Living donor kidney transplantation is preferable to deceased donor transplantation due to its superior long-term patient and graft survivals. However, ABO blood group incompatibility is a major barrier to living donor kidney transplantation. ABO-incompatible kidney transplantation has been performed in Japan since the late 1980’s, but it is still globally uncommon. The objective of this study is to compare the clinical outcomes of ABO-incompatible kidney transplantation (ABO-IKT) with that of ABO-compatible kidney transplantation (ABO-CKT) at an institution where only about two kidney transplants are performed a month on average.A single center propensity score-matched cohort study.We retrospectively collected and analyzed the data of 240 patients with end-stage kidney disease (ESKD) who underwent living donor kidney transplantation at Osaka City University Hospital from January 1999 to December 2016, of which 66 patients were ABO-IKT. The remaining 174 patients who underwent ABO-CKT were studied as the control group, and the clinical outcomes of ABO-IKT and ABO-CKT recipients were compared based on propensity score matching.After propensity score matching, there were no significant differences in both patient survival and death-censored graft survival rates between the ABO-IKT and ABO-CKT groups. Moreover, there were no significant differences in estimated glomerular filtration rate as well as frequency of acute cellular rejection, antibody-mediated rejection, infectious adverse events, malignancies, and post-operative bleeding between the two groups.Currently, ABO-IKT may be an acceptable treatment for patients with ESKD even at a low-volume transplant center. For patients with end-stage kidney disease (ESKD), kidney transplantation is the optimal renal replacement therapy, enabling greater longevity and better quality of life compared to dialysis therapy –2. The rABO-incompatible kidney transplantation (ABO-IKT) has been performed in Japan since the late 1980’s –5, but iIn this study, we compared the clinical outcomes of ABO-IKT to those of ABO-compatible living kidney transplantation (ABO-CKT) at our institution where we perform two kidney transplants a month on average.A total of 240 patients with ESKD underwent living donor kidney transplantation at Osaka City University Hospital from January 1999 to December 2016, of which 66 patients were ABO-IKT. The remaining 174 patients who underwent ABO-CKT were studied as the control group. It is known that quantitative and possibly qualitative differences exist in the expression of blood group A antigen in erythrocytes of A1 and A2. Because the A2 phenotype is known to be extremely rare in the Japanese population , we did This study was approved by the Ethics Committee of Osaka City University Graduate School of Medicine (No. 3957). Opt-out consent was obtained instead of written informed consent, which was also approved by the Ethics Committee of Osaka City University Graduate School of Medicine. We provided patients with information explaining the proposed research plan  by means of an information website of our hospital and gave them the opportunity of opt-out, and all the procedures were in accordance with the Helsinki Declaration of 2000 and the Declaration of Istanbul 2008.The primary endpoint was graft survival, censored for patient death with a functioning graft, and patient survival. The secondary endpoint was frequency of acute cellular rejection, antibody-mediated rejection, infectious adverse events, malignant tumor, and other adverse events as well as current renal function. Delayed graft function was defined as the need for at least one dialysis session within the first week of kidney transplantation. Current renal function was defined as mean estimated glomerular filtration rate (eGFR) of three most recent outpatient measurements. eGFR was calculated using the modified Modification of Diet in Renal Disease equation .Immunosuppressive agents have been improved since 1999, and we have used the optimal protocol available at the time. Our basic immunosuppressive protocol for ABO-CKT and ABO-IKT has consisted of three agents: calcineurin inhibitor (CNI) (tacrolimus or cyclosporine), antimetabolite , mizoribine) or mammalian target of rapamycin (mTOR) inhibitor (everolimus (EVR)), and methylprednisolone (MP). Basiliximab (BAS) has been administered in all recipients since 2002. Briefly, CNI and MMF or EVR was initiated 3 days before transplantation. BAS was administered at a dose of 20 mg/day at the time of transplantation and 4 days after transplantation. MP was administered at a dose of 500 mg intravenously at the time of transplantation and at 40 mg/day orally 1 to 7 days after transplantation, the dose of which was decreased to 24, 12, 8, and 4 mg/day every week.To remove the anti-A/B antibodies, the patients underwent several sessions of double filtration plasmapheresis or plasma exchange prior to kidney transplantation until the anti-A/B titers were ≤ 1:64. For the depletion of B cells and inhibition of antibody production, splenectomy was performed at the time of kidney transplantation from 1999 to 2006. Since June 2006, rituximab  has been administered instead of surgical splenectomy –12.2 2 weeks prior to transplantation, and this basic protocol was modified depending on age and anti-A/B antibody titers. In elderly recipients (≧60 years), MMF was administered at a dose of 0.5 g/day to minimize its adverse events [The basic protocol for ABO-IKT we currently use is shown in e events . Some ree events –15, and Initial (prior to desensitization), pre-operative (post-desensitization), and post-operative anti-A/B antibody titers were measured. Anti-A/B IgM antibody titers were measured using the saline agglutination test, and anti-A/B IgG antibody titers were measured using the indirect Coombs’ test.Routine biopsies of renal allografts were performed at transplantation and before the first discharge, and episode biopsies of renal allografts were performed in case of graft dysfunction. All samples were examined using light microscopy, and the samples obtained after 2006 were evaluated for deposit of C4d in the peritubular capillaries using immunofluorescent staining. Acute cellular rejection and antibody-mediated rejection were histologically diagnosed by graft biopsy specimens according to the Banff 2007–2013 criteria. Borderline changes were excluded as acute cellular rejections.Categorical variables were expressed as count and percentage, and continuous variables were expressed as median and interquartile range (IQR) or range. Categorical variables were compared using the Fisher’s exact test, and continuous variables were compared using the Mann-Whitney U-test. To reduce the effect of selection bias and potential confounding, propensity score matching generated a matched cohort at a 1 to 1 ratio composed of 132 patients, adjusted for recipient age at kidney transplantation, dialysis vintage, number of human leukocyte antigen mismatches, flow cytometry crossmatch positive, calcineurin inhibitor, and antimetabolite or mTOR inhibitor .Survival curves were estimated using the Kaplan-Meier method, and the differences in survival rates between the two groups were evaluated using the Log-rank test. In addition, the impact of desensitization for outcomes was assessed by calculating hazard ratios and 95% confidence intervals using the univariate Cox proportional hazards regression model. P<0.05 was considered statistically significant. All statistical analyses were performed with EZR , which is a graphical user interface for R . More precisely, it is a modified version of the R commander (version 2.4–0) designed to add statistical functions frequently used in biostatistics .The baseline clinical characteristics are shown in In the ABO-CKT group, 4 patients died , and in the ABO-IKT group, 2 patients died . Patient survival rates at 1, 3, 5, 7, and 10 years were 100%, 100%, 98.4%, 96.1%, and 96.1%, respectively, in the ABO-CKT group and 100%, 100%, 97.1%, 97.1%, and 97.1%, respectively, in the ABO-IKT group, and there was no significant difference between the two groups . Four anAfter propensity score matching, the patient and graft survival rates were compared. The median observation period was 4.54 (IQR 2.40–7.44) years in the matched cohort. During the period of follow-up, 1 and 4 recipients were reintroduced to dialysis and the number of deaths with a functioning graft was 2 and 2 in the ABO-IKT group and ABO-CKT group, respectively. Patient survival rates at 1, 3, 5, 7, and 10 years were 100%, 100%, 97.0%, 92.4%, and 92.4%, respectively, in the ABO-CKT group and 100%, 100%, 97.1%, 97.1%, and 97.1%, respectively, in the ABO-IKT group, and there was no significant difference between the two groups . The dea2 after propensity score matching, respectively, and the ABO-IKT group did not significantly differ from the ABO-CKT group (p = 0.363).There were no significant differences in eGFR at 1, 3, 5, 7, and 10 years after transplantation between the ABO-CKT and ABO-IKT groups after propensity score matching. Current renal function (eGFR) of the ABO-CKT and ABO-IKT recipients was 45.65 (IQR 37.61–57.61) and 44.06 (IQR 37.86–51.35) mL/min/1.73 mThe rate of acute cellular rejection in the ABO-CKT and ABO-IKT groups was 10.6% and 21.2%, respectively, after propensity score matching, and there was no significant difference between the two groups. Four recipients in the ABO-CKT group and 6 in the ABO-IKT group developed steroid-resistant acute cellular rejection requiring OKT-3 or anti-human thymocyte immunoglobulin. Although the incidence of steroid-resistant rejection in the ABO-IKT group was higher than that in the ABO-CKT group  before propensity score matching, there was no significant change in the rate of steroid-resistance acute rejection between the two groups after propensity score matching.Two recipients experienced antibody-mediated rejection due to anti-A/B antibody titers. They developed antibody-mediated rejection without an explosive post-operative elevation in anti-A/B antibody titer  and were successfully treated with steroid pulse therapy, plasma exchange, intravenous administration of immunoglobulin, and/or rituximab administration. The incidence of antibody-mediated rejection in the ABO-CKT and ABO-IKT groups was 0% and 3.0% after propensity score matching, respectively. Accordingly, there were no significant differences in the rates of antibody-mediated rejection between the two groups.Of the 66 ABO-IKT recipients, 8 patients received splenectomy, 48 received administration of rituximab, and 10 received both splenectomy and administration of rituximab for B cell depletion. They also underwent 1 to 13 sessions of plasmapheresis to remove the anti-A/B antibodies. The range of initial anti-IgM and IgG A/B antibody titers was from 1:1 to 1:4096 and from 1:2 to 1:512, respectively, and our desensitization protocol achieved pre-operative A/B antibody titers of less than 1:64. Except for the two recipients who underwent antibody-mediated rejection, all the recipients experienced no significant post-operative anti-A/B antibody titer elevation causing antibody-mediated rejection.Cytomegalovirus (CMV) infection occurred in 50.0% of the ABO-CKT recipients and 62.0% (p = 0.219) of the ABO-IKT recipients. Two patients who received splenectomy as desensitization underwent very late-onset CMV disease: one experienced CMV colitis 15 years after transplantation, and one had CMV retinitis 9 years and 9 months after transplantation. There were no significant differences in the rates of adenovirus urinary tract infection, pneumocystis pneumonia, BK virus nephropathy, malignancies, delayed graft function, and post-operative bleeding between the two groups.In this present study, we compared the clinical outcomes between ABO-IKT and ABO-CKT recipients based on propensity score matching. As a result, there were no significant differences in graft and patient survival rates between the two groups. These results suggested that ABO-IKT may be an acceptable treatment for patients with ESKD even at an institution where only about two kidney transplants a month are performed on average.Due to the short supply of deceased donor grafts, living donor kidney transplantation accounts for about 30% of