To analyze the access to and use of medicines for high blood pressure among the Brazilian population according to social and demographic conditions.Pesquisa Nacional Sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos , a nationwide cross-sectional, population-based study, with probability sampling, carried out between September 2013 and February 2014 in urban households in the five Brazilian regions. The study evaluated the access and use of medicines to treat people with high blood pressure. The independent variables were gender, age, socioeconomic status and Brazilian region. The study also described the most commonly used drugs and the percentage of people treated with one, two, three or more drugs. Point estimations and confidence intervals were calculated considering the sample weights and sample complex plan. Analysis of data from  Prevalence of high blood pressure was 23.7% (95%CI 22.8–24.6). Regarding people with this condition, 93.8% (95%CI 92.8–94.8) had indication for drug therapy and, of those, 94.6% (95%CI 93.5–95.5) were using the medication at the time of interview. Full access to medicines was 97.9% (95%CI 97.3–98.4); partial access, 1.9% (95%CI 1.4–2.4); and no access, 0.2% (95%CI 0.1–0.4). The medication used to treat high blood pressure, 56.0% (95%CI 52.6–59.2) were obtained from SUS , 16.0% (95%CI 14.3–17.9) from Popular Pharmacy Program, 25.7% (95%CI 23.4–28.2) were paid for by the patients themselves and 2.3% (95%CI 1.8–2.9) were obtained from other locations. The five most commonly used drugs were, in descending order, hydrochlorothiazide, losartan, captopril, enalapril and atenolol. Of the total number of patients on treatment, 36.1% (95%CI 34.1–37.1) were using two medicines and 13.5% (95%CI 12.3–14.9) used three or more. Access to medicines for the treatment of high blood pressure may be considered high and many of them are available free of charge. The most commonly used drugs are among those recommended as first-line treatment for high blood pressure control. The percentage of people using more than one drug seems to follow the behavior observed in other countries. Non-communicable diseases (NCD) are a global health problem and have influenced worldwide initiatives aimed to their control and reduction31 report that despite the increase in crude mortality rates in recent years, age-specific mortality rates have decreased. According to the author, this was due to the success of a number of public policies to reduce tobacco use and expand access to basic health care. Prominent among these public policies are Plano de Reorganização da Atenção ao Diabetes e HipertensãoPolítica Nacional de MedicamentosPolítica Nacional de Assistência FarmacêuticaPlano Nacional de Enfrentamento das DCNT (Brazilian Plan to Combat NCD) in Brazil for the period 2011-2022Schmidt et al.31. High blood pressure is a treatable medical condition and, if properly controlled, can delay or even prevent the development of symptomatic cardiovascular disease,Among NCD, high blood pressure accounts for most of the patientsIn Brazil, basic health care policies, including the expansion of free access to drugs, are considered examples of public initiativesThe data for this analysis is taken from PNAUM , a cross-sectional, population-based study. The study population of PNAUM consisted of people living in permanent private households in urban areas of the five Brazilian regions. The study analyzed data of people aged 20 or older. The questionnaires were answered directly by the person or by a caregiver, when they were unable to communicate or provide information on diseases and medicines used.The sampling plan was complex and resulted in a probability sampling of the Brazilian population residing in urban areas of Brazil. Information on the sample, sampling procedures and other methodological procedures of PNAUM, including instruments used in the interview, field operation aspects and specificities of data collection are available in the PNAUM methodological articleThe use of medicines to treat high blood pressure was investigated based on the following questions: “Has a doctor ever said you have hypertension or high blood pressure?”; “Do you have any medical indication to take any kind of medicine for high blood pressure?”; “Are you taking any of those medicines?”. Later, they were asked about the drugs being used for high blood pressure and detailed information on source and payment, among others aspects. Whenever possible, the drug names were copied from the packaging. When no packaging was available, the names declared by the interviewees were recorded.Associação Brasileira de Empresas de Pesquisa (ABEP – Brazilian Association of Survey Companies)The sociodemographic characteristics analyzed were: gender, age group , economic status according to The access to medicines was classified as full, partial or no access. Full access was the situation in which people had all medicines needed to care for the disease in the last 30 days; partial, when any medicine was missing due to financial difficulty or unavailability at the Unified Health System (SUS); and no access, when no drugs were obtained in the last 30 days, also due to financial difficulty or unavailability at SUS. The denominator comprised people with medical indication to treat high blood pressure with drugs, excluding cases of intentional abandonment of treatment. Abandonment was defined as cases in which, despite medical indication, people were not using medications for high blood pressure; and cases in which they declared to be using the drugs, but had been without in the last 30 days. In both situations, abandonment cases were restricted to lack of medicines for reasons other than financial difficulty or unavailability at SUS.Reported medicines for high blood pressure were classified into four groups, according to the reported use for treating high blood pressure. Group 1 consisted of drugs definitely used for high blood pressure, such as diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Group 2 included drugs associated with patients’ care with high blood pressure, such as statins and acetylsalicylic acid. Group 3 corresponded to medicines unrelated to high blood pressure treatment, but reported by respondents as used for that disease. Group 4 comprised all teas or other supplements not classified as medicines. This classification was based on high blood pressure treatment guidelines and a review of the literature for some controversial cases in group 2.The overall results of this analysis include all medications. The drugs analysis relates exclusively to drugs specifically used for high blood pressure treatment (group 1).In the analysis of drugs used for high blood pressure treatment, fixed-dose combinations were broken down into isolated drugs. For example, for people who used a medicine with a fixed combination of hydrochlorothiazide and amiloride, each one of those drugs was analyzed separately in the evaluations that considered the number of specific drugs for the treatment of high blood pressure.Pearson’s Chi-square test was used for percentage bivariate comparison, considering p < 0.05 as significant values.Comissão Nacional de Ética em Pesquisa  and is registered under number 18947013.6.0000.0008. All interviews were conducted after the respondents or their legal representatives had read and signed the consent form.This study was approved by the Prevalence of self-reported high blood pressure in Brazil was 23.7% (95%CI 22.8–24.6), ranging from 16.3% in the North region to 26.0% in the Southeast region. In the 20-39 age group, prevalence was 6.0%, reaching 59.0% in the 60 or over group .Of the total number of people who reported high blood pressure, 93.8% affirmed having medical indication to treat the disease with medication. This indication ranged from 78.0% in the 20-39 age group to 98.1% in the group aged 60 or over .Among people who reported having indication for drug therapy, 94.6% were using the medication at the time of the interview. Use of medication increased with age. Among Brazilian regions, the North and Northeast regions had the lowest frequency of drug use, while the South and Southeast regions had the highest frequency of use .Full access to medicines for high blood pressure care was higher in the South region and lower in the Midwest and Northeast regions. Partial access, i.e., lack of part of the drugs in the previous 30 days, was higher in the Midwest region and lower in the South region. Prevalence of access to all necessary medicines for high blood pressure care was similar between the different economic classes. Failure to obtain any hypertension medication for financial difficulties or unavailability at SUS was very low throughout the country, with minor, non-significant differences between the age groups . IntentiOf all the medicines reported for use in high blood pressure, group 1 (medicines definitely used to treat high blood pressure) corresponded to 90.5%, group 2 (drugs associated with high blood pressure treatment), to 4.1%, group 3 (drugs not indicated for high blood pressure), to 3.2%, and group 4 (supplements and herbs), to 2.3%. Of medicines used specifically to treat high blood pressure (group 1), 92.4% were single-drug and 7.6% were fixed-dose combinations, the most common being hydrochlorothiazide combined with losartan or atenolol or amiloride. Separately, the most common specific drugs used to treat high blood pressure were, in descending order: hydrochlorothiazide, losartan, captopril, enalapril, amlodipine and atenolol, which