObesity was found to be associated with poorer hypertension control. This is compatible with available evidence reporting a stable linear relation between adiposity and blood pressure, independent of age and body fat distribution . High BMIn this study non-white hypertensive patients (mestizo or black) were more likely to have uncontrolled hypertension, regardless of socio-economic condition. Differences associated with ethnicity could be related to lifestyle differences or to genetic factors such salt sensitivity, which is more common in black people . There aLowering blood pressure significantly reduces the risk of major cardiovascular events and all-cause mortality  and hypeWhile there is still room for improvement, the figures observed in this study are outstanding at the international level and illustrate that hypertension treatment and control is achievable in a resource-constrained setting such as Cuba. The country’s primary health care approach and social equity in access to care can be seen as key to overcome system barriers to blood-pressure control and sustained clinical outcomes. This may inspire policy makers in other developing countries to adapt their public health systems’ set up and functioning to respond to the growing need for better chronic care.


Considerable technical improvements transformed extracorporeal techniques for carbon dioxide removal in an attractive option to avoid worsening respiratory failure and respiratory acidosis, and to potentially prevent or shorten the duration of IMV in patients with exacerbation of COPD and asthma. In this review, we will present a summary of the pathophysiological rationale and evidence of ECCO Patients with obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), may experience acute exacerbations with severe hypercapnic respiratory failure. Hypercapnia results from acute worsening of expiratory flow limitation caused by the increased small airway resistance with consequent development of dynamic alveolar hyperinflation and intrinsic positive end-expiratory pressure (PEEP). In the most severe cases, these may be refractory to conventional therapies and mechanical ventilation, becoming life-threatening.2R) represents an attractive approach in this setting.Extracorporeal carbon dioxide removal (ECCO2R), due to the relative ease and efficiency in blood CO2 clearance granted by extracorporeal gas exchangers as compared to oxygen delivery [The last decade has seen an increasing interest in the provision of extracorporeal support for respiratory failure, as demonstrated by the progressively increasing number of scientific publications on this topic. In particular, remarkable interest has been focused on extracorporeal carbon dioxide removal (ECCOdelivery .2R devices has been developed. More efficient veno-venous (VV)-ECCO2R devices have become available and have replaced the arterio-venous approach, having the advantage of not requiring arterial puncture.In recent years, a new generation of ECCO2R devices offer lower resistance to blood flow, have smaller priming volumes, and provide a much more efficient gas exchange with relatively low extracorporeal blood flows (0.4–1 L/min) [2 and improvement in the work of breathing [The new VV-ECCOreathing –6.In both asthma and COPD exacerbations, diffuse narrowing of the airways results in detrimental physiological consequences. Airway narrowing prevents the lungs from completely emptying (“air trapping”) due to resistance to expiratory flow and bronchial closure at higher than normal lung volumes. Air trapping results in dynamic hyperinflation (DHI)  which isPharmacotherapy with bronchodilators and systemic corticosteroids are part of the medical therapies, administered specifically to reduce the pathophysiological airflow obstruction and improve symptoms.The recognition for the need for noninvasive ventilation (NIV) is indicated if the patient fails to improve clinically and if the level of pH remains less than 7.32 despite medical therapy . HoweverOverall, the goal of mechanical ventilation is to provide adequate gas exchange and reduce the work of breathing while waiting for airflow obstruction to resolve. However, mechanical ventilation itself may aggravate alveolar hyperinflation by worsening DHI, which may lead to worsened hypercapnia, barotrauma, alveolar rupture leading to pneumothorax and further hemodynamic deterioration .Furthermore, if treated with IMV, these patients receive sedatives and likely neuromuscular blockade to facilitate ventilatory support . SedatioWhen conventional therapeutic options are not successful, novel therapies such as extracorporeal life support are entertained as a possible salvage therapeutic modality.2 elimination with ECCO2R could potentially improve the acid–base balance, reduce patient’s work of breathing with a consequent reduction in respiratory rate and ventilatory drive, and lower alveolar ventilation. The lower tidal volumes and respiratory rate result in the extension of the expiratory time, suiting better the high expiratory time constant of the respiratory system with expiratory flow