all kidney transplants performed in the United States and for approximately 90% in Japan –18. The There have been concerns about the suboptimal long-term outcomes of ABO-IKT which requires desensitization. Opelz et al reported that early patient survival was lower in ABO-IKT than in ABO-CKT due to a higher rate of early infectious deaths, although patient and death-censored graft survival rates were similar, by analyzing the international Collaborative Transplant Study (CTS) database . In a U.Desensitization protocols for ABO-IKT had not been established until recently. Our desensitization protocol consists of immune-modulation to remove anti-A/B antibodies prior to transplantation, B cell depletion therapy (splenectomy and/or rituximab administration), and pharmacotherapy. ABO-IKT is immunologically a high-risk procedure because of ABO incompatibility, but intensive immunosuppressive protocols for ABO-IKT may cause over-immunosuppression. We therefore modify our basic protocol depending on recipient age, rebound of antibody titers, or baseline antibody titer –15. AlthIn our study, only two patients underwent antibody-mediated rejection by anti-A/B antibodies and were successfully treated with intensive treatment including plasmapheresis. We did not experience graft loss due to antibody-mediated rejection with an explosive elevation in anti-A/B antibody titer. These results suggested that our intensive desensitization for ABO-IKT including B cell depletion, plasmapheresis, and pharmacotherapy may prevent intractable antibody-mediated rejection. On the other hand, steroid-resistant acute cellular rejection requiring OKT-3 or anti-human thymocyte immunoglobulin was more frequent in the ABO-IKT group than in the ABO-CKT group in the present study before propensity score matching. However, there was no significant difference in steroid-resistant acute cellular rejection between the two groups after propensity score matching . The incThere was no significant difference in the rate of infectious complications including CMV between the two groups in our study, although intensified desensitization for ABO-IKT has been reported to be associated with an increased risk of infectious complications –26. SpleRecently, there have been various studies to avoid excessive immunosuppression due to desensitization, not only without B cell depletion therapy –31, but KPD enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible pairs in order to find potentially compatible transplant donors. Single-center KPD has been reported from several countries including India, Romania, and Turkey. Multicenter or national KPD programs exist in many countries including the United States, Canada, Australia, the Netherlands, the United Kingdom, and Switzerland –36. PairKPD has some ethical issues, because the kidney of the donor may not be transplanted to the intended recipient but to an unknown recipient. Furthermore, coercion has been a concern for living donation, and it is possible that KPD places donors under even greater pressure to donate, because incompatibility is eliminated as an excuse to avoid donation . There aThere may be several limitations in the present study. The study was conducted using a retrospective design, and the number of patients enrolled in this study was small. Despite these limitations, excellent clinical outcomes of ABO-IKT were obtained by propensity score matching which were not significantly different compared with those of ABO-CKT at our institution where we perform only about two kidney transplants a month on average.In conclusion, at present, ABO-IKT may be an acceptable treatment for patients with ESKD even at a low-volume transplant center. ABO-IKT may increase the frequency of kidney transplants and may lead to the shortening of dialysis therapy or even its avoidance. Because KPD is not allowed in Japan due to ethical reasons, such a program may not be necessary, but further studies are needed to clarify this matter.


Background: Hypertension very often accompanies progression of chronic kidney disease (CKD) in children. A cross-sectional analysis of hypertension prevalence in dialyzed children in Poland was designed with a comparison with the data previously recorded 10 years earlier.Methods: Two cohorts of children were analyzed: 59 subjects dialyzed in 2013, and 134 children from the previous study performed in 2003 that were reevaluated according to the current methodology. The incidence of hypertension (defined by SDS of sBP or dBP >1.64), clinical data, medical history, dialysis modalities and selected biochemical parameters of dialysis adequacy were analyzed.Results: The prevalence of hypertension increased from 64% in 2003 to 78% in 2013. The efficacy of antihypertensive treatment remained unsatisfactory (61% proper BP control). Preservation of residual urine output and strict fluid balance may prevent development of hypertension in children on dialysis.Conclusions: Despite the higher awareness of hypertension and its complications in dialyzed children, the incidence of this entity has increased during the last decade, with the percentage of undertreated patients comparable to that observed 10 years ago. Thus, more attention should be paid to therapy efficacy in this population to prevent further damage to the cardiovascular system and to decrease morbidity. Usually, the percentage of hypertensive patients increases along with the progression of CKD from stage 1 to 5. In the cohorts of dialyzed children, regardless of the populations studied, all the authors reported the values over 70%.,The activation of the renin–angiotensin–aldosterone system and sodium retention play a pivotal role in renal hypertension regardless of the stage of the disease.,,,In numerous studies, it has been ascertained that special attention should be paid to adequate diagnosis and treatment of hypertensive dialyzed children. At least for 10 years, nephrologists have been aware of a low effectiveness of high blood pressure treatment in this population.To evaluate the changes in hypertension prevalence and the therapeutic approach to hypertension in chronically dialyzed children  that could have happened within the last 10 years, a cross-sectional analysis in all pediatric dialysis units in Poland was designed.The study was designed as a cross-sectional analysis of hypertension prevalence among the Polish population of chronically dialyzed children in the period of April to June 2013. All the 11 pediatric dialysis centers were approached with a request to collect data. Ten centers responded. The historical data of 134 dialyzed children from the study performed in 2003 were reassessed and combined with these recently obtained.The inclusion criteria encompassed age (0–18 years) and chronic dialysis (HD or PD) for at least 3 months. The study group consisted of 59 chronically dialyzed children (aged 3–222 months). Detailed characteristics of this group are presented in 3). A specific clinical form to be filled out (by treating physician) for every patient included into the study was designed. The data were sent back to coordinating center, checked for consistence and analyzed.The study form included the following records: CKD data, dialysis modality, its efficacy, anthropometrics, blood pressure values, additional clinical data , as well as selected laboratory parameters  measurements were performed employing a standard procedure applied for every clinical center (different oscillometric devices). Blood pressure during the routine PD clinical visit and a mean of three consecutive measurements (in a week) just before the hemodialysis procedure  were recorded.Blood pressure measurements were compared to the normative values of the Polish population and the standard deviation score  was calculated.,Patients’ height was assessed employing standard methods. For the purpose of the analysis, in case of HD children, posthemodialysis weight was recorded, whereas morning weight  was determined for PD children. Anthropometric measurements were compared to the Polish national growth charts.t-test or Mann–Whitney test. For multiple group comparisons, the authors used the nonparametric analysis of variance . If analysis of variance (ANOVA) yielded significant results, post hoc intergroup comparisons were performed using the Bonferroni–Dunn test. The Spearman’s rank correlation coefficient was used to evaluate associations between continuous variables. The chi-square and Fisher exact test were applied to compare the categorical variables. Multivariate analysis (in pooled groups) was performed using general linear regression model which estimated the effect of hypertension, time and confounding clinical variables. p values lower than 0.05 were considered significant.Statistical analysis. The results are expressed as medians and 25th–75th percentiles. Statistical comparisons between the groups were made by the two-sided unpaired p = 0.04). The aggregate (2003–2013) hypertension rate in the dialyzed children in Poland equaled 68%.In the current cohort of patients, 38/59 were diagnosed as hypertensive by the managing physician and treated, whereas 8/59 patients had abnormal high blood pressure values (diastolic or/and systolic) and were left untreated. Thus, the final hypertension prevalence was 78%, being higher than the reevaluated (with new growth and blood pressure charts) data originating from 2003, where the reevaluated prevalence rate was 64% (86/134)  demonstrated the same rate of hypertension as older patients.The percentage of patients with BP within the normal range (below 95th percentile) among hypertensive children was assessed. It was found that 22/38 children were undertreated and eight underdiagnosed (treating physician did not report hypertension), leading to an overall number of 30/46 (65%) children treated inadequately. After comparing these observations with the 2003 cohort, no significant increase in the treatment efficacy (65% in 2003) was found. After analysis of the influence of age on treatment efficacy, we revealed that children below and over 5 years of age revealed a similar prevalence of hypertension and a comparable rate of successful treatment as older ones.Clinical complications of hypertension and CKD included microangiopathy  and cardiomyopathy . Seven (15%) hypertensive children were positive for the former complication, whereas eight (17%) demonstrated the latter. Only one normotensive child presented with cardiovascular complications .p = 0.0196). Nevertheless, in both cohorts, CAKUT was the most frequent diagnosis.Two groups of children were compared with respect to the clinical factors that proved their significance in the previous studies. The distribution of underlying diagnosis of CKD (CAKUT/glomerulonephritis/other) among hypertensives and normotensives was similar; likewise was the PD/HD ratio . Figure Based on the previous studies, a comparison between selected biochemical parameters in normotensive and hypertensive children was performed, first in the cohort of 2013, then for the pooled cohort of 2003–2013. The authors intended to find potential factors associated with systolic and diastolic blood pressure , length of CKD , total protein  and hemoglobin . Diastolic BP correlated with age at CKD diagnosis  and daily diuresis . The analysis showed that diastolic blood pressure differed significantly depending on the underlying diagnosis . Patients with glomerulonephritis as the cause of CKD had higher diastolic blood pressure when compared to CAKUT (p =0.0064) and patients with other causes of CKD (p = 0.0372).Clinical and biochemical factors were included into the correlation analysis. Systolic BP SDS correlated negatively with daily urine output (p = 0.0179) and urinary output  for systolic blood pressure SDS and urinary output  for diastolic blood pressure SDS. Duration of CKD was associated with diastolic blood pressure, but this relation did not reach statistical significance .The multivariate analysis (within the pooled group of 2003–2013 children) proved the significance of duration of CKD  as 64%, whereas in 2013 as 78%. The increase was an unexpected phenomenon, because of major increase in clinical knowledge about dialyzed children hypertension. The authors expected to find an increase rather than a decrease of therapy