corresponded to approximately 81.0% of all reported drugs .Among respondents treated with specific drugs for hypertension, 49.9% used only one drug, 36.1% used two, and 13.5% used three or more drugs . High blPrograma Farmácia Popular (program-specific or accredited drugstores) and 2.3% elsewhere. Payment by the actual patients corresponded to 25.7% of medications used to treat this condition.Of medicines used to treat high blood pressure, 56.0% were obtained from SUS, 16.0% from Pesquisa Nacional por Amostra de Domicílios , found a prevalence of 11.3% for men, 16.5% for women and 14.0% for both genders and all ages. In a summary measure of several studies, Schmidt et al.31 found a 17.3% prevalence for men and women over 20. Among men, the prevalence of 19.2% was slightly higher than in the 2008 survey, when it was estimated at 17.3% (95%CI 17.0–17.6%). In the VIGITEL telephone surveyPesquisa Nacional de Saúde Prevalence of self-reported high blood pressure in this study was 23.7% for all ages, 18.5 in men and 28.1 in women. Barros et al.When compared with previous population studies, prevalence of self-reported high blood pressure in this study confirms the upward trend of this disease in all age groups. The figures found in the Vigitel survey are higher, probably because this tool included only state capitals and metropolitan areas of Brazil, where prevalence of hypertension tends to be higher, whether due to increased presence of risk factors, greater access to diagnosis or a combination of both factors.In this study, the question on the use of medicines for high blood pressure was preceded by another question about the existence of medical indication for treatment of high blood pressure with medications. This question was included after the study identified that one of the reasons participants were not using drugs was the lack of medical indication.25, found that 17.0% of patients did not use high blood pressure medication. The study shows that of people with hypertension, 6.2% had no medical indication to treat the disease with medication, and only 5.4% of those with indication were not using the drugs. The difference in the results of both studies may be due the authors assuming that all patients with high blood pressure should use medicines to treat the condition.Ferreira et al.Indication for treatment with medication is high. This may reflect late diagnosis, given that in stage 1 hypertension, lifestyle change is the first indication, with drug treatment only introduced six months after that measure failsAnalysis of PNADAlso consistent are the lower rates of medicine use among younger age groups. This study shows that younger people receive less indication for drug treatment, and when they do, adherence is very low compared to older people. Consequently, young people miss the opportunity to prematurely reduce cardiovascular risks with the use of medicines and may experience further harm in future complications of the clinical condition.,Overall, indication and use of medications were high, which should be considered positive, especially because it is an asymptomatic clinical condition. However, a more accurate assessment of treatment adequacy and follow-up is needed as a next step in the care of hypertension. Evidence shows that inadequate understanding of the nature of hypertension leads to discontinuation of treatment when blood pressure levels are normalized. Other causes for temporary interruption or undertreatment of the disease are the occurrence of side effects, forgetfulness, or reasons related to health services, such as organization and structure, sometimes involving the relationship between doctor and patientEstratégia de Saúde da Família  in 41 municipalities in the South and Northeast regions in 2005, found that 81.2% had full access, albeit with regional differences, rates being higher in the South. Increased age, better socioeconomic status and higher education level were factors associated with greater access. In one state capital in southern Brazil, access was 95.8%Programa de Saúde da Família  in another state capital in southern Brazil, overall access to medicines was also 95.0%Popular (Popular Pharmacy Program), which accounted for 16.0% of medicines used in hypertension care.Nationwide data on access to medicines are still scarce, especially at the household level. Paniz et al.Aqui Tem Farmácia Popular (Popular Pharmacy Here). Thus, almost three out of four medicines used in high blood pressure care were funded by SUS.Most part of the medicines used in hypertension care is available for free, whether from the SUS network or drugstores accredited by the program Relação Nacional de Medicamentos Essenciais  for 2013Of the 10 drugs most commonly used to treat hypertension, only chlorthalidone did not feature in ,The most commonly used drugs were hydrochlorothiazide, followed by losartan, captopril and enalapril. These results are similar to those found in other studies in which diuretics and renin-angiotensin system antagonists are the drugs used to treat high blood pressureHigh blood pressure treatment with more than one drug is observed in other countries. In England, 45.0% of patients undertake monotherapy; 36.0%, two drugs; 14.0%, three drugs; and 4.0%, four drugsIn short, prevalence of high blood pressure continues to increase among the adult Brazilian population. Access to medicines to treat this disease proved to be quite high. Compared with previous studies, this increase appears to be consistent. Pharmaceutical care public policies may explain this phenomenon. Most of the drugs used are among those recommended in the literature as first-line drugs for high blood pressure treatment. In this study, the number of drugs used shows the same trend observed in the United States and England, i.e., a growth in the number of drugs needed to keep blood pressure under adequate control.,Full access to medicines for high blood pressure can be seen as the first step in the treatment of this clinical condition, but not the only one. About 50.0% of treated patients do not have adequate blood pressure control


BACKGROUND. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and there is an established association between vasculopathy affecting the kidney and eye. Optical coherence tomography (OCT) is a novel, rapid method for high-definition imaging of the retina and choroid. Its use in patients at high cardiovascular disease risk remains unexplored.METHODS. We used the new SPECTRALIS OCT machine to examine retinal and retinal nerve fiber layer (RNFL) thickness, macular volume, and choroidal thickness in a prospective cross-sectional study in 150 subjects: 50 patients with hypertension  with no underlying cause identified); 50 with CKD (estimated glomerular filtration rate (eGFR) 8–125 ml/min/1.73 m2); and 50 matched healthy controls. We excluded those with diabetes. The same, masked ophthalmologist carried out each study. Plasma IL-6, TNF-α , asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1), as measures of inflammation and endothelial function, were also assessed.RESULTS. Retinal thickness, macular volume, and choroidal thickness were all reduced in CKD compared with hypertensive and healthy subjects . RNFL thickness did not differ between groups. Interestingly, a thinner choroid was associated with a lower eGFR  and, in CKD, with proteinuria  as well as increased circulating C-reactive protein , IL-6 , ADMA , and ET-1 . Finally, choroidal thinning was associated with renal histological inflammation and arterial stiffness. In a model of hypertension, choroidal thinning was seen only in the presence of renal injury.CONCLUSIONS. Chorioretinal thinning in CKD is associated with lower eGFR and greater proteinuria, but not BP. Larger studies, in more targeted groups of patients, are now needed to clarify whether these eye changes reflect the natural history of CKD. Similarly, the associations with arterial stiffness, inflammation, and endothelial dysfunction warrant further examination.TRIAL REGISTRATION. Registration number at www.clinicalTrials.gov: NCT02132741.SOURCE OF FUNDING. TR was supported by a bursary from the Erasmus Medical Centre, Rotterdam. JJMHvB was supported by a bursary from the Utrecht University. JRC is supported by a Rowling Scholarship. SB was supported by a Wellcome Trust funded clinical research fellowship from the Scottish Translational Medicine and Therapeutics Initiative, and by a Rowling Scholarship, at the time of this work. ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994). Chorioretinal thinning relates to the degree of inflammation and kidney injury in patients with kidney disease. Cardiovascular disease (CVD) remains the leading cause of death worldwide, contributing to ~30% of all deaths globally in 2010 , and is Renal microvascular changes are considered important in the development of CKD. Currently, these can only be assessed reliably through renal biopsy, which is not without risk. Furthermore, interval renal biopsy, to assess changes in the kidney’s microvasculature over time and in response to therapy, is impractical. The kidney and eye are remarkably similar in their developmental, structural, and pathogenic pathways . InteresOptical coherence tomography (OCT) is a novel, noninvasive, and rapid method for cross-sectionally imaging the retina and choroid . Recent Fifty patients with hypertension, 50 patients with varying degrees of CKD, and 50 healthy controls were recruited into the studies. Subject demographics and medications are shown in  < 0.0001 for CKD vs. healthy and for CKD vs. hypertensive subjects). The retina was ~10% thinner at these outer positions in CKD compared with the other 2 groups, and at all positions women had thinner retinas than men (P < 0.05). In keeping with a thinner retina, CKD patients had a reduced macular volume compared with both patients with hypertension and healthy volunteers (P < 0.0001 for both) . Neither retinal thickness nor macular volume related to systolic BP (SBP), diastolic BP (DBP), estimated glomerular filtration rate (eGFR), or proteinuria in any of the 3 subject groups. For macular volume, the area under the receiver operator curve (ROC) was 0.82 . 