limitation. By these physiological mechanisms, ECCO2R can counteract the vicious circle of dynamic hyperinflation, and its detrimental respiratory and cardiovascular consequences. The derived beneficial effects on respiratory mechanics, ventilatory muscle efficiency, work of breathing, and cardiovascular function may improve gas exchanges and relieve dyspnea. By these mechanisms, ECCO2R thus can potentially prevent NIV failure, facilitate weaning from IMV, and therefore contribute to avoid the unwanted complications of sedation and immobilization.During exacerbation, relieving the native lung from at least part of the CO2R is designed to remove carbon dioxide (CO2) and, unlike extracorporeal membrane oxygen (ECMO), does not provide significant oxygenation.ECCO2 is removed by diffusion. A flowing gas known as “sweep gas” containing little or no CO2 runs along the other side of the membrane, ensuring a diffusion gradient from blood to the other side, hence promoting CO2 removal.The device consists of a drainage cannula placed in a large central vein or artery, a membrane lung , and a return cannula into the venous system Fig. . Blood i2R requires much lower blood flow rates, due to the significant differences in CO2 and oxygen (O2) kinetics. Almost all the O2 in blood is carried by hemoglobin, which displays sigmoidal saturation kinetics. Assuming normal hemoglobin and venous O2 content, each liter of venous blood can only carry an extra 40–60 mL of O2 before the hemoglobin is fully saturated. Blood flows of 5–7 L/min through the extracorporeal artificial membrane lung are therefore required to supply enough O2 for an average adult. Conversely, most CO2 in blood is dissolved or in the form of bicarbonate, displaying linear kinetics without saturation. Considering that 1 L of blood is transported around 500 mL of CO2, in a perfectly efficient system flow of 0.5 L/min would be enough to remove all of the CO2 produced by an average adult, which is about 250 mL/min [2 diffuses more readily than O2 across extracorporeal membranes because of higher solubility. However, in practice, ECCO2R is usually able to remove up to 25% of carbon dioxide production given the limitations of blood flow and membrane efficiency [2 clearance greatly depends on the fresh sweep gas flow through the membrane lung, this is usually maximized in the low blood flow ECCO2R systems. Therefore, the efficiency of CO2 clearance of the different available devices is critically determined by other important parameters, including the size of the cannula, the rate of recirculation of blood in the circuit, the efficiency of the pump, the total surface area of the artificial lung, and the cardiac preload [2 clearance.In contrast to ECMO, where the need for oxygenation requires high blood flow rates, ECCO0 mL/min , 18. Alsficiency . As the  preload , 21. Imp2 is removed by the effect of the “sweep gas,” and blood is then returned into the venous circulation , commonly introduced via the right internal jugular vein. The setup is very similar to renal replacement therapy, and in fact, some systems are trying to combine the two in one [2R compared to the AV approach is the less invasiveness by avoiding arterial cannulation, and the potential for early mobilization of patients. It is also possible to set up an ECCO2R system through cannulation of two central veins, one for drainage and the other for reinfusion .In the veno-venous configuration, blood is drawn from a central vein by a draining cannula, using a centrifugal or roller pump to generate flow across the membrane. COion Fig. a. Singleo in one , 23  bypass, equipped with an artificial gas exchanger across the AV shunt, which allows the “sweep gas” to remove CO2  is a significant worldwide health burden. Currently, it is the fourth leading cause of death worldwide, and is the only leading cause of death that is rising, and will likely become the third cause of death by 2020 , 28.Acute exacerbations of COPD (aeCOPD) constitute a significant cause of morbidity and mortality among these patients. Patients with moderate to severe acute exacerbations develop alveolar hyperinflation that may lead to increased work of breathing, muscle fatigue, and hypercapnia, creating a vicious loop refractory to medical treatment –31. The Patients with COPD requiring IMV develop a considerable reduction in respiratory muscle strength, with higher risk of prolonged weaning and/or failure to wean, compared to other causes of acute hypercapnic respiratory failure. Up to 60% of the ventilatory time in these patients is spent for weaning  and is v2R to support respiratory function of a COPD patient was published in Pesenti et al. [One of the first reports on the application of ECCOi et al. . However2R, investigators began applying the technique to prevent intubation or to assist weaning from IMV in this patients’ population. Several studies in both VV and AV configurations were published, including a meta-analysis  or 6 months (both groups 33%) compared to the control group.Kluge et al.  in the s2R through a 15.5-Fr dual-lumen cannula achieving a mean blood