adequacy.In a large European registry, abnormal blood pressure was significantly more prevalent in: (1) cohorts of very young patients (under 3 years of age) as compared to 13- to 17-year olds (odds ratio (OR): 2.47); (2) during the first year compared to an over 5-year period of renal replacement therapy (RRT) duration (OR: 1.80); and (3) in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis .,The authors faced a comparable (65%) rate of children treated inadequately in 2003 and 2013. Chavers et al. reported in 2009 that the 74% of hypertensive hemodialyzed children were undertreated in the United States.The numbers of failures in hypertension treatment between 2003–2013 were comparable. The explanation of this phenomenon is not simple, but it can be hypothesized that in the cohort of 2013, the clinical condition of the dialyzed children was more severe as compared to the former group (selection bias). On the other hand, it may be assumed that the awareness of necessity for standard hypertension diagnosis and treatment among Polish nephrologists did not increase. This may lead to suboptimal preventive cardiovascular care that may worsen cardiovascular mortality in young adults in the near future.,The lifespan of children on dialysis in the United States is 40–60 years shorter and for transplant patients, about 20–25 years shorter than that of an age- and race-matched US population.,,In the CKD study, the features associated with elevated BP included: black race, shorter duration of CKD, the absence of antihypertensive medications and elevated serum potassium.,,Previous studies showed that patients with uncontrolled hypertension were younger and had shorter CKD 5 stage duration.In the most extensive analysis by Hallbach at al., significant differences in BP control by dialysis modality and disease etiology were assessed and the highest percentage of uncontrolled hypertension was found in hemodialyzed patients and patients with glomerular diseases.With respect to fluid overload as a risk factor for high blood pressure, both direct and indirect measurements were applied. In the 2003 cohort, relative fluid overload was assessed by hemoglobin concentration or total protein/albumin concentration.The present study has some strengths and limitations. Firstly, a cross-sectional analysis was designed to compare the populations of dialyzed children after a decade. The important point of this analysis was the participation of all (but one) the same pediatric dialysis centers in Poland. There was no bias in changing the treatment policy due to change of attending physicians. All the children in the study were of the Caucasian origin, which allowed to use the recently published national growth and blood pressure population charts.On the other hand, the cross-sectional design of the study provided reliable data on the hypertension prevalence (as it was aimed), but a longitudinal observation of the children cohort could have given more data on risk factors associated with the RRT procedures.Relatively small number of patients in the 2013 cohort might be a weak point of the paper. The number of dialyzed children decreased within this period, which may be noted as a success of pediatric nephrology and transplantation in Poland. During the last decade, the overall number of dialyzed children in Poland decreased of 40% due to more efficient diagnosis and nephroprotection  and higher rate of successful transplantations. To overcome this weakness, authors combined two cohorts of patients to obtain statistical significance in the multiple regression analysis.From the methodological point of view, it should be pointed that the anthropometric and blood pressure measurements were not standardized for every center and hypertension was not confirmed by ABPM. Nevertheless, according to the 4th Report, casual blood pressure measurement is an accepted method of diagnosing hypertension. In 2003, there was no adequate equipment for ABPM in Polish dialysis units.Summarizing the results of this study, it should be emphasized that despite the availability of modern diagnostic and treatment methods, in chronically dialyzed children in Poland, hypertension is highly prevalent, partially underdiagnosed and in most cases undertreated.A significant improvement in this field was expected, but after comparing the data from 2003 and 2013, no progress was made during this period, despite the success in reduction of number of dialyzed children.


Chronic kidney disease (CKD) is a burgeoning epidemic in sub-Saharan Africa. Abnormal blood pressure variations are prevalent in CKD and potentiate the risk of cardiovascular morbidity and mortality. Certain genetic variants (angiotensin II receptor type 1 1166 A>C and angiotensin-converting enzyme insertion and deletion polymorphisms) and biomarkers such as interleukin–6, tumor necrosis factor, soluble (s) E-selectin, homocysteine, and highly sensitive C-reactive protein have been shown to affect blood pressure variability among non-African CKD, hypertensive. and nonhypertensive CKD population. However, the contributions of the pattern, genetic, and environmental determinants of ambulatory blood pressure in African CKD have not been characterized. Understanding these interactions may help to develop interventions to prevent major cardiovascular events among people with CKD.The overarching objective of this study is to identify, document, and develop approaches to address related phenomic, genetic, and environmental determinants of ambulatory blood pressure patterns in African CKD and non-CKD hypertensive patients compared with normotensive controls.This is a longitudinal short-term follow-up study of 200 adult subjects with CKD and 200 each of age-matched hypertensives without CKD and apparently healthy controls. Demographic information, detailed clinical profile, electrocardiography, echocardiography, and 24-hr ambulatory blood pressure measurements will be obtained. Blood samples will be collected to determine albumin-creatinine ratio, fasting plasma glucose, lipid profile, electrolytes, urea and creatinine, C-reactive protein, serum homocysteine, fibroblast growth factor–23, and complete blood count, while 2 mL blood aliquot will be collected in EDTA (ethylenediaminetetraacetic acid) tubes and mixed using an electronic rolling system to prevent blood clots and subsequently used for DNA extraction and genetic analysis.A total of 239 participants have been recruited so far, and it is expected that the recruitment phase will be complete in June 2020. The follow-up phase will continue with data analysis and publications of results.This study will help stratify Nigerian CKD patients phenotypically and genotypically in terms of their blood pressure variations with implications for targeted interventions and timing of medications to improve prognosis.DERR1-10.2196/14820 Chronic kidney disease (CKD) is rising in public health importance in Nigeria and contributes significantly to the increased burden of cardiovascular disease (CVD) in the country and sub-Saharan Africa in general -4. It haPoorly managed CKD is often associated with rapid progression to end-stage renal disease (ESRD) and cardiovascular disease (CVD) ,10. The CKD’s contribution to CVD is through many pathophysiologic mechanisms, cardinal among which is the failure of nocturnal blood pressure (BP) dipping. Studies have shown that being a nondipper increases the risk of CVD by 2.4 fold in patients with CKD -14. FurtPrevious studies have identified various biomarkers in non-African non-CKD hypertensive blacks to be associated with BP variability, including interleukin–6, tumor necrosis factor–alpha, soluble (s) E-selectin, homocysteine, and high-sensitivity C-reactive protein -18. SomeThe current approach to reducing the CVD burden is chronotherapy, through which 24-hour optimal BP control is ensured. However, not all patients respond well to chronotherapy, suggesting that the mechanism underlying the nondipping of BP and nocturnal hypertension in CKD is not completely understood ,20. StudThe mutations in the two genes have been shown to cause abnormal activation of the renin-angiotensin-aldosterone system (RAAS) with characteristic elevations in the systemic levels of renin, aldosterone, and angiotensin II, which eventually lead to potassium ion loss and sodium ion retention, left ventricular hypertrophy, and atrial fibrillation ,23. AbnoThis study seeks to identify, document, and develop approaches to address related phenomic, genetic, and environmental determinants of ambulatory BP patterns in African CKD and non-CKD hypertensive patients compared with normotensive controls. We will also explore the associations between genetic variants in the RAAS pathway and nocturnal BP variations and its cardiovascular sequelae among CKD patients.Evaluate the contributions of traditional and novel sociodemographic, clinical, and environmental risk factors to ambulatory BP patterns in African CKD and hypertensive patients compared with normotensive controlsDetermine AGTR1 1166 A>C and ACE I/D genotypes and allele distributions among nondipper Nigerians with CKD and nonhypertensive CKD while comparing the same among dippers and nondippersDetermine the association between AGTR1 1166 A>C and ACE I/D genotypes and ambulatory BP phenotypes Determine the association between AGTR1 1166 A>C and ACE I/D genotypes and cardiovascular risk factors  among Nigerians with CKD and nonhypertensive CKDDetermine the association between AGTR1 1166 A>C and ACE I/D genotypes and major cardiovascular events  among Nigerians with CKD and nonhypertensive CKDDetermine the genes by environmental interactions that are associated with nocturnal BP variability among Nigerians with CKDUnique environmental risk factors will contribute to ambulatory BP pattern in African CKD and hypertensive individuals of African ancestry.Polymorphisms of AGTR1 1166 A>C and ACE I/D are higher among CKD dippers compared with CKD nondippers.Polymorphisms of AGTR1 1166 A>C and ACE I/D are associated with ambulatory BP phenotypes and cardiovascular risk factors in CKD and non-CKD hypertensives.Polymorphisms of AGTR1 1166 A>C and ACE I/D are associated with cardiovascular risk factors among patients with CKD.Polymorphisms of AGTR1 1166 A>C and ACE I/D do not interact with environmental factors  in the development of nondipping.This is a longitudinal short-term follow-up study of 200 adult subjects with CKD and 200 each of age-matched hypertensives without CKD and apparently healthy controls. The CKD cases and non-CKD hypertensive patients will be recruited from the medical outpatient clinics at the University College Hospital, Ibadan, and the Nigerian Institute of Medical Research (NIMR) , Yaba, LThe study was approved by the University of Ibadan/University College Hospital Research Ethical Committee with approval number UI/EC/18/0291. Participants are required to give written informed consent to participate in the study.The study will be carried out in the NIMR and the Department of Medicine, University of Ibadan University College Hospital, a teaching hospital with a 850-bed capacity and several community care centers in Ibadan and other sites within the state from where CKD cases are referred. It has full complements of all clinical and nonclinical departments. The hospital provides both preventive and curative services and is equipped with cardiac, neuroimaging, and other laboratory facilities. From the registry, a monthly average of 50 cases of CKD are seen in the renal clinic.NIMR is the hub for research, human resource capacity building, and collaboration for national development in the country. It is a foremost health research institute established in 1977 to conduct basic, applied, and implementation science research on infectious and noncommunicable diseases of public health importance in Nigeria. NIMR is made up of five major divisions: Microbiology, Public Health, Biochemistry and Nutrition, Molecular Biology and Biotechnology, and Clinical Sciences and has three support research units: Centre for Human Virology and Genomics, Centre for Tuberculosis Research, and Centre for Alternative Medicine and Research.The inclusion criteria for the study are being aged ≥18 years and having a diagnosis of CKD, while the exclusion criteria