3 yielded good sensitivity and specificity for the detection of CKD.Figure 2, Por both) . HoweverP < 0.001 for both), a reduction in choroidal thickness of ~15%–20%  thickness did not differ between the 3 subject groups studied . Choroid~15%–20% . For subr = –0.55, P < 0.001 for locations I, II, and III for hypertension; r = –0.38, P < 0.05 for locations I, II and III for CKD) but this was not the case in healthy subjects. However, SBP correlated inversely with choroidal thickness in healthy  but not in diseased subjects; DBP did not correlate with choroidal thickness in any of the 3 groups.In patients with hypertension and CKD, increasing age was associated with a thinner choroid  concentration, a lower eGFR, and greater degrees of proteinuria . InteresP < 0.05) but did not differ between hypertension and CKD. Whereas IL-6 did not associate with choroidal thickness in healthy and hypertensive subjects, a thinner choroid, at all 3 locations, correlated with a higher concentration of IL-6 in CKD (P < 0.0001 for both), but unlike IL-6 did not associate with choroidal thickness in those with CKD .Plasma IL-6 was higher in those with hypertension and CKD compared with healthy subjects (6 in CKD . CirculaP < 0.05 for both) and also correlated with choroidal thickness in these patients (P < 0.0001 for both), also correlated inversely with choroidal thickness  demonstrated that CRP, proteinuria, and IL-6 were independent predictors of choroidal thickness in CKD at locations I and II. Proteinuria was also an independent predictor in location III, as was age .Given the intercorrelation of the variables included in multivariable analysis we went on to utilize a principal component analysis strategy . In ordeGiven the associations between chorioretinal thicknesses and measures of systemic inflammation, we explored these relationships with renal histological inflammation. In patients with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, an autoimmune disorder characterized by intense small vessel inflammation in multiple organs often including the kidneys, the extent of glomerular histological inflammation — focal necrotizing lesions and cellular crescents  — did noFinally, 20 of our 50 CKD subjects had had previous assessment of arterial stiffness , 15 usinTo explore whether we might be able to perform future mechanistic studies to better understand our clinical data, we aimed to use OCT to measure chorioretinal thicknesses in mice with either hypertension alone or hypertension with associated renal injury. Mice with hypertension alone showed no chorioretinal thinning. By comparison, and in keeping with our clinical data, animals with matched hypertension and renal injury developed choroidal thinning , althougWe have shown, to our knowledge for the first time, that patients with varying degrees of predialysis CKD exhibit substantial retinal and choroidal thinning, alongside a reduction in macular volume, compared with age- and sex-matched healthy volunteers as well as matched subjects with hypertension. Interestingly, for the choroid, there were strong correlations between its thickness and the level of systemic inflammation (measured using high-sensitivity CRP [hsCRP]) and degree of renal dysfunction (represented by eGFR and proteinuria). Together, these findings suggest that the retinal and choroidal changes seen in those with CKD may be representative of a generalized systemic microvascular injury, and may also reflect underlying renal injury.The Chronic Renal Insufficiency Cohort (CRIC) study, which assessed the relationship between CKD and retinal pathology, revealed a high prevalence of fundus pathology in CKD patients, probably because half of the patients had long-standing diabetes . Few stuImportantly, and in comparison with CKD, we found no differences between healthy and hypertensive subjects in any of the parameters studied. As for CKD, there are few studies that have examined OCT measures in patients with hypertension and only 1 with robust methodology . Here, MThe retina is a complex neurovascular tissue. Photoreceptors resting on the retinal pigment epithelium form the outer layer, and the RNFL the innermost layer. Between the photoreceptors and RNFL are the neural processing cells including horizontal, amacrine, and bipolar cells synapsing with retinal ganglion cells whose axons form the RNFL. It is possible that the reduction in retinal thickness and macular volume seen in those with CKD is due to the atrophy of these cells probably as a result of compromised blood supply due to microvascular injury. The choroid is a largely vascular organ and so the thinning here is likely to reflect purely microvascular damage and loss. As seen in There are a number of potential explanations for the changes we have observed. Hypertension is an important and common contributor to microvascular injury in a number of organs including the kidney and the eye , 24. HowHowever, we did see associations between systemic  inflammation and 2 important vascular risk factors, eGFR and proteinuria, and these may go some way in providing a mechanism to explain our observations. Inflammation is an important contributor to the development of cardiovascular and renal disease. hsCRP correlated inversely with choroidal thickness in CKD and was an independent predictor of thickness. On this basis, we assessed circulating IL-6 and TNF-α, both important mediators of inflammation in CVD and CKD. These were raised in CKD patients and IL-6 correlated inversely with choroidal thickness, consistent with its involvement in the process. Indeed, IL-6 is considered to be important in the pathogenesis of a number of eye conditions , 27 and Given the relationships seen between choroidal thickness and both eGFR and proteinuria we assessed endothelial function. Plasma ADMA, an endogenous inhibitor of nitric oxide synthase, and plasma ET-1 were measured as components of the nitric oxide and ET systems, respectively. Both contribute to vascular dysfunction in CKD and an imbalance (more ET-1/less nitric oxide) may contribute to vasoconstriction, inflammation, and atherosclerosis , 33. CirAs limitations, medications taken by our patients, such as angiotensin-converting enzyme inhibitors, β-blockers, and statins may have had effects on the OCT parameters studied. However, all patients were stabilized on their therapies and this is an unavoidable limitation of such studies. Furthermore, we observed undulation of the choroidal-scleral interface, limiting the power of single-point choroidal thickness measurements, and suggesting future studies should examine choroidal volume. This quantifies the overall disease burden and may be helpful in understanding disease pathophysiology and for assessing the response to treatment in chorioretinal disorders . FinallyA growing number of studies support the link between diseases affecting the eye and the kidney. As is the case for CKD, common eye diseases such as age-related macular degeneration (AMD) and glaucoma are strongly associated with age and vascular risk factors such as hypertension, diabetes, and smoking . FurtherSee Supplemental Information for more information.This was a prospective, cross-sectional controlled study performed at the Anne Rowling Regenerative Neurology Clinic at the Royal Infirmary of Edinburgh. Subjects were recruited from the hypertension and renal outpatient clinics at the Royal Infirmary of Edinburgh and Western General Hospital, Edinburgh. Age- and sex-matched controls without any comorbidity were recruited from the community. We used a frequency matching protocol for the recruitment of patients with hypertension and healthy volunteers. For every 5 patients with CKD recruited we matched these, based on age and sex, with 5 hypertensive patients and 5 healthy volunteers. Hypertension was defined as a documented clinic BP greater than or equal to 140/90 mmHg (prior to starting any treatment) with no underlying cause identified. Both incident and prevalent patients with hypertension were included. Renal patients were categorized into the 5 stages of CKD on the basis of the Kidney Disease Outcome Quality Initiative (K/DOQI) classification . We exclAll subjects abstained from alcohol-, nicotine-, and caffeine-containing products for 24 hours, and food for 4 hours, prior to the study but continued their normal medications . All studies were performed at the same time of day in a quiet, temperature-controlled room using the same OCT equipment by the same ophthalmologist who was masked to study group. SBP and DBP were recorded in duplicate, with an appropriately sized cuff, using a validated oscillometric sphygmomanometer, the Omron HEM-705CP , and valAll subjects underwent a single examination of both eyes using the Heidelberg SPECTRALIS Spectral-Domain OCT machine . Each examination comprised 3 scan protocols for each eye: (a) a horizontal line scan through the macula, centered