flow of 430 mL/min. Of the 20 patients, seven were at risk of failing NIV, two were difficult to wean from NIV, and 11 had failed liberation from MV. With ECCO2R, none of the patients failing NIV required endotracheal intubation, and both patients with difficult weaning from NIV were weaned. However, only three of the 11 IMV patients were liberated successfully. Moreover, significant complications arose in a number of patients: bleeding requiring blood transfusion was reported in three patients, deep vein thrombosis was diagnosed in one patient after removal of the ECCO2R catheter, one patient experienced pneumothorax due to catheter insertion, and one died from hemorrhage when the iliac vein was perforated during ECCO2R catheter placement.Burki et al.  treated 2R versus 21 historical controls treated with NIV alone with regard to the cumulative incidence of intubation. They reported that ECCO2R with a 14-Fr dual-lumen catheter and blood flow rates of 177–333 mL/min not only improved respiratory acidosis but also reduced the need for intubation by 75%  and significantly reduced the in-hospital mortality . However, this came with a cost of 52% prevalence of ECCO2R-related side effects and led the authors to suggest the end point of future studies should be long-term mortality.Del Sorbo et al.  compared2R, which was associated with a high incidence of complications. However, in this study, there was an inclusion of patients with relative contraindications to NIV, and there was an unexpectedly high incidence of hypoxemic patients [Braune et al.  in the Epatients .2R  in reducing the PaCO2 in a series of 30 patients with acute hypercapnic respiratory failure due to aeCOPD, who refused endotracheal intubation after failing NIV. The duration of ECCO2R was 2–16 days, and it was possible to prevent endotracheal intubation in 27 patients.Finally, Morelli et al.  confirme2R in a patient with aeCOPD. They demonstrated a successful reduction in PaCO2, minute ventilation, and ventilator pressures.Cardenas et al.  made the2R allowed the weaning from mechanical ventilator in only three patients.Burki et al.  in a sub2R was initiated. By using a dual-lumen cannula (20–23 Fr) with blood flow rates of 1–1.7 Lt/min, with a sweep gas flow from 1 to 7 L/min, they were able to extubate all five patients within 24 h of treatment . Once extubated, patients were rehabilitated while on ECCO2R, with a mean time to ambulation of 29.4 ± 12.6 h after ECCO2R. Moreover, all patients survived to hospital discharge.Abrams et al.  reportedRoncon-Albuquerque Jr. et al.  using a 2R in the management of patients with COPD exacerbations from a number of ongoing or planned clinical trials  .2R has been applied as rescue therapy.Although necessary, mechanical ventilation may aggravate alveolar hyperinflation as it was described above. To prevent these potential detrimental effects, ECCO2R as an adjunct to IMV for refractory asthma was first reported in 1981 [2R, could also be suitable in these cases. Indeed, the use of ECCO2R in patients with asthmatic exacerbation has been reported, although in a limited number of cases.ECCO in 1981 . Subsequ in 1981 –55. In t2R seems to be effective in improving or mitigating hypercapnic acidosis and possibly in reducing the rate of endotracheal intubation, its use is associated with a range of vascular, hematological, and other complications (Table Although ECCOns Table .Table 4EArterial cannulation is associated with higher risk than venous catheterization, with specific complications including distal limb ischemia, compartment syndrome of the lower limb requiring fasciotomy or limb amputation, as devastating consequences .2R. The low flow renders systemic anticoagulation mandatory, increasing the risk of significant bleeding including cerebral, gastrointestinal, and nasopharyngeal bleeds. In the studies on ECCO2R for COPD to date, the rate of clinically significant hemorrhagic complications ranges between 2% and 50% [The occurrence of bleeding events is the most frequent complication of ECCO and 50% .Thrombocytopenia is also commonly observed, as well as hemolysis.Conversely, thrombus formation is higher at lower blood flow rates because of increased exposure time to the membrane lung and circuit. Clots may detach and enter the patient’s bloodstream, plugging the membrane or obstructing the cannula if anticoagulation is not achieved.2R was a complex technique requiring intensive monitoring and surgical expertise. Due to a high rate of complications, it was avoided by all but few high expertise centers. With newer simplified systems, ECCO2R devices can be easily used and can be initiated by most intensivists. However, given the lack of conclusive clinical evidence and the relatively high rate of associated complications, its use should be restricted to investigational applications in specific cohorts of patients.In the past, ECCO2R appears very promising for patients with acute exacerbation of obstructive diseases refractory to conventional treatment, but systematic evaluation is needed to prove its clinical efficacy.In summary, minimally invasive ECCO