are diagnosis of autosomal polycystic kidney disease or sickle cell nephropathy .Chronic kidney disease: estimated glomerular filtration rate less than 60 mL/min/1.73 m2 on two or more occasions at least 3 months apartHypertension: systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg or both and on antihypertensive medicationDiabetes mellitus: fasting blood sugar ≥126 mg/dL or on medications for diabetesWaist circumference: >102 cm  and >88 cm Obese: body mass index ≥30 kg/m2Dyslipidemia: total cholesterol >200 mg/dL , high-density lipoprotein <40 mg/dL , <50 mg/dL , or low-density lipoprotein >130 mg/dL Hyperuricemia: serum uric acid >7 mg/dL  and >6 mg/dL The inclusion criteria for the study are being aged ≥18 years and having a diagnosis of hypertension, while the exclusion criteria are diagnosis of autosomal polycystic kidney disease, sickle cell nephropathy, or CKD .The inclusion criteria for the study are being aged ≥18 years and apparently clinically normal, while the exclusion criteria are subjects with autosomal polycystic kidney disease, sickle cell nephropathy, or CKD.The study will be in 2 phases. In the initial phase, data will be collected in standard case report form (available on request) and information regarding bio-data, risk factors for CVD, lifestyle, stage of CKD, and comorbidities will be obtained. Other important variables will include clinical features and medication use of participants.Demographic information, detailed clinical profile, electrocardiography, echocardiography, and 24-hour ABPM will be obtained. In addition, the dialysis vintage, frequency of comorbidities, family history of hypertension and kidney disease, medication, and medication adherence using pill count will be accessed.Participants will subsequently be assessed at 6 months, 1 year, and 2 years for any cardiovascular adverse outcomes. Major adverse cardiovascular events such as cardiac death and hospitalization for cardiac events will be assessed while noncardiovascular death and events will also be noted. Serum creatinine will be assessed.Anthropometric measurements  will be performed using World Health Organization guidelines ,27. A se24-hour ABPM will be done using Spacelabs 90207 monitors  which will be placed on the nondominant hand within the first week of recruitment. The machine will be programmed to read every half hour from 7:00 am to 10:00 pm and hourly from 10:00 pm to 7:00 am during weekdays. Patients will be encouraged to proceed with their routine daily activities but avoid strenuous physical activities and keep motionless at the time of measurement. Dipping pattern, white coat effects, and nocturnal and daytime hypertensions will be deduced from the readings.Venous blood samples (5 mL) will be drawn from each study participant after an overnight fast by medical personnel with phlebotomy training at each site. All tests and examinations will be performed between 8:00 am and 10:00 am daily. Three mLs aliquot of the blood sample will be collected in plain tubes to determine albumin-creatinine ratio, fasting plasma glucose, lipid profile, electrolytes, urea and creatinine, C-reactive protein, serum homocysteine, fibroblast growth factor–23, and complete blood count, while the remaining 2 mL aliquot will be collected in EDTA (ethylenediaminetetraacetic acid) tubes and mixed using an electronic rolling system to prevent blood clots and subsequently used for DNA extraction and genetic analysis.Early morning urine and fasting blood sample will be collected. Estimated glomerular filtration rate (eGFR) will be calculated using the Modification of Diet in Renal Disease 4-variable equation. Subjects will be followed up at 3-month intervals for 1 year.2, 50 mmol KCl, 10 mmol Tris-HCl (pH 8.3), and 1.5 U of Taq polymerase (Promega Corp). Amplification will be carried out for 30 cycles with steps of denaturation at 94°C for 1 minute, annealing at 54°C for 1 minute, and extension at 72°C for 1 minute. The PCR products were subjected to electrophoresis in 1% agarose gels. Amplification of the D allele resulted in a 190-bp DNA fragment and amplification of the I allele resulted in a 490-bp fragment. Homozygotes had a single 190 (DD)– or 490 (ID)–bp band; heterozygotes had one 190-bp and one 490-bp band. The PCR products will be analyzed on 2% agarose gels with a 100-bp DNA Ladder (Promega Corp), and images were acquired and analyzed using a gel imaging system.QIAamp DNA Blood Mini Kits (Qiagen) will be used to extract DNA from blood cells. A 287-bp I/D polymorphism in the intron 16 of the ACE gene will be examined by polymerase chain reaction (PCR). The sequences of the sense and antisense primers were 5′-CTG GAG ACC ACT CTT TCT-3′ and 5′-GAT GTG GCC ATC ACA TTC GTC AGA-3′, respectively. Both forward and reverse primers will be synthesized by Inqaba Biotec. The PCR will be performed in a final volume of 20 μL, containing 100 ng of genomic DNA, 40 pmol of each primer, 200 μmol each of the four dNTP, 3 mM MgCl2, 200 µM each of the deoxynucleotide triphosphates, 10 picomoles each of the forward and reverse primers, and 1.5 U of Taq DNA polymerase. PCR amplification will then be carried out in the SimpliAmp Thermal Cycler (Applied Biosystems). The conditions for PCR amplification consisted of 2 minutes denaturation at 94°C, followed by 40 cycles of 1 minute at 94°C, 1 minute annealing at 60°C, extension for 2 minutes at 72°C, and final extension for 10 minutes at 72°C. The resulting PCR products of the expected size (850-bp) will subsequently be analyzed by agarose gel electrophoresis with 1% agarose gel prestained with 0.5 µg/mL ethidium bromide in Tris-borate-EDTA buffer (pH 8.3) at 70 volts for 1 hour. To characterize the polymorphism, PCR products will be digested overnight with the restriction endonuclease Dde I (BioLabs Inc) at 37°C. This is expected to cut the product into two pieces, 600-bp and 250-bp long. An additional Dde I recognition site will be created in the C-type variant at nucleotide 1166, which is located within the 250-bp fragment. Therefore, the homozygote AA is expected to produce two bands (600-bp and 250-bp long), heterozygote AC to produce four bands , and homozygote CC to produce three bands . Analysis of the digested PCR products will also be done by agarose gel electrophoresis by using 3% agarose gel prestained with ethidium bromide in Tris-borate-EDTA buffer (pH 8.3), using gel electrophoresis apparatus (Promega Corp) and ultraviolet transillumination (Applied Biosystems). All the PCR products will be analyzed with a 100-bp DNA Ladder (Promega Corp), and gel images of DNA bands will be acquired and analyzed using a gel imaging system.The AGTR1 gene will be genotyped for 1166 A>C polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method as described by Zhu et al  using thThe primary outcomes will be a composite of cardiovascular events  requiring hospitalization and death. Secondary outcomes will be a composite of ESRD, 50% decline in eGFR, and doubling of serum creatinine. Composite of hospitalization from cardiovascular events such as myocardial infarction, heart failure, and stroke will be significantly higher among CKD subjects compared with controls.t test and analysis of variance where there are more than 2 groups. Continuous variables not normally distributed will be compared by the Mann-Whitney U test or the Kruskal-Wallis test where there are more than 2 groups. Correlations between two continuous variables will be assessed using Pearson correlation statistics. Linear and multiple logistic regression analyses will be used to determine factors predicting nondipping of BP and cardiovascular sequelae. The allele frequencies of the candidate gene variants will be determined for the AGTR1 1166 A>C and ACE I/D in CKD nondipper and controls. A test for associations between the variants and BP phenotypes will be performed by fitting covariate-adjusted logistic regression models in which each variant will be presented as a predictor variable whose values are equal to the number of copies of the minor allele  or presence of at least one copy of the minor allele  or presence of two copies of the minor allele . All tests of association will be adjusted for gender, age , severity of CKD, and other relevant covariates. Both ACE DD/ID and AGTR1 1166 A>C polymorphisms will also be evaluated for Hardy-Weinberg Equilibrium in the control group. The logistic model can be represented as logit[(pr=D)] = α + β1G + β2Sex+ β3Age . Statistical significance for the adjusted odds ratio will be set at 0.05.The statistical analysis will be carried out using R (The R Foundation), and all categorical variables will be compared by chi-square test or Fisher exact test where indicated. Continuous variables that are normally distributed will be compared by means of the Student The power analysis for the genetic analysis is based on the primary analysis to assess the main effects of AGTR1 1166 A>C and ACE I/D polymorphisms and their interaction with environmental factors in Nigerians with CKD. Based on minimum allele frequencies of 0.12 and 2×105 for AGTR1 1166 A>C and ACE I/D polymorphisms, respectively. We will also assume that three genotypes of AGTR1 1166 A>C are equally distributed, and the probability of developing nondipping in the reference genotype group is 0.3. Data will be analyzed using SPSS version 20 (IBM Corp). Given a sample size of 600 (200 per group), this study design would have at least 80% power to detect a minimum odds ratio of 2.0 in patients with any of the three gene variants, using Bonferroni correction with type I error of 5%.The study is supported with an International Society of Hypertension (ISH) Research Scholar Grant Award. A total of 239 participants have been recruited so far, and it is expected that the recruitment phase will be complete in June 2020. The follow-up phase will continue with data analysis and publications of results.The prevalence of CKD and the associated adverse outcomes are on the increase in Nigeria ,5,9,10. There is evidence of association of AGTR1 1166 A>C and ACE I/D polymorphisms with CKD and cardiovascular diseases, their roles in non-BP dipping at night, and nocturnal hypertension, but this remain unclear among African blacks. The effects of these polymorphisms on Nigerian CKD patients either in the context of BP regulation or response to antihypertensive medications and other cardiovascular risk factors  have not been evaluated.Given the fact that genetic environment influences the pathogenesis of CKD, cardiovascular risk factors, and cardiovascular diseases, there is a need to stratify Nigerian CKD patients genotypically using a translational research approach prior to integrating supportive therapy of CKD management for improved prognosis. Unraveling the role of these genetic polymorphisms among nondipper Nigerian patients with CKD will provide insight into the mechanisms underlying nondipping and CVD complications. This will also guide appropriate stratification into risk of ESRD progression and CVD risk profiling for adequate treatment plans, prevention plans, and appropriate policy changes.Furthermore, identification of CKD patients at risk of nondipping using molecular and genetic markers will guide in appropriate use of cardiovascular risk stratification and predicts response to chronotherapy.This case control study of 600 participants with 3 arms of 200 each, comprising CKD nondippers, CKD dippers, and apparently healthy controls will use comprehensive phenotyping and genotyping of RAAS pathway variants to identify genetic risk markers among CKD nondippers. It will be the first major study to assess this among African blacks.This study will also explore the potential of the use of PCR-RFLP as a laboratory test for CKD with hypertension prior to treatment initiation for better stratification of patients for morning or night antihypertension medications in Nigeria. This innovative tool is rapid, cost effective, and highly applicable to larger cohorts of CKD patients compared with the more laborious, time-consuming conventional ABPM required for the identification of nondippers and patients with nocturnal hypertension. The PCR-RFLP technique will become a routine point-of-care test for personalized treatment of hypertension among affected CKD patients in the country.