over the fovea, with EDI enabled for greater choroidal visualization; (b) a macular volume scan consisting of 61 horizontal B-scans with a separation of 120 μm covering the whole macular area; and (c) a peripapillary circular line scan centered over the optic disc, with Nsite Axonal Analytics software automated segmentation of the RNFL .Measurements recorded included retinal thickness, RNFL thickness, macular volume, and choroidal thickness. The images took advantage of the proprietary TruTrack active eye tracking and Automatic Real-Time (ART) software, which averages the image over 100 scans, to generate a single high-resolution scan image. OCT measurements of retinal thickness were performed according to the ETDRS protocol . The ETDg for 20 minutes at 4°C. Samples were stored at –80°C until analysis.Venous blood samples for ADMA, ET-1, IL-6, and TNF-α were collected in EDTA tubes. These were immediately centrifuged at 2,500 Plasma ADMA concentrations were measured using an optimized and fully validated high-performance liquid chromatography method, as previously described  , in which a high-fidelity micromanometer  was used to determine carotid-femoral PWV .P = 0.05, we needed to include ~22 subjects; for RNFL thickness the corresponding figure was ~30 subjects. Thus, we aimed for 35 subjects in each group. Data were stored and analyzed in Prism, version 6.0 (GraphPad Software Inc.). Data are presented as mean ± standard deviation (SD). Thicknesses were examined by 2-way ANOVA, comparing thicknesses between all 3 patient groups at each macular location using Tukey correction for multiple comparisons. For blood measurements, differences between groups were assessed using parametric or nonparametric analyses as appropriate and similarly, correlation coefficients calculated using the Pearson or Spearman method as appropriate. Stepwise linear regression was used for multivariable analysis using variables showing linear relationship with choroidal thickness . Significance was set at a P value of less than 0.05. To measure the sensitivity and specificity of macular volume and subfoveal choroidal thickness at different values, a conventional ROC curve was generated using healthy subjects as controls. The area under the curve was calculated to ascertain the quality of these OCT metrics as biomarkers of CKD. An area of 0.5 is no better than expected by chance, whereas a value of 1.0 signifies a perfect biomarker.This study was powered on the basis of a healthy subfoveal choroidal thickness of 235 ± 53 μm  and a heThe clinical study was carried out with the approval of the local research ethics committee and the written informed consent of each subject. The investigations conformed to the principles outlined in the Declaration of Helsinki.ND, DJW, BD, SC, JRC, SB, and DT designed the study. CB, JJMHvB, TR, JRC, RK, RM, AC, MKH, PJG, IMM, TMCP, and LW performed the study and carried out the blood analyses. CR and FS performed the animal studies and analyzed the data. MT analyzed the data. All authors were involved in the writing and critical appraisal of the manuscript.


Systolic left ventricular function strongly influences the blood pressure waveform. Therefore, pressure-derived parameters might potentially be used as non-invasive, diagnostic markers of left ventricular impairment. The aim of this study was to investigate the performance of pressure-based parameters in combination with electrocardiography (ECG) for the detection of left ventricular systolic dysfunction defined as severely reduced ejection fraction (EF).Two populations, each comprising patients with reduced EF and pressure-matched controls, were included for the main analysis (51/102 patients) and model testing (44/88 patients). Central pressure was derived from radial readings and used to compute blood flow. Subsequently, pulse wave analysis and wave intensity analysis were performed and the ratio of the two peaks of forward intensity (SDR) was calculated as a novel index of ventricular function. SDR was significantly decreased in the reduced EF group , as was central pulse pressure, augmentation index and ejection duration (ED), while the QRS-duration was prolonged. SDR and ED were independent predictors of ventricular impairment and when combined with QRS in a simple decision tree, a reduced EF could be detected with a sensitivity of 92% and a specificity of 80%. The independent power of ED, SDR and QRS to predict reduced EF was furthermore confirmed in the test population.The detection or indication of reduced ejection fraction from pressure-derived parameters seems feasible. These parameters could help to improve the quality of cardiovascular risk stratification or might be used in screening strategies in the general population. Heart failure represents a serious global health problem that is becoming more and more frequent in the aging population: prognoses in the US predict prevalence to rise by 46% from 2012 to 2030 , according to the results of a Kolmogorov-Smirnov test for normality, categorical data as total number (percentage). Between-group differences of continuous data were quantified with an unpaired t-test  or Welch test  if normally or log-normally distributed and with the Mann-Whitney-U test elsewise. For proportions, the chi squared test was used. The performance of the different parameters as binary classifiers of a reduced EF was analyzed using logistic regression, receiver-operator characteristics (ROC) and the area under the ROC curve (AUC). AUCs were compared using the method of DeLong as implemented in MedCalc. The added predictive value of single variables in the stepwise classification schemes was evaluated by the net reclassification improvement as described in , while HR, LVETI, augmentation index as well as central and brachial PP were not included. With this model, the Youden index was maximal at a sensitivity of 76% and a specificity of 88% resulting in 80% correctly classified subjects. Adjustment for medication as a confounding factor increased the AUC further to 0.93  and the percentage of correctly classified subjects to 87% with a sensitivity of 88% and a specificity of 84%, compare Baseline characteristics of the test population were very similar to the main, development population, see Results obtained with the classification scheme from In this study, a new marker of impaired systolic function, the ratio of the first to second peak of forward wave intensity (SDR) derived from pressure waveforms alone, was introduced and investigated as a discriminator between subjects with reduced EF and controls. Furthermore, the combination of SDR with other pressure-derived measures and QRS-duration from ECG was examined.The influence of left ventricular impairment on the shape of the central pressure wave is reflected in the reduction of central PP and augmentation index found in this study as well as in previous works –11. Alsof. The first peak S is related to left ventricular contractility [While augmentation index and PP are both indirect measures of and strongly influenced by wave reflections, forward wave intensity is comprised of forward travelling waves only. These forward waves are generated by the left ventricle and result in two dominant peaks in the wave intensity dIactility , whereasactility . Their ractility  and Curtactility , who botA similar approach was taken by Ntsinjana and coworkers to analyze ventricular function in children with HFpEF . EquivalAs a ratio, SDR is virtually independent of the sampling frequency, making its value comparable between different investigators using different instruments. Furthermore, the computation of SDR is not affected by the absolute scaling of blood flow, which enables the use of a (volumetric) blood flow model for the estimation of flow velocity. The model used here has been investigated previously in patients with and without heart failure with reduced EF ,24,29. IIn ROC curve analysis, ED and SDR reached the largest AUC from all pressure-derived parameters considered in this study. Furthermore, the results of multivariable logistic regression analysis indicated no independent additive association of either PP, augmentation index, HR or LVETI to EF-status beyond ED and SDR. This might be explained by the intrinsic link between HR and ED on the one hand and the impact of HR and ED on both PP and augmentation index on the other hand ,25. In cSystolic heart failure is reflected in various abnormalities in the ECG signal, including temporal and morphological characteristics , and a nBased on a community-based study performed in Germany, Fischer et al. concluded that echocardiographic screening for LVSD cannot be recommended in the unselected, middle-aged population because asymptomatic LVSD is rare and most patients with LVSD present with cardiovascular comorbidities . HoweverRecently, operator-independent methods based on oscillometric pressure cuffs have been introduced for the assessment of central hemodynamics . Thus, aThe study population was collected in a 1:2 fashion regarding the proportion of patients with reduced EF to controls, which does not reflect the real, low prevalence of approximately 1% for systolic heart failure and 2% for LVSD in general population ,33. HoweThe detection or indication of reduced ejection fraction from parameters derived from pulse wave readings seems feasible. These parameters could help to improve the quality of cardiovascular risk stratification and might potentially be incorporated into cheap, noninvasive screening strategies in the general population.