Variability in HbA1c is associated with a higher risk of cardiovascular disease and microvascular complications in patients with type 2 diabetes. The present study evaluated the severity of somatic nerve dysfunction at different stages of chronic glycemic impairment, and its correlation with different cardio-metabolic parameters. The study was conducted on 223 patients with type 2 diabetes. We calculated the intrapersonal mean, standard deviation (SD), and coefficient of variation of HbA1c for each patient using all measurements obtained for 3 years prior to the study. Patients were divided into quartiles according to the SD of HbA1c, and we constructed composite scores of nerve conduction as the severity of peripheral neuropathy. Linear regression analysis was performed to evaluate the influence of independent variables on mean composite scores. Those with higher SD-HbA1c had a higher body mass index, mean and index HbA1c, triglyceride and uric acid level, urinary albumin excretion and albumin-creatinine ratio, proportion of insulin therapy, and prevalence of hypertension as the underlying diseases, but lower estimate glomerular filtration rate (eGFR). In addition, those with higher SD-HbA1c showed lower amplitudes and reduced motor nerve conduction velocity in tested nerves, and lower sensory nerve conduction velocity in the sural nerve. Furthermore, those with higher SD-HbA1c had higher composite scores of low extremities. Multiple linear regression analysis revealed that diabetes duration, SD-HbA1c, and eGFR were independently associated with mean composite scores. Based on our results, HbA1c variability plus chronic glycemic impairment is strongly associated with the severity of peripheral neuropathy in patients with type 2 diabetes. Aggressively control blood glucose to an acceptable range and avoid blood glucose fluctuations by individualized treatment to prevent further nerve damage. Diabetic peripheral neuropathy (DPN), including autonomic and somatic neuropathy, is a very important microvascular complication of diabetes. The most common somatic neuropathy, diabetic sensorimotor polyneuropathy (DSPN), is an important cause of foot ulcer and amputation in diabetic patients that can result in delayed diagnosis due to a protracted asymptomatic course  with type 2 diabetes who visited the outpatient diabetic clinic at Kaohsiung Chang Gung Memorial Hospital in Taiwan were recruited. Exclusion criteria were (1) no follow-up within the first 6 months of outpatient clinic visit and (2) the numbers of HbA1c measurements are < 4. Thus, we enrolled 223 participants were enrolled in the study. The study was approved by the Ethics Committee of Chang Gung Memorial Hospital Institutional Review Board .−1.154 × [age]−0.203 × [0.742 if female] × 1.233, where 1.233 is the adjusting coefficient for Chinese patients , body height and weight, waist circumstance, systolic blood pressure (SBP) and diastolic blood pressure (DBP) during autonomic function testing, microvascular complication of diabetes (retinopathy and nephropathy), and laboratory parameters were obtained at baseline. DSPN was diagnosed in patients who not only had neurological symptoms/signs and abnormalities in nerve conduction evaluations but also fulfilled the diagnostic criteria of DSPN based on the clinical research Report of the American Academy of Neurology  waist circumstance >90 cm for men and >80 cm for women; (2) serum triglyceride level ≥150 mg/dL or having a prescription for elevated triglyceride levels; (3) serum high-density lipoprotein cholesterol (HDL-C) < 40 mg/dL in men and < 50 mg/dL in women or having a prescription for low HDL-C levels; and (4) elevated blood pressure .n/(n – 1)]0.5, where n is the number of HbA1c measurements) to minimize any effect of different numbers of HbA1c measurements on the values calculated  of HbA1c were calculated using all measurements obtained 3 years prior to the study start date. The SD-HbA1c and CV were considered as measures of glycemic variability and normalized glycemic variability, respectively. The number of individual visits could influence SD-HbA1c values , we defined the adjusted SD of HbA1c as the SD of HbA1c divided by [The NCS were performed using Nicolet Viking machines. All measurements were recorded using standard laboratory methods. All studies included surface recording and stimulation. The belly-tendon montage was used and supra-maximal stimulation was applied. All data obtained were compared with reference values from our laboratory . Categorical variables were compared using chi-square or Fisher's exact tests. Continuous variables that were not normally distributed were logarithmically transformed to improve normality prior to analysis. Three separate statistical analyses were performed. First, trends between more than two groups were analyzed using linear polynomial contrasts ANOVA for normally distributed variables. Second, correlation analysis was used to evaluate the relationship between composite scores of nerve conduction and variables including age, diabetes duration, body mass index (BMI), waist circumstance, systolic and diastolic blood pressure, and peripheral blood studies for vascular risks. Third, two stepwise models of multiple linear regression analysis were performed to evaluate the influence of independent variables on the mean composite scores of nerve conduction. Factors that were significantly correlated with the mean composite scores of nerve conduction were assessed using the model 1 multiple linear regression analysis. Subsequently, results from model 1 were further analyzed using the model 2 multiple linear regression analysis. Fourth, the changes in composite scores of nerve conduction and HbA1c variability and cardio-metabolic parameters during follow-up were defined as follows: delta = (data after the follow-up) – (data at the beginning). A correlation analysis was used to determine the relationship between changes in HbA1c variability and those in composite scores of nerve conduction after controlling with the follow-up duration (months). All statistical analyses were conducted using the SAS software package, version 9.1 .P = 0.04) and body mass index (P = 0.004), higher mean and index HbA1c values , higher triglyceride and uric acid levels , higher urinary albumin excretion (mg/day), higher albumin-creatinine ratio (mg/mg) , lower eGFR (P < 0.0001), higher prevalence of hypertension and metabolic syndrome as the underlying disease (P = 0.03 and 0.001), and a higher proportion of insulin therapy as treatment (P = 0.001).The 223 patients with diabetes in this study included 78 women  and 145 men . Patient characteristics and complication rates at last assessment are presented in P = 0.001), peroneal (P = 0.04), and tibial (P = 0.001) nerves; and lower sensory nerve action potential (SNAP) values in the median (P < 0.0001), ulnar (P < 0.0001), and sural (P < 0.0001) nerves. Patients with higher SD-HbA1c had lower motor nerve conduction velocity (MNCV) values in median (P < 0.0001), ulnar (P = 0.02), peroneal (P = 0.02), and tibial (P = 0.001) nerves; and lower sensory nerve conduction velocity (SNCV) values in the sural nerve (P = 0.04). Furthermore, patients with higher SD-HbA1c also had higher composite score of low extremities (P = 0.026).The NCS in patients with type 2 diabetes, stratified by ascending quartiles of GV (SD-HbA1c), are listed in P-value) were as follows: age , diabetes duration , systolic blood pressure , uric acid , hs-CRP , mean HbA1c , CV HbA1c , SD HbA1c , and eGFR (mL/min/1.73 m2) . Furthermore, correlation analysis was used to test the influence of GV on composite scores after controlling for age, diabetes duration, eGFR, and mean HbA1c  and SD-HbA1c .The correlation analysis used to test the influence of glycemic variability and other vascular risk factors on composite scores of nerve conduction are listed in The effects of the variables on composite scores of nerve conduction in patients with type 2 diabetes relating to the correlation analysis are listed in r = 0.555, P = 0.049.Among the 223 cases, 21 patients died during the follow-up period. The mean follow-up period of the remaining 202 patients was 67.2 months. The changes in parameters including composite score of nerve conduction and glycemic variability during the follow-up period were determined as follows: data in the final follow-up examination—baseline data. The correlation analysis was used to determine the relationship between the changes in mean, CV and SD HbA1c and those in composite scores after controlling with the NCS follow-up duration (months) . The staTo date, this is the first study to confirm the hypothesis that HbA1C variability is strongly associated with composite scores of nerve conduction, which are indicative of the degree of severity of DSPN, in patients with type 2 diabetes. We examined the severity of somatic nerve dysfunction by creating a composite score to assess different stages of chronic glycemic impairment, and correlated this score with different cardio-metabolic parameters to obtain four major findings.First, patients with higher SD-HbA1c values had increased body weight and body mass index, higher mean and index HbA1c values, higher triglyceride and uric acid levels, higher urinary albumin excretion and albumin-creatinine ratios, an increased proportion of insulin therapy and prevalence of hypertension and metabolic syndrome, and lower eGFR. Second, patients with higher SD-HbA1c values had lower CMAP, SNAP, and MNCV on tested nerves and lower SNCV on sural nerve. Third, patients with higher SD-HbA1c values also had higher composite score of low extremities. Finally, multiple linear regression analysis revealed that diabetes duration, SD-HbA1c, and eGFR were independently associated with mean composite scores of nerve conduction.Aggressive control of blood glucose is pivotal for patients with type 2 diabetes, and can prevent microvascular  and macrovascular  complications  contribute to the severity of DPN (Tkac and Bril, This study has several limitations. First, we excluded patients who were lost to follow-up within the first 6 months from the outpatient clinic and the numbers of