One hundred forty-four deaths were recorded. Area under the curve using ROC analysis for NT-proBNP showed: all causes of death (0.761), CVD-related (0.750), infection and malignancy-related (0.702) and others and unknown (0.745). After adjusting for age, sex, hemodialysis vintage, cardiothoracic ratio, mean pre-dialysis systolic blood pressure, dry weight and basal kidney disease, the hazard ratios  per 1-log NT-proBNP calculated using multivariate Cox analysis were: all causes of death, 3.83 (2.51–5.85); CVD-related, 4.30 (2.12–8.75); infection and malignancy-related, 2.41 (1.17-4.93); and others and unknown origin, 5.63 (2.57–12.37). NT-proBNP was significantly associated not only with CVD-relate but also with non-CVD-related deaths in this population of prevalent chronic dialysis patients.N-terminal-pro-B-type-natriuretic peptide (NT-proBNP) was a predictive marker of cardiovascular disease (CVD)-related death in chronic dialysis patients. NT-proBNP was also correlated with markers of inflammation, malnutrition and protein-energy wasting. We hypothesized whether NT-proBNP was also associated with non-CVD death in chronic dialysis patients. A prospective observational study for incidence of death in chronic dialysis patients was conducted. Prevalent chronic dialysis patients ( Numerous factors have been surveyed as predictors of mortality in hemodialysis patients. In cardiovascular disease (CVD), death from classical Framingham atherosclerotic risk factors, hypertension, dyslipidemia, smoking, glucose intolerance and left ventricular hypertrophy have not been thought sufficient to predict mortality . Blood pThe N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) is an N-terminal inactive protein that is cleaved from proBNP to release active peptide BNP. NT-proBNP is a biomarker of left ventricular stress in non-CKD patients . It is aThis study was conducted in accordance with the principles contained in the Declaration of Helsinki, and was granted ethical approval by the University of Miyazaki Research Ethics Committee (No. 516). Informed consent was not obtained from participants because all data were anonymized.We enrolled 1310 prevalent chronic hemodialysis patients  from 27 dialysis centers on December 31, 2010. Using the same cohort as we previously reported [Clinical data comprising age, sex, hemodialysis vintage, basal kidney disease, pre-dialysis blood pressure, dry weight, cardiothoracic ratio (CTR), cause of death, and transfer to other clinics or hospitals were collected. All data on each patient was reported by an attending physician. This information for each patient was added to the patient’s own check sheet and the attending physician checked new events monthly, then the information including a questionnaire was sent back to the University of Miyazaki as we previously reported . Mean prEach cause of death was reported by attending physicians and reconfirmed with medical records, searched by YS and TT if necessary. Causes of death were defined as we previously reported . CVD deaNT-proBNP was measured using electrochemiluminescence immunoassays  using serum drawn before the first dialysis session. Blood pressure was measured in the supine position by trained staff after at least 5-min rest. The CTR was calculated using a chest X-ray taken before the first dialysis session.All statistical analyses were performed with SPSS version 20.0 J software . Data are expressed as mean ± SD, except for raw NT-proBNP, which is expressed as median and 25th–75th percentile. Clinical parameters according to classification of NT-proBNP quartiles were compared using one-way analysis of variance or the Kruskal–Wallis test as appropriate. Categorical parameters were compared using the chi-square test. To examine the correlation between NT-proBNP and clinical parameters, the Spearman rank correlation test was used.The diagnostic performance of NT-proBNP for mortality was assessed by analysis of the receiver operating characteristic (ROC) curve. The ROC curve was a plot of sensitivity vs. (1-specificity) for all possible cut-off values. To identify the optimal cut-off point, we chose the closest point to the left upper corner of the ROC curve . Survivap Values <.05 was considered statistically significant.We used univariable and multivariable Cox analyses to examine the independent association between the level of NT-proBNP and mortality. In the multivariable analysis, these associations were assessed with adjustments for age, sex, hemodialysis vintage, CTR, pre-dialysis systolic blood pressure, dry weight and basal kidney disease. NT-proBNP data were normally distributed in logarithmic transformed data but not in raw data. The median value (25th–75th percentile) of the raw data were 4855 (2209–12358) ng/L, mean value ± SD of the digit number was 3.74 ± 0.54. These data were clearly elevated compared with the normal range (<125 ng/L) in patients without kidney function failure.r = 0.31, p < .01)     (Logarithmic NT-proBNP correlated well with age (p < .01)  and CTR p < .01) , but notp = .01) , mean prp < .01) , or dry p < .01) .During the study period, a total of 144 deaths were recorded . Among tWhen the clinical data were compared among survivors and non-survivors, who were classified into four causes of death, non-survivors were found to be significantly older than survivors . NT-proBTo clarify the cut-off point that would distinguish between a better and worse prognosis, ROC curves and Kaplan–Meier analyses were performed. Sensitivity and specificity for all causes of death was assessed using ROC . For theWe examined the significance of NT-proBNP at predicting mortality using Cox analysis . With unWe identified that NT-proBNP was associated with future infection and malignancy-related or others and unknown cause of death in addition to CVD-related deaths in this population of prevalent chronic dialysis patients.NT-proBNP accumulates in patients with kidney failure, especially those on chronic dialysis. Our data revealed that the accumulated NT-proBNP level was strongly associated with not only CVD-related deaths but also non-CVD-related ones. Recently, increasing NT-proBNP levels during the study period were reported to be associated with sudden death, cardiovascular events, and mortality in diabetic dialysis patients . NT-proBNT-proBNP has been reported as a predictor for cardiovascular mortality in dialysis patients . FurtherThe reasons that NT-proBNP, considered a circulatory marker, was associated with non-CVD-related death in this study are not known. We can speculate that those patients might have had chronic heart failure resulting in a chronic pulmonary congestive state, regardless of severity. Such a state is a known risk factor for morbidity from pneumonia ,28 and mProBNP was also degraded by adipose tissue, which is sometimes much less in dialysis patients, especially those with a lower body mass index (BMI) . These pThe reasons why higher NT-proBNP levels are associated with malignancy-related death are unclear; however, some of these might be as follows. First, malignant patients usually have a lower BMI, and as stated above, these patients have been found to have higher levels of proBNP . Second,In multivariate analysis, increments in pre-dialysis systolic blood pressure were associated with a better prognosis, especially for all causes and cardiovascular-related deaths. In the general population, controlling and lowering blood pressure is recommended to prevent heart failure; however, for dialysis patients, there is no accurate optimum blood pressure level. At times, physicians have observed that an increased dialysis vintage results in lowered blood pressure, yet a lower blood pressure does not always mean a good prognosis.This study had some limitations. The cohort comprised of prevalent chronic hemodialysis patients, and was not an incident cohort. Therefore, some sick patients might have died before being enrolled in our study. We could not identify the real cause of death among sudden death or unknown origin cases. Among them, there might have been some patients who had suffered from acute myocardial infarction or stroke. We did not have echocardiogram data, which have been reported to show a significant relationship with NT-proBNP ,18,24. I


Electronic health  services could provide a solution for monitoring the blood pressure of at-risk patients while also decreasing expensive doctor visits. However, a major barrier to their implementation is the lack of integration into organizations.Our aim was to design a Care Pathway for monitoring the blood pressure of at-risk patients, in order to increase eHealth implementation in secondary preventive care.A qualitative design study was used in this research. Data were collected by conducting visual mapping sessions including semistructured interviews with hypertension patients and doctors. The data were transcribed and coded and thereafter mapped into a Care Pathway.Four themes emerged from the results: (1) the current approach to blood pressure measuring has disadvantages, (2) risk and lifestyle factors of blood pressure measuring need to be considered, (3) there are certain influences of the at-home context on measuring blood pressure, and (4) new touchpoints between patients and health professionals need to be designed. These in-depth insights combined with the visualization of the current blood pressure process resulted in our Care Pathway design for monitoring the blood pressure of at-risk patients as secondary preventive care.The Care Pathway guides the implementation of eHealth devices for blood pressure self-measurement. It showcases the pathway of at-risk patients and increases their involvement in managing their blood pressure. It serves as a basis for a new service using eHealth. The arrival of internet-enabled health , which ushered in large online health databases and platforms, caused a change in the attitude of health-conscious consumers and their relationship with health professionals. Health professionals are no longer the main source of health care information. Many consumers seek confirmation of their general practitioners’ (GP) decisions on the Internet, enabling them to be more active in their health management -3. For iTo deal with higher demand for health care, social care, and social pensions from an ageing population and in the face of a shrinking workforce, the care models must be redesigned. Costs must be reduced without compromising the quality and accessibility of health care . To achiSelf-measured blood pressure devices have been around for many years but have not been extensively implemented in health services . Early oThe current approach to monitoring blood pressure of at-risk patients is used as tertiary preventive care, while eHealth services can make the shift to secondary preventive care. In order to make this shift, the current situation of monitoring blood pressure was researched. Communication and data streams between all the actors are important to design a Care Pathway for secondary preventive care. The major barrier that must be overcome in implementing preventive eHealth services is its lack of integration into organizations. The embedding of ICT requires care provider pathways that cross organizational boundaries. Care Pathways can be described as a concept for making patient-centered care operational  and gainThe objective of our research is to design a Care Pathway for monitoring blood pressure of at-risk patients, focusing on the exchange of data and communication between the individuals involved. To do so, we will first define the current situation and use this to create a Care Pathway that focuses on clarifying how processes should be carried out and by whom in order to increase the adoption of eHealth services . The folFor this research, a qualitative approach is used to explore this relatively new field. A qualitative research approach allows us to gain a better understanding of underlying opinions, reasons, and emotions . A phenoA visual mapping toolkit with an interview guide were used to organize generative sessions with the participants. As a result, a Care Pathway was co-created . This waPurposeful sampling was used to identify and select individuals who had experiences with the studied phenomenon of eHealth . For theAll interviewed patients had been diagnosed with high blood pressure after several measurements taken by their GP and 24-hour measurement at home. For one day they carried a blood pressure device around that measured their blood pressure every 30 minutes for 24 hours. All were prescribed medicines and had a GP consultation at least once a year. Patient 1 is part of an eHealth monitoring program and therefore regularly measures his blood pressure by