Cardiovascular complications are the most prominent causes of morbidity and mortality among chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients undergoing standard hemodialysis (HD) therapy. Cardiovascular disease risk is increased significantly through persistent hypertension and blood pressure (BP) fluctuation, which are the most common complications of CKD. It was hypothesized that an extended approach with lengthier and more frequent dialysis sessions, referred to in this paper as “extended hemodialysis” (EHD), can potentially lower and stabilize blood pressure, and consequently reduce the rate of morbidity and mortality. A greater reduction of volume  with higher frequency can improve patient quality of life (QOL). Eleven papers, including clinical trials and systematic reviews were chosen and analyzed. The extracted data was used to evaluate the change in blood pressure levels between standard HD and EHD. Overall, the studies showed that EHD resulted in improved blood pressure management; therefore, we concluded that there will be a decrease in cardiovascular disease risk, stroke, and morbidity and mortality rate. There will be also an improvement in patient QOL due to beneficial effects of the EHD. Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are two main global health concerns with prevalence as high as 11–13% and 0.1% in the general population, respectively ,3. AccorLikewise, the patient quality of life (QOL) does not follow up to the expectations set by the massive burden of resources required for managing CKD and ESRD. Previous studies have reported a poorer QOL in patients with ESRD than those with other chronic diseases, and even cancer . In addiHypertension is a common complication of CKD and persists among most patients (80–90%) with ESRD on maintenance HD ,12,13. IA search of available literature was done in Medline and Embase to Week 4 of June 2017. The Cinahl and Cochrane databases were searched for systematic reviews. The search terms selected were “hemodialysis” or “dialysis,” and “daily” or “extended” or “frequent” or “home,” combined with “hypertension” as an MESH term using the Boolean search operator AND. Animal and non-English studies were excluded. We found 137 related papers. We reviewed abstracts manually for relevancy to the study topic. Papers were included if they dealt with short daily HD, daily HD, or nocturnal HD, and their effects on hypertension as an outcome of interest. The included study designs were clinical trial and systematic reviews. We excluded all case reports including studies with fewer than five subjects, editorials, or studies that did not include a comparator group. We reduced our scope to eleven papers. After critically analyzing the results of the articles found, we used a logical step-by-step approach in making inferences regarding the management of hypertension and quality of life in ESRD patients.p = 0.004).Kotanko et al. measured the effects of frequent HD on BP in the randomized controlled Frequent Hemodialysis Network Trials. These trials are the largest published randomized trials of frequent HD, permitting robust evaluations of these interventions on BP. The results of these trials showed that frequent HD reduced BP in both frequent in-center HD and with frequent nocturnal HD sessions at home. The daily trial lowered pre-dialysis systolic BP by −7.7 mmHg [95% CI: −11.9 to −3.5] and diastolic BP by −3.9 mmHg. In the Nocturnal Trial, compared to 3× weekly HD, two months of frequent HD lowered systolic BP by −7.3 mmHg and diastolic BP by −4.2. In the randomized controlled trial by Culleton et al., 2007, pre-dialysis systolic BP in a 6-month follow up decreased in patents randomized to nocturnal HD by 7 mmHg and increased in patients randomized to current standard HD by 4 mmHg with a mean difference of 11 mm Hg (95% CI: −2 to 24 mm Hg). Zimmerman et al., 2014 also found a statistically significant decrease in systolic BP from study entry to the end of the run-in phase , and an alteration of diastolic BP by −7.1 mm Hg . In a systematic review and meta-analysis by Suri et al. (2006), 10 of 11 studies suggested improvements in blood pressure in DHD.In this review, we found a significant trend in BP improvement among patients undergoing EHD in comparison to those undergoing the current standard HD. The included studies varied considerably with respect to patient population, dialysis time, frequency, location, methods of outcome assessment, and follow-up times. The lowering of inter-dialytic BP for daily HD is consistent. In order to illustrate the importance of a normotensive BP, it is important to outline the basic physiology of BP control and how it is affected by standard HD and EHD. EHD results in a decrease in inter-dialytic period, lower intradialytic BP fluctuations, and increased duration of volume removal per session, all leading to a variety of benefits.In the case of short HD duration as seen in standard HD, the fast removal of solutes from the patient’s intravascular space results in an abrupt decrease of extracellular osmolality. This causes fluid shift into the interstitial and intracellular space, which may lead to brain edema. Increasing the HD frequency will reduce solute/toxin accumulation. This, in conjunction with a longer period of HD, will reduce the intra-dialytic solute shift and provide more time for equilibration. A less significant shift also means that the patient will have fewer symptoms, less nausea, and an increased appetite. This allows for a more balanced diet, and will not require the patient to drink as much water in order to replenish the decrease in plasma volume.Patients undergoing standard HD can have an estimated intake of 1–2 L of water per day . A standFinally, through the aforementioned mechanisms, the myocardium will be subjected to reduced toxic effects and stress, additionally decreasing the risk of cardiovascular disease. Inter-dialytic potassium accumulation between two sessions of standard HD followed by rapid potassium removal in a 4 h session could lower the resting membrane potential of cells, leading to significant changes in myocyte excitability, and an increased risk of cardiac arrhythmia . HoweverThe physiological improvements that can be seen and inferred in EHD patients can also play a large role in determining the QOL of CDK and ESRD patients. There are several factors we can examine that will impact the patient QOL in an objective manner, and are improved through the use of EHD. One of the most important factors is the patient’s inter-dialytic weight gain, where a higher inter-dialytic weight gain is shown to significantly increase diastolic BP in patients . More seOne may argue that the outlined improvements will not compensate for the increased cost and patient access issues. However, the current data indicates that the annual costs required for daily and nocturnal HD are significantly reduced in comparison to standard HD . This isIn conclusion, the use of EHD can improve patient QOL, due to decreased myocardial stress through lower inter-dialytic weight gain, lower blood pressure fluctuations, and lower and more stable blood pressure. It is essential to raise awareness amongst the public and doctors about the benefits of longer and more frequent HD methods. In addition, serious reconsiderations must be made regarding the current implementation of EHD due to its beneficial impact on BP control, cardiovascular health, and patient QOL. Considering the significance and prevalence of ESRD, and its impact on society, we can hope that future studies and sustainable EHD models will further establish the importance and application of increasing dialysis hours and frequency.