HbA1c measurements are <4. Thus, there is uncertainty in assessing the role of chronic glycemic impairment and other cardio-metabolic parameters in unselected type 2 diabetes. Second, while there was a positive association between HbA1c variability and composite scores of nerve conduction in this observational study, it is unclear whether the role of the association is causal. A prospective longitudinal study is necessary to evaluate the efficiency of composite scores of nerve conduction as a scale of severity in clinical follow up. Third, we only used composite scores of nerve conduction as the quantitative approaches of severity of DSPN. Because only large fiber function was assessed, it may not account for at all the variability in severity found in DSPN, including any statistical bias. Other quantitative approaches to assess the severity of DPN, such as morphological severity and/or Neuropathy Impairment Score of the Lower Limbs, should be taken into account for future studies. Fourth, our study only included a Chinese population with type 2 diabetes. Finally, although the sample size was small, the number of variables that we considered for the multiple linear regression analysis was also small. Furthermore, based on the stepwise procedures, only three variables were selected as variables that were important in predicting the composite score. Therefore, the maximum likelihood estimates of the coefficients are valid in this analysis.Based on our results, the severity of neuropathy assessed by detailed electro-physiological testing was clearly associated by high HbA1c variability. As HbA1c variability is considered a prognostic factor, aggressively control blood glucose to an acceptable range and avoid fluctuations in blood glucose by more individualized treatment to prevent further nerve damage.The data from this study can be acquired from the corresponding author upon reasonable request.Y-RL participated in the design of the study and drafted the manuscript. W-CC, C-CH, N-WT, H-CW, W-CL, B-CC, Y-JS, C-MS, and S-YH participated in the sequence alignment and clinical evaluation of patients. C-CH performed the statistical analysis. C-HL conceived the study, and participated in its design and coordination, and helped draft the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h : from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg , compared to placebo. Fractional lithium excretion increased by 19.6% , suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9%  and 33.0% , respectively. Free water clearance (FWC) decreased by −885.3 mL/24 h . These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials ( HbA1c ≥63 mmoL/moL, eGFR <82 mL/min/1.73 m2 vs. ≥82 mL/min/1.73 m2, UACR <199.7 mg/g vs. ≥199.7 mg/g, and use of diuretics at baseline (yes/no). The median was used to stratify the subgroups. Subgroup analyses were performed by adding relevant subgroups and an interaction term between treatment assignment and subgroup to the mixed models. Data processing and analyses were performed using SAS software, version 9.4 of the SAS System for Windows . Secondly, the effects of dapagliflozin on specific volume markers, namely urinary osmolality, NT-proBNP, copeptin, and renin were assessed in the following baseline subgroups: HbA1c levels, as well as urinary glucose excretion : from 3.2 to 7.2 mmoL/moL, p < 0.01) , and 24-h urine albumin excretion was reduced by 52.0% , relative to placebo.Dapagliflozin, compared to placebo, decreased HbA < 0.01) . Estimatp < 0.01) and urinary osmolality by 60.4 mOsmoL/kg , relative to placebo (p = 0.02), but there was no change in 24-h urinary sodium excretion (p < 0.01) increase in fractional lithium excretion relative to placebo, suggesting that, during chronic treatment with dapagliflozin, sodium reabsorption in the proximal tubule is inhibited (p < 0.01), decreased body weight by 1.3 kg, and increased serum sodium and urea, but did not change NT-proBNP (p < 0.01) and copeptin increased by 33.1% , relative to placebo , or whether they had renal impairment.The effects of dapagliflozin on urinary osmolality, NT-proBNP, copeptin, and renin in the overall study population were consistent irrespective of HbAClinicalTrials.gov identifier: NCT03152084) was designed to prospectively assess short-term and long-term changes in several volume-related markers, such as 24-h urinary sodium, blood pressure, and copeptin. This study has limitations. Unfortunately, direct measurements of plasma volume were not available for the included studies. However, prior studies already showed that SGLT2 inhibitors decrease extracellular fluid/plasma volume ,9,18,19.In conclusion, this study shows that dapagliflozin increased urinary osmolality, urinary glucose, and fractional lithium excretion, and it decreased blood pressure and body weight. These results suggest that dapagliflozin exerts a diuretic effect through both osmotic and natriuretic diuresis in individuals with type 2 diabetes and kidney damage. During prolonged treatment with dapagliflozin, compensatory mechanisms are activated to restore body-fluid homeostasis.