himself. Patients 2 and 3 obtain information about their blood pressure only during their yearly consultation.The research was performed according to the principles of the Helsinki Declaration and Nuremberg and was checked and reviewed by the human research ethics committee (HREC) of the Delft University of technology . We did To generate insights into the interactions between the actors and the data streams, a visual mapping toolkit was designed, as introduced and outlined in a design research protocol by Meeuwen, Walt Meijer, and Simonse . This toSix mapping sessions were performed with three patients and three GPs. The visual mapping session was built up in several levels since people’s needs and values are often difficult to discuss . The parThe interview guide was constructed for the different actors, providing structure to the interviews while still maintaining the freedom to go into depth on certain topics . The strTriangulation was used in the analysis by clustering the data from in-depth interviews, visual mapping sessions, and documentation . First, Before designing the Care Pathway, the current blood pressure process was visualized , drawn fOn four themes that emerged from the data analysis, there is common agreement: (1) the current approach to blood pressure measuring has disadvantages, (2) risk and lifestyle factors of blood pressure measuring need to be taken into account, (3) there are certain influences of the at-home context on measuring blood pressure, and (4) new touchpoints between key actors need to be designed. Themes 1 and 2 relate to the current situation of blood pressure measuring and point out strengths and pitfalls. Theme 3 reveals important insights into self-measuring and monitoring blood pressure at home, and the perceived positive effects on patients’ well-being, accuracy of measurement results, and health care costs and the negative effect of insecurity. Theme 4 extracts the new elements in the co-designed Care Pathway. The coding tree in One of the essential disadvantages of blood pressure measuring is that it is a snapshot of one measurement that varies over time. This drawback was quoted 27 times by participants . Those risk factors are part of someone’s lifestyle. The patients often stated that they have tried to adopt a healthier lifestyle after being diagnosed with high blood pressure (12 quotes).The GP prescribed medicines but I didn’t want to take them. So, I started doing sports andPatient 3losing weight, but getting stress under control was hard.Patient 3Both the specialist internal medicine and patients pointed out that lifestyle is hard to change, while lifestyle modification could also help lower blood pressure.Measuring blood pressure at home enables patients to be in control of their own health care (16 quotes). Moreover, it gives a better overview and therefore more accurate measurements (9 quotes). Patients measure their blood pressure in a trusted environment at standard moments. This increases the reliability of the measurements. The benefit of self-measuring is that it reduces the influence of different context factors that can affect a person’s blood pressure temporarily (6 quotes). Patients can decide when to measure and analyze their measurements themselves:People enjoy measuring their blood pressure at home because it gives them power over their own health and they can try to influence it by looking at their lifestyle: if I eat less salt, does my blood pressure drop?GP 1We also observed a difference in attitude among the participants towards blood pressure measuring. GP 1 and Patients 2 and 3 mentioned that this might put too much emphasis on their condition and that they do not want to be confronted with it too much:Blood pressure measuring is a hot item, but it can make people feel unhappy as well. We should not exaggerate it, but it’s definitely an important factor.GP 1Patients pointed out that measuring their blood pressure at home has benefits (6 quotes), but they do have insecurities about the self-measurement (15 quotes). Patients are insecure about how to perform a measurement and self-interpret the results, and they are anxious about the accuracy of the product:Every time I measure, I wonder: do I measure technically good? Do I operate the product in the right way? Do I measure at the right moment?Patient 1data exchange of the results through an app (39 quotes) or email and would prefer occasional feedback on the data overviews from a care professional, either the GP or GP assistant (29 quotes). The GPs are also in agreement that there should be personal contact between a GP and patient because:To ensure the successful implementation of the eHealth product, new touchpoints between the different key actors were defined. Both the patients and the GPs want to keep scheduling regular consulting moments, which can be with the GP or the GP assistant. From the analysis of all co-creation sessions, we concluded that patients prefer to measure their own blood pressure at home but would also like to have contact with their GP occasionally. All patients mentioned that they would prefer ...you can use personal contact to motivate patients.GP 2The patients want to be able to view and analyze their own data to have a sense of control (13 quotes):I like the feeling that I can look at my own results. That is important to me … I want to keep an eye on my GP.Patient 1Concerning the frequency of contact moments, interestingly the patient with eHealth experience wanted to be checked more frequently and preferred having this done by the GP:...a GP would have probably responded to that, but the assistant did not.Patient 1The others agreed that the current frequency of GP consultations, every 6 or 12 months, is preferable (28 quotes), as they are not then constantly reminded about their blood pressure. There is a further division in whom patients want to share and discuss their data with. Patients 2 and 3 were satisfied with having a consultation once a year done by a GP assistant, under the supervision of the GP, who has greater expertise. The participants also wanted to keep the specialist in the loop to help with the interpretation of the blood pressure data concerning the risks of their particular health condition (9 quotes). Overall, we concluded that participants would prefer a Care Pathway that includes both self-measurement and professional care monitoring.The new design of the Care Pathway for at-risk patients as secondary preventive care is displayed in When the blood pressure is too high, the patient will receive a blood pressure monitor for at-home use and start to self-measure the blood pressure, generating an overview over a period of 3 months.The measured data will be saved by the device and automatically transferred to the health record system.The GP assistant receives an e-message if the patient’s blood pressure is too high.Instantly the GP assistant analyzes the data and provides direct feedback to the patient.In some incidents, this feedback message might state that the data needs to be checked by the GP.For most incidents, the GP assistant is expected to do the monitoring and communicates with the patient.In stable situations, there is a  contact moment every 3 months.Furthermore, the GP assistant will also communicate with the pharmacists on changes in medication doses.The blood and medication monitoring remain under the supervision of the GP, who will make the final decisions concerning medication and further diagnoses and treatments.Another aspect that is similar to the current process is that if the GP cannot control the blood pressure or if a patient has many other risk factors, the GP will refer the patient to a specialist (in most cases the internist). The specialist will examine the patient further.This study developed a Care Pathway with a new secondary preventive care service that embeds at-home blood pressure measurement activities into the health care organization of diagnoses and treatment of at-risk patients. The study showed that in the current situation the GP measures the blood pressure during a consultation and prescribes medicines when the blood pressure is too high after a couple of measurements. This routine activity for at-risk patients is considered to belong to tertiary preventive care, where the care for patients is curative and reimbursed against higher costs. This Care Pathway design realizes a service shift to secondary preventive care, in which incidents and additional diseases can be tracked down in an earlier stage.First, the routine activity is performed at the source, the patient is self-involved in executing the blood pressure measurements, leading to a feeling of being in control but also to a commonly acknowledged need to exchange and share the data with professional care providers. Second, this new touchpoint of data sharing and professional monitoring is performed by GP assistants with the additional benefit of earlier detection and reinforcement of lifestyle changes. Third, the data reporting is automated from the eHealth device into the health record system, integrating the patient as an implicit user of the health record system. A principal aspect of the design of a Care Pathway is the gathering of in-depth insights, not only on the current process but also on the future of health care services envisioned in co-creation sessions.With this pathway design study, we showed that the activity of blood pressure monitoring can be shifted to the patient who can use an eHealth device at home under the precondition that the use is embedded into the Care Pathway, with a point of contact and safety service of incident monitoring at the organization of the GP practice.These in-depth findings confirm the principal drive behind the patient-centered movement in which patients are actively involved and take greater responsibility for their own health . This paReasons to measure blood pressure at home have been researched in other studies ,43. An iThe Care Pathway visualizes a clear role division and indicates that high involvement is needed to increase collaboration between the parties. Prior research found implementation barriers related to the shortage of funding . To succDespite the strengths of generative sessions with multiple stakeholders, several limitations need to be discussed. The Care Pathway created in the current study is primarily based on the Dutch health care system. For implementation in other countries, additional design research is required. To repeat the method of inquiry and reuse the visual mapping toolkit to redesign clinical workflows of blood pressure self-measurement into care pathways in other countries in Europe, the United States and Asia will add to the body of knowledge on care pathway design and the generalizability of these designs.In design research, and in particular in generative sessions, the data obtained are rich and mainly dependent on the context. The sample size of this in-depth qualitative design research was limited to 6 participant sites, offering enough robustness for the pathway design. In this qualitative research, we used words and drawings as the main data source. Both need to be interpreted subjectively by the design researchers. The means of seeking objectivity that we used in this research were triangulation and multiple coding . HoweverA next avenue of research is also to organize pilot studies on to what extent lifestyle adaptations through monitoring can contribute to lowering a patient’s blood pressure. Furthermore, the Care Pathway could benefit from additional research that weighs the costs versus benefits of blood pressure self-measurement with eHealth  and focuFor health professionals involved in eHealth innovation, this paper provides an example of a pathway model design that embeds eHealth technologies into an integrated service. The design method of generative sessions with the visual toolkit enabled the co-design of the example eHealth services. The pathway design method enabled the embedding of the eHealth devices into the service, providing the organization a person-centered perspective.This research resulted in a Care Pathway of blood pressure monitoring for at-risk patients as secondary preventive care. The Care Pathway was designed to guide the implementation of eHealth devices for self-measurement of blood pressure. It showcases the pathway of at-risk patients and increases their involvement in managing their blood pressure. Furthermore, the Care Pathway leads to more accurate and reliable blood pressure data about patients, which could contribute to lower use of medicines and better insight into lifestyle influences on blood pressure. The Care Pathway serves as a basis for a new service that uses eHealth in future health care.