Uncontrolled hypertension remains an important issue in daily clinical practice worldwide. Although the majority of patients are treated in primary care, most of the data on blood pressure control originate from populationbased studies or secondary healthcare.The aim of this study was to evaluate the frequency of uncontrolled hypertension and associated risk factors among hypertensive patients followed at primary care facilities in Kinshasa, the capital city of Democratic Republic of the Congo.A sample of 298 hypertensive patients seen at primary healthcare facilities, 90 men and 208 women, aged ≥ 18 years, were consecutively included in this cross-sectional study. The majority (66%) was receiving monotherapy, and diuretics (43%) were the most used drugs. According to 2007 European Society of Hypertension/European Society of Cardiology hypertension guidelines, uncontrolled hypertension was defined as blood pressure ≥ 140/90 or ≥ 130/80 mmHg (diabetes or chronic kidney disease). Logistic regression analysis was used to identify the determinants of uncontrolled hypertension.Uncontrolled hypertension was observed in 231 patients (77.5%), 72 men and 159 women. Uncontrolled systolic blood pressure (SBP) was more frequent than uncontrolled diastolic blood pressure (DBP) and increased significantly with advancing age (p = 0.002). The proportion of uncontrolled SBP and DBP was significantly higher in patients with renal failure (p = 0.01) and those with high (p = 0.03) to very high (p = 0.02) absolute cardiovascular risk. The metabolic syndrome  emerged as the main risk factor associated with uncontrolled hypertension.Uncontrolled hypertension was common in this case series and was associated with factors related to lifestyle and diet, which interact with blood pressure control. Hypertension is the most prevalent treatable cause of cardiovascular (CVD) and chronic kidney disease (CKD).1Patients with hypertension and one or more co-morbidities increasingly form a significant part of the primary care practitioner’s case load.In Democratic Republic of the Congo (DRC), despite the ever-growing prevalence of hypertension, data on uncontrolled hypertension are scarce and rely upon few population-based studies.From 30 April to 24 August 2012, all consecutively appearing patients with known hypertension and regularly followed at healthcare centres of the Roman Catholic Church Network (BDOM) were asked to participate in this cross-sectional study. Inclusion criteria were: age ≥ 18 years, being on antihypertensive treatment for at least three months, and giving a written informed consent to participate in the study.Data were obtained using a standard questionnaire, which collected information on age, gender, education level, duration of hypertension, the number and class of drugs taken for hypertension or other conditions, compliance with antihypertensive drugs, family history of hypertension (FH-HT), diabetes (FH-DM) or cardiovascular disease (CVD), smoking and alcohol use, and physical activity.2 (m). Overweight and obesity were defined as BMI > 25 and > 30 kg/m2.8A physical examination was performed on each patient to measure height, weight, waist circumference (WC), blood pressure and pulse rate. Height and weight were measured with reference to recommended procedures. Body mass index (BMI) was calculated as weight (kg)/heightSeated blood pressure (BP) was measured using an electronic device, OMRON M3 Intellisense , on the left arm at the level of the heart after five minutes’ rest. BP was measured three times and the mean of the last two readings was used for analysis. Pulse pressure (PP) was calculated as systolic (SBP) minus diastolic blood pressure (DBP). Mean arterial pressure (MAP) was DBP + PP divided by 3.While on their usual diet, a venous blood sample was taken from an antecubital vein for the determination of levels of serum uric acid, cholesterol and its sub-fractions, and triglycerides using enzymatic methods (Biomérieux France). Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula.9For estimated glomerular filtration rate (eGFR) determinations, the abbreviated equation from the MDRD study was used.Capillary blood glucose was determined using Accu-chek Compact plus glucometer  with the glucose oxidase method. Reactive Dipstick Condor Teco  was used to determine semi-quantitative proteinuria. A resting electrocardiogram (ECG) was performed for each patient and the Sokolow index was calculated. The 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelinesSubjects were classified as having: controlled SBP and DBP if current antihypertensive treatment was accompanied by clinic SBP < 140 mmHg and clinic DBP < 90 mmHg; uncontrolled SBP only if SBP was ≥ 140 mmHg and DBP < 90 mmHg; uncontrolled DBP only if DBP was ≥ 90 mmHg and SBP < 140 mmHg; uncontrolled SBP and DBP if SBP and DBP were ≥ 140 mmHg and ≥ 90 mmHg, respectively.12The metabolic syndrome was defined according to International Diabetes Federation criteria.8 Diabetes was defined as blood glucose level ≥ 126 mg/dl (6.99 mmol/l) or current use of antidiabetic drugs.13Excessive alcohol intake was defined by regular intake of two or more glasses per day of beer or equivalent for at least one year, knowing that one glass of beer contains 10 g of alcohol.15Physical activity in leisure time was categorised as active for subjects who exercised for at least four hours per week, and inactive or sedentary for all the others.2, respectively. According to the 2007 ESH/ESC guidelines,12 moderate, high and very high absolute CV risk were defined as 10–20, 20–30 and ≥ 30% probability of a CV event in the next 10 years, respectively. Proteinuria was defined as dipstick proteinuria ≥ 1+.19ECG-determined left ventricular hypertrophy (ECG-LVH) was defined as a Sokolow index > 35 cm.The study was conducted in accordance with the principles of the 18th World Assembly . The study protocol was submitted to the ethics committee of Kinshasa School of Public Health of the University of Kinshasa and received clearance under the number ESP/CE/024/2012.Data are expressed as mean ± standard deviation (SD) or relative frequency (%). Chi-squared and Student’s t-tests were used to compare categorical and continuous variables, respectively. Skewed continuous variables were compared using the non-parametric Mann–Whitney test. Stepwise logistic regression analysis was used to identify correlates of uncontrolled hypertension; odds ratio (OR) and confidence interval (CI) were obtained for each independent variable. To remain in the model a factor had to reach a p-value ≤ 0.05. All statistical analyses were performed with SPSS version 20 for Windows at the Division of Epidemiology and Biostatistics of Kinshasa School of Public Health, University of Kinshasa.2, a WC of 90 ± 11 cm, a SBP of 151 ± 24 mmHg and a DBP of 87 ± 14 mmHg.A total of 298 hypertensive patients, 208 women and 90 men, were recruited in this study. Clinical characteristics of the study population as a whole are given in A family history of hypertension or diabetes was present in 50 and 31% of patients, respectively. In 67% of patients, the duration of hypertension was less than 10 years. The majority of patients (66%) were receiving monotherapy, most with diuretics (43%) . Of the Uncontrolled hypertension was observed in 231 patients (77.5%), 72 men and 159 women, of whom 43, 24 and 5% had uncontrolled SBP and DBP, isolated uncontrolled SBP and isolated uncontrolled DBP, respectively . The freCompared to patients with controlled hypertension , those wIn multivariate analysis, the metabolic syndrome (MetS) and non-compliance with antihypertensive therapy emerged as the main risk factors for uncontrolled hypertension . CompareThe main findings of this cross-sectional study were as follows: first, uncontrolled hypertension with mainly uncontrolled SBP was frequent in these case series; second, the frequency of uncontrolled hypertension and that of uncontrolled SBP increased with reduced eGFR and advancing age, respectively; third, the MetS emerged as the main risk factor for uncontrolled hypertension.In this study, 77.5% of patients had uncontrolled hypertension. This observation agrees with previous reports highlighting the fact that in most countries, less than 30% of patients achieve BP goals,21The frequency of uncontrolled hypertension observed in the present study was somewhat higher than that reported in primary care settings by Rayner et al. (60.2%)Our clinically generated frequency of uncontrolled hypertension was quite similar to the 76.4% reported by Dzudie et al.30Apart from differences in methodology applied and population characteristics studied, the higher frequency of uncontrolled hypertension in sub-Saharan Africa appears to be multifactorial and is determined by patients, care providers and healthcare systems.32Non-compliance with antihypertensive therapy emerged in our study as the second risk factor associated with uncontrolled hypertension but the difference was not statistically significant. In many studies, non-compliance with antihypertensive therapy was responsible for two-thirds of the cases of uncontrolled hypertension.With regard to the care provider, clinical therapeutic inertia has been reported to be a major contributor to uncontrolled hypertension.Uncontrolled SBP is more frequent and its frequency increases with advancing age, especially after 60 years. A greater frequency of uncontrolled SBP has been reported by Yaméogo et al. in Burkina Faso and Ayodele et al. in Nigeria.26In our study, the frequency of uncontrolled SBP and DBP increased with reduced eGFR. Schmitt et al.36In univariate analysis, diabetes and low HDL-C levels were significantly associated with uncontrolled hypertension, whereas in multivariate analysis, the MetS and self-reported non-compliance emerged as the main predictors of risk for uncontrolled hypertension; however, the differences observed in non-compliance did not reach the level of statistical significance.Poor adherence to therapeutic plans and non-compliance with antihypertensive therapy have been reported to be perhaps the most important factors responsible for poor BP control.37Previous reports have associated the MetS with an increased risk of uncontrolled hypertension.38Several potential limitations of the study need to be underscored. The cross-sectional design of the study did not allow us to establish clear evidence of a causal relationship between the variables of interest. The study sample size was not large enough to be empowered to detect additional associations. The frequency of uncontrolled hypertension could have been overestimated by the lack of inclusion of home blood pressure monitoring while defining BP control.Uncontrolled hypertension was frequent in the present case series and was associated with factors related to lifestyle and diet, which interact with blood pressure control.