VT) to deliver the clinically desired minute ventilation, selecting RR and VT based on Otis’ equation on least work of breathing. However, the resulting VT may be relatively high, especially in patients with more compliant lungs. Therefore, a new mode of adaptive ventilation  was developed which automatically minimizes inspiratory power with the aim of ensuring lung-protective combinations of VT and RR. The aim of this study was to investigate whether AVM2 reduces VT, mechanical power, and driving pressure (ΔPstat) and provides similar gas exchange when compared to adaptive mechanical ventilation based on Otis’ equation.Adaptive mechanical ventilation automatically adjusts respiratory rate (RR) and tidal volume . Each patient underwent 1 h of mechanical ventilation with AVM2 and 1 h of adaptive mechanical ventilation according to Otis’ equation . At the end of each phase, we collected data on VT both in the whole study population  and in the subgroup of patients with ARDS . Similar reductions were observed for ΔPstat  and total mechanical power . There was a small decrease in PaO2/FiO2  and no differences in PaCO2, pH, and hemodynamics.Comparing adaptive mechanical ventilation with AVM2 to the approach based on Otis’ equation (AVM), we found a significant reduction in Adaptive mechanical ventilation with automated minimization of inspiratory power may lead to more lung-protective ventilator settings when compared with adaptive mechanical ventilation according to Otis’ equation.DRKS00013540) on December 1, 2017, before including the first patient.The study was registered at the German Clinical Trials Register ( VT), and inspiratory time, based on the clinically required minute ventilation (V̇E) and on the expiratory time constant (RCe) of the patient’s respiratory system.Adaptive mechanical ventilation provides automated selection and continuous adaptation of basic ventilator parameters like respiratory rate (RR), tidal volume  as “adaptive lung ventilation” . With ASreathing . Severalreathing . Howevernt lungs .VT according to Otis’ equation and might therefore also deliver large VT, as observed for ASV by Dongelmans and coworkers [Recently, adaptive ventilation modes similar to ASV have been released by different manufacturers, including “Adaptive Ventilation Mode” , “Work of Breathing Optimized Ventilation” , and “Adaptive Minute Ventilation” . All of these select the combination of RR and oworkers .VT that minimizes inspiratory power during adaptive mechanical ventilation, assuming a square-wave pressure pattern as it occurs during pressure-controlled breaths. This concept of inspiratory power assumes that during a pressure-controlled breath, airway pressure rises immediately from positive end-expiratory pressure (PEEP) to the set inspiratory pressure and is maintained stable throughout the course of inspiration. The resulting inspiratory power can then be calculated as follows: first, the inspiratory pressure difference above PEEP is multiplied with VT to yield the area of the pressure-volume-loop, which is equal to the work per breath. Subsequently, the work per breath is multiplied with RR to yield the inspiratory power in J/min. The RR that is associated with minimal inspiratory power can then be calculated by the algorithm using a fixed-point iteration .In a recent methodological publication on advanced modes of mechanical ventilation and optimal targeting schemes , van derV̇E, this should lead to lower VT and reduced driving pressure (ΔPstat) when compared to “traditional” adaptive ventilation based on Otis’ equation [For a given equation .This concept was implemented in a new adaptive ventilation mode  which was specifically developed to minimize inspiratory power and deliver more “lung-protective” ventilatory settings when compared to adaptive mechanical ventilation based on Otis’ equation.VT, ΔP, and mechanical power delivered by the ventilator.We hypothesized that, when compared to “traditional” adaptive mechanical ventilation based on Otis’ equation (AVM), ventilator settings selected by AVM2 would be more lung-protective in terms of Between December 2017 and June 2018, we conducted a prospective, randomized, cross-over study including 20 critically ill patients admitted to the interdisciplinary intensive care units (ICUs) of the University Medical Center Schleswig-Holstein, Campus Kiel, Germany. The study was approved by the Ethics Committee of the Medical Faculty of the Christian Albrechts University in Kiel (D551/17) and registered at the German Clinical Trials Register (DRKS00013540) on December 1, 2017, before including the first patient. Written informed consent was obtained from the patient’s legal representatives prior to study inclusion.We included intubated adult patients requiring controlled mechanical ventilation, with the presence of an arterial line, which was required for arterial blood gas sampling.e of higher than 1.5 s, patients with a ratio of arterial partial pressure of oxygen to inspired fraction of oxygen (PaO2/FiO2) of less than 100 mmHg, arterial pH of less than 7.2, or arterial partial pressure of carbon dioxide (PaCO2) of more than 70 mmHg despite optimization of mechanical ventilation, severe hemodynamic instability, high-frequency oscillatory ventilation, and spontaneous breathing activity.We excluded patients with significant expiratory flow limitation, as evidenced by an RCV̇E was adequate to deliver clinically acceptable pH and gas exchange. If any changes in V̇E were necessary to achieve the desired pH of more than 7.25 and the desired range of PaCO2 (35 mmHg < PaCO2 < 70 mmHg), the ventilator settings were adjusted by the attending ICU physician according to local clinical practice.Before study inclusion, all patients were ventilated in a conventional pressure-controlled mode. After obtaining written informed consent, patients were randomized in a 1:1 ratio to one of two groups: group “AVM-AVM2”, first ventilated according to Otis’ equation with AVM and then according to “minimized inspiratory power” with AVM2, or group “AVM2-AVM”, ventilated with both modes in the reversed order  was documented and selected as “desired” target value. Depending on group allocation, patients were then switched to either AVM or AVM2 and ventilated with the selected mode for the duration of 1 h. If necessary, target V̇E was adjusted to keep etCO2 constant  of 2.2 ml/kg predicted body weight:With AVM, the RR necessary to achieve target V̇E was calculated by the ventilator according to the following equation:With AVM2, the RR to achieve target π = Pi ≈ 3.14; e = Euler’s number ≈ 2.72; RCe = expiratory time constant; V̇E = expiratory minute ventilation; VDA = anatomical dead space) in cmH2O, PaO2/FiO2, PaCO2, pH, alveolar minute ventilation (V̇A), mean arterial pressure (MAP), and heart rate (HR).The primary endpoint of the study was the automatically delivered VT, ΔP, mechanical power, and Paw,mean as well as hemodynamic data on MAP and HR were averaged during the last 5 min of each 1-h period. Real-time data of flow and airway pressure were stored by the ventilator at a sampling rate of 100 Hz and analyzed off-line after the end of the study procedure. An arterial blood gas (ABG) sample was taken to assess PaO2/FiO2, PaCO2, and pH. ΔP was calculated as the difference between end-inspiratory plateau pressure during an inspiratory hold maneuver of 2–3 s and PEEP. Static respiratory system compliance (Crs) was then calculated by dividing expired VT by ΔPstat.For assessment of the study endpoints, ventilator data on Total mechanical power per breath was derived from the integral of the inspiratory pressure-volume curve for each breath in the 5-min interval and multiplied with RR to obtain a result in Joules per minute (J/min).V̇A, physiological dead space (VD) was estimated according to the modified Bohr equation [VT to calculate alveolar VT. Finally, alveolar VT was multiplied with RR to yield V̇A.To assess equation . Subsequn = 20 was calculated to detect an average difference in VT of 1 ml/kg assuming a standard deviation of change in VT of 1.5 ml/kg with a power of 80% at a significance level of p ≤ 0.05. Statistical analyses were performed with GraphPad Prism 5.0 . Data were assessed for normal distribution using the D’Agostino&Pearson omnibus K2 normality test. Parametric continuous data are expressed as mean ± SD, whereas nonparametric continuous data are expressed as median (interquartile range). Comparisons between AVM and AVM2 were performed using the paired two-sided t test for parametric data and the Wilcoxon matched-pairs test for nonparametric data. The relationship between automatically selected VT and Crs was assessed with Pearson’s correlation coefficient (r) for both modes.A sample size of Details on numbers of patients screened, excluded, randomized, and analyzed are shown in the CONSORT-diagram Fig. . Basic pThe numerical results for the whole study population are presented in Table VT by 1.05 ± 0.4 ml/kg, ΔPstat by 1.1 ± 1.3 cmH2O, and total mechanical power by 1.8 ± 2.3 J/min. RR and Paw,mean were significantly higher with AVM2. V̇A did not differ between the two modes. Inspiration-to-expiration ratio (I:E) was 1:2.0 ± 0.5 with AVM and 1:1.1 ± 0.1 with AVM2, resulting in a significantly higher Paw,mean with AVM2 despite lower VT and ΔPstat.In comparison to AVM, ventilation with AVM2 led to statistically significant reductions in 2/FiO2 by 21 ± 39 mmHg with AVM2 and no significant differences in PaCO2 or pH. There were no differences in hemodynamics between both modes. We observed a statistically significant reduction in static Crs by 4.1 ± 5.6 ml/cmH2O with AVM2 as compared to AVM.In ABG samples, we found a small but statistically significant reduction in PaOVT was reduced by 1.3 ± 0.3 ml/kg with AVM2 . In this subgroup, ΔPstat was reduced by 1.5 ± 1.2 cmH2O  and total mechanical power was reduced by 1.9 ± 1.6 J/min to a value of 15.6 ± 3.2 J/min with AVM2 . The complete results of the subgroup of patients with ARDS are presented in Table In the ten patients with ARDS, VT was positively correlated to static Crs . To our knowledge, there are no controlled studies comparing ASV 1.1 to ASV based on Otis’ equation or to AVM. It would be interesting to assess the differences between ASV 1.1 and AVM2 in a future study.Recently, the original ASV  has also been modified to reduce the delivered We must admit that there is currently no evidence of improved long-term outcomes when using adaptive mechanical ventilation in the management of critically ill patients with and without ARDS. Observational studies have repeatedly shown that the implementation of lung-protective ventilation in daily clinical practice is slow and incomplete. In the LUNG SAFE study, less than two thirds of patients with ARDS were ventilated with tidal volumes of 8 or less ml/kg predicted body weight and there was no evidence to suggest that lower tidal volumes were used in patients with a less compliant respiratory system . ConceivIn conclusion, our results indicate that adaptive mechanical ventilation with minimization of inspiratory power may be more lung-protective in patients undergoing controlled mechanical ventilation without spontaneous efforts than adaptive mechanical ventilation according to Otis’ equation.Additional file 1. Plots of VT, ΔPstat and mechanical power against RCe. This additional file presents data on the correlation between VT, ΔPstat and mechanical power with RCe for AVM and AVM2 as well as the difference of these parameters between AVM and AVM2 plotted against RCe.