We investigated the relationship of neonatal and maternal serum creatinine  with various maternal/infant characteristics at different gestational ages (GA). We reviewed medical records of neonates admitted to NICU. We collected data on birth weight, GA, Apgar scores, medications, etc. Spearman’s test was used to analyze the correlation between serum creatinine and continuous variables, and the Mann-Whitney U and Kruskal-Wallis tests for continuous variables between groups. The changes in nSCr, mSCr, and nSCr/mSCr ratio because of gestational age and the points in gestational changes in trends were estimated using joinpoint trend analysis. From 614 neonate and mother pairs, we found that nSCr was significantly correlated with GA. However, mSCr at >28 wks decreased with GA. The nSCr/mSCr ratio was correlated with GA. In infants born <29 weeks, pregnancy-induced hypertension (PIH)  and mSCr  were significantly associated with nSCr. In term infants, maternal magnesium administration , respiratory distress syndrome , PIH , and mSCr  were significantly associated with nSCr. nSCr reflected mSCr at all gestational ages. The correlation between nSCr and mSCr in preterm infants  was stronger than in term infants . Renal function is typically estimated by glomerular filtration rate (eGFR) . The simThis retrospective cohort study took place in the neonatal intensive care unit (NICU) of Fukushima Medical University Hospital, Japan between 2006 and 2014. Recruitment of neonates for this study was limited to neonates admitted to this NICU. The study was approved by the ethics committee of Fukushima Medical University. The additional inclusion criteria was daily urine output > 1.0 ml/kg/h. Exclusion criteria included congenital anomalies, oligohydramnios, and severe renal malformations diagnosed by prenatal ultrasound. Preterm infants were recruited and followed until discharge.Blood samples were collected through a cord blood or peripheral venipuncture for serum creatinine measurements from each neonates at birth, day 14, and one month and plasma creatinine day 7. Although we routinely measured serum tests at birth, day 14 and day 28 for other research, we collected plasma on day 7 to save the volume. And blood samples of the mother were collected before birth. Creatinine was measured using a sarcosine oxidase enzymatic assay on TBA-c16000 . The method of analysis remained unchanged during the study period.th percentile), and Apgar score as postnatal risk factors.We determined PIH, hemolytic low platelet syndrome (HELLP) syndrome, antibiotic administration, steroid administration, and magnesium administration, as prenatal risk factors, and GA, BW, gender, indomethacin administration, neonatal antibiotic administration, SGA  in premature neonates born at < 30 wks. Blood pressure was monitored by continuous invasive blood pressure monitoring for premature neonates born at <27 wks, whenever possible. While prophylactic indomethacin was not used, we administered indomethacin to infants with hemodynamically significant patent ductus arteriosus.Most of the infants born at < 28 wks were ventilated using conventional ventilation or high-frequency oscillatory ventilation. Infants with respiratory distress syndrome (RDS) received intratracheal surfactant.Data on antenatal problems, use of antenatal steroids, maternal magnesium administration, PIH, HELLP, BW, GA, gender, Apgar score, SGA, RDS, mSCr and nSCr were collected from medical records. Continuous variables were presented as medians. Data were analyzed using SPSS for Windows, release 11.0 . Correlation between the variables of BW, GA, Apgar Score, mSCr, and nSCr were analyzed using Spearman’s rank correlation (r). For continuous variables, the Mann-Whitney U and Kruskal-Wallis tests were used for continuous variables between groups. Variables at a p level < .05 at univariate analysis were entered into a multiple regression analysis. Standardized coefficient was expressed as β. Multicollinearity of independent variables was assessed by using variance inflation factor (VIF). VIF exceeding is regarded as indicating serious multicollinearity, and values grater than 4.0 may be a cause for concern. Due to high correlation between BW and GA, each variable was entered separately into Models 1 and 2. BW was entered into Model 1, and GA was entered into Model 2.The changes in nSCr, mSCr and nSCr/mSCr ratio due to gestational age and the points in gestational changes in trends were estimated using joinpoint trend analysis. Recently, this method has been applied to not only birth trends and cancer trends, but to clinical examination values as well . We usedThe flow chart in As shown in In term infants, univariate analysis showed that only Apgar Score was significantly associated with mSCr . In mSCrIn terms of nSCr at one month of life, univariate analysis showed that BW, GA, RDS, PIH, use of antibiotics, and use of indomethacin were significantly associated with nSCr in preterm infants . MultivaFurthermore, there was a significant difference in nSCr in infants born at <25 wks during the first month of life . HoweverOur study suggested that there was a relationship between nSCr and mSCr levels in Japanese neonates born with or without mother’s complications. Especially, nSCr and mSCr with PIH were significantly higher than nSCr and mSCr without PIH in preterm delivery. A previous study reported that fetal plasma creatinine levels reflected maternal creatinine levels from 15 wks until term . Lao et In our study, the nSCr/mSCr ratio gradually increased with GA. This result was different from the previous study by Lao . This dind hour of life.Some studies have investigated creatinine levels in premature infants during the early postnatal period –22. The Our study had several limitations. Although our study was one of the larger studies to explore nSCr in infants, it included a relatively small number of infants in the highest GA group. In this study, nSCr from early postnatal days should have been investigated, however, we did not collect samples from the earliest day of life to reduce phlebotomy losses in first weeks in our NICU policy. Gallini et al. reported that sCr peaked during the first days of life in preterm infants . Auron aIn summary, we conclude that nSCr reflected mSCr at all gestational ages, but the correlation between nSCr and mSCr in preterm infants was stronger than in term infants. We also conclude that the nSCr/mSCr ratio gradually increased with GA. However, in infants born at <29 wks, GA was a factor in the delayed decrease of their nSCr that extended beyond a month of life. In addition, nSCr at one month decreased with advancing GA.S1 Table(DOC)Click here for additional data file.


Median follow-up was 6.4 years. During follow-up, 873 (19%) patients died: 370 (42%) from cardiovascular causes, 309 (35%) from cancer, and 194 (22%) from other causes. After adjustment for age, sex and classic cardiovascular risk factor, hazard ratios  for any death according to the four eGFRcysC categories were: 1 (reference), 1.4 (1.1–1.7), 2.9 (2.3–3.6) and 4.4 (3.0–6.4). The hazard ratios of all-cause and cause-specific mortality increased linearly below kidney functions of 80 ml/min/1.73 m2. Weaker results were obtained for eGFRcr. To conclude, we found in optimal cardiovascular drug-treated post-MI patients an inverse graded relation between kidney function and mortality for both cardiovascular as well as non-cardiovascular causes. Risk of mortality increased linearly below kidney function of about 80 ml/min/1.73 m2.Chronic kidney disease (CKD) is highly prevalent among older post-myocardial infarction (MI) patients. It is not known whether CKD is an independent risk factor for mortality in older post-MI patients with optimal cardiovascular drug-treatment. Therefore, we studied the relation between kidney function and all-cause and specific mortality among older post-MI patients, without severe heart failure, who are treated with state-of-the-art pharmacotherapy. From 2002–2006, 4,561 Dutch post-MI patients were enrolled and followed until death or January 2012. We estimated Glomerular Filtration Rate (eGFR) with cystatin C (cysC) and creatinine (cr) using the CKD-EPI equations and analyzed the relation with any and major causes of death using Cox models and restricted cubic splines. Mean (SD) for age was 69 years (5.6), 79% were men, 17% smoked, 21% had diabetes, 90% used antihypertensive drugs, 98% used antithrombotic drugs and 85% used statins. Patients were divided into four categories of baseline eGFR Causes of death were coded according to the International Classification of Diseases, 102. First, absolute mortality rates were calculated within each eGFR category. Second, we conducted Cox proportional hazards analysis, obtaining hazard ratios (HR) and 95% Confidence Intervals (CI) estimating the strengths of associations for various eGFR categories with mortality using eGFR ≥90 ml/min/1.73m2 as reference. The