Subarachnoid hemorrhage (SAH) has a high case fatality rate and young mean age at onset compared with other types of stroke, but the pathogenesis of SAH is not fully understood. We examined associations of systolic and diastolic blood pressure with incident nontraumatic SAH in a large prospective study in China.In 2004 to 2008, 512 891 adults (59% women) from the general population were recruited into the CKB study (China Kadoorie Biobank). Participants were interviewed, measured, and followed up for fatal and nonfatal events. After excluding those with prior vascular disease, Cox regression analysis was used to relate blood pressure to incident SAH events. Analyses were adjusted for major confounders and corrected for regression dilution to give associations with long-term average blood pressure.At baseline, mean age was 51  years, and mean systolic blood pressure/diastolic blood pressure was 130.6/77.6  mm Hg. During 3.5 million person-years of follow-up, there were 553 incident SAH cases , yielding an overall annual incidence rate of 12.9 per 100 000. Higher average levels of blood pressure were linearly and positively associated with higher risks of incident SAH: a 10 mm Hg higher systolic blood pressure and a 5 mm Hg higher diastolic blood pressure were associated with hazard ratios for SAH of 1.21  and 1.20 , respectively. There was no evidence that the hazard ratios varied by age or sex or by levels of other vascular risk factors. Elevated blood pressure  accounted for 23% of all SAH cases.The incidence of SAH in China was comparable with estimates from Western populations. Higher levels of blood pressure were positively associated with higher risks of SAH, and elevated blood pressure accounted for about a quarter of all SAH cases. Overall, about one-third of Chinese adults have hypertension, but only one-third of those are diagnosed, and of those, only half are treated.9 Meta-analyses of prospective studies reported that hypertension is associated with about a 2-fold higher incidence of SAH.11 However, the effects of blood pressure on SAH risk in China have not been well established and may differ from those in other parts of the world.Established risk factors for spontaneous (nontraumatic) SAH include elevated blood pressure, smoking, and high alcohol intake.Reliable assessment of the incidence of SAH and its association with blood pressure requires large prospective studies with ascertainment of both nonfatal and fatal events, avoidance of misclassification between stroke types (requiring high rates of brain imaging), and repeat measures of blood pressure . The aims of the present report were to use the CKB study (China Kadoorie Biobank) of 0.5 million adults to (1) estimate the age- and sex-standardized incidence of SAH in the study population; (2) assess the shape and strength of the associations of blood pressure with risk of SAH after adjustment for major confounders and correction for regression dilution; and (3) determine the proportion of all SAH cases because of elevated blood pressure.12 Participants were identified through public registry records and invited to attend a local assessment center. Information on prior medical history, lifestyle factors, and use of medication were collected using interviewer-administered electronic questionnaires. Measurements of blood pressure, weight, and height were also recorded on all participants at baseline. Ethics approval was obtained from the relevant local, national, and international ethics committees, and all participants provided written informed consent. Data from the baseline survey, first resurvey, and cause-specific mortality are available to all bona fide researchers (www.ckbiobank.org). Additional data may be made available on a collaborative basis by contacting the study investigators.The CKB study is a prospective study of adults aged 30 to 79 years who were recruited from 10 diverse areas  of China in 2004 to 2008.12Blood pressure was measured by trained staff with a UA-779 digital sphygmomanometer (A&D Instruments) using standardized procedures at all study sites. Measurements were recorded twice, after at least 5 minutes in a seated position, and the mean of both the measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was recorded. If the values of SBP differed by >10 mm Hg, a third measurement was recorded, and the mean of the last 2 measurements was used.InternationalStatistical Classification of Diseases and Related Health Problems, Tenth Revision (SAH [I60]); >90% of incident stroke cases had confirmation of diagnosis by computed tomography/magnetic resonance brain imaging. Residential records were used to identify participants who moved out of the study regions and, by so doing, were lost to follow-up. By January 1, 2016, 37 289 (7.3%) participants had died and only 4875 (1%) participants were lost to follow-up.In 2008, a resurvey was performed of ≈5% of participants selected using cluster random sampling, with administrative units  as the sampling units, using the same procedures as those for the baseline survey. Repeat blood pressure measures were used to correct the prospective analyses for regression dilution to give associations with long-term average  blood pressure. Deaths were identified by electronic linkage to local records of the Disease Surveillance Points system of the Chinese Center for Disease Control and Prevention. Nonfatal events were collected using linkage to stroke registries, mortality registries, and health insurance records. All fatal and nonfatal events were coded using the 13 was used to estimate hazard ratios (HRs) for the associations of blood pressure with SAH incidence, with adjustment for age at risk (5-year age groups), sex, area, education, smoking, alcohol intake, and body mass index.Analyses excluded participants with missing information for blood pressure or other key variables (n=2), individuals with SBP <80 or ≥250 mm Hg (n=116) or with DBP <40 or ≥150 mm Hg (n=62), and individuals with a prior history of vascular disease , leaving 489 613 participants for the present analyses. After these exclusions, the incidence rates of SAH were calculated and standardized to the age and sex distribution of the study population. Cox regression analysisThe HRs per 10 mm Hg higher SBP were obtained by fitting SBP as a continuous variable in men and women separately for each decade of age at risk .11 Repeat measurements of blood pressure in random samples of participants were used to correct for this regression dilution bias.14 The amount by which the true association was underestimated by using baseline instead of long-term average  values of the risk factor of interest was expressed as the regression dilution ratio. Analyses of the associations of SAH with blood pressure were corrected for regression dilution by using the appropriate regression dilution ratios for each age- and sex-specific group. Hence, age- and sex-specific HRs were then corrected for age- and sex-specific regression dilution ratios  to give HRs for 10 mm Hg higher usual SBP.The combined effects of random measurement errors and within-person fluctuations of blood pressure over time will underestimate the associations of blood pressure recorded at baseline with incidence of SAH.In categorical analyses, baseline blood pressure was divided into the following groups: 80 to <125, 125 to <145, 145 to <165, 165 to <185, and 185 to <250 mm Hg for SBP and 40 to <75, 75 to <85, 85 to <95, 95 to <105, and 105 to ≥150 mm Hg for DBP. HRs were estimated relative to the lowest blood pressure groups, and the 95% CIs were calculated using the variance of the log risk. HRs were plotted against the mean SBP or DBP in each group, with the effect of increasing the slope of association by a factor equal to the inverse of the regression dilution ratio.d×(relative risk−1)/relative risk, where Pd represents the proportion of all SAH cases in a given blood pressure group (using the same blood pressure groups as described above), and relative risk is approximated by the group-specific HRs  relative to the lowest blood pressure group.15 The overall fraction of SAH cases attributable to blood pressure was calculated as the sum of the fractions in each of the blood pressure groups. All analyses used SAS software (version 9.3), and Figures were plotted using R software (version 3.3).Assuming causality, the fraction of SAH cases attributable to elevated blood pressure in each blood pressure group was estimated by PBetween June 2004 and July 2008, 512 891 adults were recruited, yielding an overall response rate of ≈30% of the resident population in each of the areas studied. After exclusions, 489 613 participants remained. Mean age at baseline survey was 51  years, and 59% of participants were women  years. Overall, the weighted mean regression dilution ratios for SBP and DBP were 0.58 and 0.58, respectively . In both men and women, the incidence rates were lower in urban than in rural areas (9.9 versus 14.5 per 100 000), although these differences were more marked in men. The mean age at incident SAH event was 61  years. Separate incidence rates are provided for individuals classified by smoking, drinking, overweight, and use of antihypertensive medication at baseline.2), or use of antihypertensive medication at baseline  rates of attrition.The incidence rates of SAH in China were higher than those reported in previous studies in Chinese populations and are consistent with worldwide estimates. The present study demonstrated strong, positive linear associations of levels of blood pressure with risk of SAH among Chinese adults. The shape and strength of these associations were comparable with those reported in previous prospective studies in Western populations. These findings have important implications for the prevention of SAH in China. Interventions producing moderate population-wide reductions in blood pressure should result in substantial reductions in the burden of SAH. Based on both the high loss of productive life years by SAH and the increasing prevalence of hypertension in China, the importance of such interventions cannot be understated.The chief acknowledgment is to the participants, the project staff, and the China National Center for Disease Control and Prevention and its regional offices for access to death and disease registries. The Chinese National Health Insurance scheme provides electronic linkage to all hospital admission data.The CKB study (China Kadoorie Biobank) is jointly coordinated by the University of Oxford and the Chinese Academy of Medical Sciences. The funding body for the baseline survey was the Kadoorie Charitable Foundation, Hong Kong, China, and the funding resources for the long-term continuation of the study include UK Wellcome Trust , Chinese National Natural Science Foundation , and the National Key Research and Development Program of China . Core funding was provided to the Clinical Trial Service Unit, University of Oxford, by the British Heart Foundation, UK Medical Research Council, and Cancer Research UK. B. Lacey acknowledges support from the National Institute for Health Research Oxford Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.None.