proportional hazards assumption was fulfilled in all models according to the graphical approach and Schoenfeld residuals. Analyses were adjusted for the n-3 fatty acid treatment groups of the Alpha Omega Trial (using 3 dummies: placebo vs three active treatments) and for the following potential confounders: age, sex, diabetes, current smoking, serum total/HDLcholesterol ratio, use of statins and of anti-hypertensive medication, and systolic and diastolic blood pressure (model 1). To evaluate a possible modifying role of risk factors, we repeated the previous analyses in strata of sex, diabetes, current smoking, alcohol use and physical activity. In a separate analysis we adjusted additionally for hsCRP (model 2), since the level of CRP is weakly associated with cysC.), median (interquartile range [IQR]), or number (proportion) where appropriate. We estimated GFR with the cystatin C-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation from 2012, recommended by the KDIGO 2012 guideline as the confirmatory test, taking into account age, sex and race.,22 Resulith cysC. Third, tith cysC.), the kncysC was 78.8 (20.6) and eGFRcr was 82.7 (21.3) ml/min/1.73m2. At baseline mean (SD) kidney function did not differ among the four treatment groups , being for eGFRCysC 79.3 (20.4), 79.3 (20.7), 78.7 (20.9) and 77.8 (20.4) ml/min/1.73m2 (P = 0.3), respectively, and for eGFRcr 83.0 (21.1), 83.8 (21.4), 81.9 (21.2) and 82.2 (21.5) ml/min/1.73m2 (P = 0.1), respectively. The correlation of log-transformed hsCRP with eGFRcysC was -0.29 and with eGFRcr -0.10 (both P<0.001).Baseline characteristics of all patients according to four categories of cysC-based eGFR at baseline are presented in cysC are presented in cysC of 60–89, 30–59, and <30 ml/min/1.73m2 compared with the reference was 1.8, 4.7 and 6.7 times higher, which corresponded to an excess rate of 1.2, 5.5 and 8.6 deaths/100 py. Using proportional hazards regression analysis we found after multivariable adjustment a graded inverse relation between kidney function and all-cause mortality (2 did not attenuate the results. After stratification for treatment with or without fish oil (EPA-DHA) and multivariable adjustment we found no differences in risk for all-cause mortality among the four eGFR categories (P for interaction = 0.2). After stratification by age, diabetes, history of self-reported stroke, smoking, alcohol use, physical activity we found no evidence for effect modification. 2.We accrued 28,840 person-years of follow-up. During a median follow-up of 6.4 y (IQR: 5.3 to 7.6), 873 (19.1%) patients died. The absolute mortality rates (95%-CI) per 100 person-years (py) in post-MI patients for the four eGFRortality  Tables. cysC and cardiovascular death  were cardiovascular. We found a strong inverse graded relation between eGFRar death . Risk ofdeath  were due to cancer. We found a weak inverse relation between mortality from cancer and kidney function. Due to the low number of deaths from cancer (n = 5) in the lowest category of kidney function, adjusted hazard ratios could not be calculated.2. After exclusion of patients who had cardiovascular disease as secondary cause of death, compared with the reference the hazard ratio for eGFRcysC <60 ml/min/1.73m2 for other causes of death was 3.64 (95%-CI: 1.38 to 9.59). Of all non-cardiovascular-non-cancer deaths, 72 were due to diseases of the respiratory system. We found a similar hazard ratio for eGFRcysC <60 ml/min/1.73m2 and death due to diseases of the respiratory system of 3.46 (95%-CI: 1.48 to 8.12). Among never smokers the hazard ratio for eGFRcysC <60 ml/min/1.73m2 for other causes of death was 3.43 (95%-CI: 0.91–13.0).Of all deaths, 194 (22%) had non-cardiovascular-non-cancer causes. We found a strong inverse relation between lower kidney function and non-cardiovascular-non-cancer death  Figs. We2. Compared to a normal kidney function (≥90 ml/min/1.73m2) the multivariable adjusted relative risk for all-cause-mortality was 1.4-fold greater for cystatin C-based kidney function between 60–89 ml/min/1.73m2, 2.9-fold for 30–59 ml/min/1.73m2 and 4.4-fold for <30 ml/min/1.73m2. Impaired kidney function was related to both cardiovascular as well as non-cardiovascular mortality, although its relation with cancer was much weaker.This is the largest cohort study of older state-of-the-art drug-treated post-myocardial infarction patients, without severe heart failure, that shows a strong inverse graded relation between kidney function and all-cause mortality. Relative risk of mortality increased linearly below a kidney function of about 80 ml/min/1.73mcysC-range of 60–89 with ≥90 ml/min/1.73m2. Another meta-analysis, including population-based and high-risk cohorts, showed that individuals aged 65–74 years with an eGFR of 45 or 80 ml/min/1.73m2 had a mean all-cause mortality rate of 3.7 and 2.3 per 100 py, respectively.[2, respectively. However, in contrast to the patients in the Alpha Omega Trial, participants included in this meta-analysis with a history of myocardial infarction enrolled before the year 2000, did most likely not receive optimal cardiovascular drug-treatment such as statins and dual antiplatelet therapy.[Our results extend the observations of a meta-analysis that showed a graded inverse relation between kidney function and all-cause mortality. This met therapy.,262, which is substantially higher than the threshold of approximately 60 ml/min/1.73m2 in the meta-analysis of Hallan et al.[2 below which the risk for cardiovascular mortality increased steadily.[2.[We found that the relative risk of all-cause mortality increased linearly below an eGFR of 80 ml/min/1.73man et al. Most liksteadily. Our resuadily.[2. In contr2 had a doubled relative risk of death from cancer compared to those with a kidney function ≥90 ml/min/1.73m2. Fried et al. showed in a community-based cohort of older individuals (mean age 75 years), of whom 21% had a history of cardiovascular disease, a relative risk of 1.30 (0.97 to 1.74) for death from cancer among those with an eGFRcysC <60 compared with an >80 ml/min/1.73m2.[The present study showed a proportion of cardiovascular and non-cardiovascular mortality in post-MI patients of 42% and 58%, respectively. This is in accordance with findings in the general population, patients with CKD, and (pre-)dialysis patients.–32 In oun/1.73m2. Growing We found a strong inverse relation between kidney function and non-cardiovascular-non-cancer mortality. Although we adjusted for smoking, we cannot exclude residual confounding. However, this inverse relation persisted when we confined our analysis to life-time never smokers. After exclusion of patients who had cardiovascular disease as secondary cause of death, the relation between kidney function and other causes of death remained similar. Comparable results were obtained between kidney function and mortality from respiratory diseases. Common traditional cardiovascular risk factors, such as smoking and inflammation, among patients with kidney disease may explain the relation with non-cardiovascular death e.g. respiratory diseases.Non-GFR determinants of cystatin C, such as inflammation, may enhance the relation between cystatin C-based eGFR and different causes of death. However,Staging of CKD is used for risk stratification in clinical guidelines to improve patient outcome by identifying high-risk groups. The lower relative mortality risk associated with CKD at older ages has been used as an argument for age-specific CKD diagnosis and staging. However,Our study has several limitations. First, we previously showed in the Alpha Omega Trial that a daily low dose of fish oil retards kidney function decline by 30% in post-myocardial infarction patients. Since paper se is a risk factor for mortality. Serum cystatin C and creatinine were analyzed in a central laboratory. Ascertainment of mortality was complete. Of all patients only 6% of kidney function measurements were missing.Our prospective cohort study has several strengths. We showed an inverse graded relation between mortality and kidney function based on two different endogenous markers of kidney function, suggesting that impaired kidney function We found in older post-myocardial infarction patients who received state-of-the-art drug treatment that kidney function, independent of classic cardiovascular risk factors, predicted all-cause, cardiovascular as well as non-cardiovascular mortality in a graded fashion.S1 Table≥90 ml/min/1.73m2 was taken as the reference category. *Due to the low number of events in the lowest category of eGFR further adjustment could not be performed.AR absolute risk, CI confidence interval, No number, py person years, Model 1: adjusted for the intervention with n-3 fatty acids, age, sex, diabetes, current smoking, ratio serum cholesterol/HDL, statin-use, anti-hypertensive medication, systolic blood pressure, and diastolic blood pressure. Model 2: in addition to Model 1 additional adjustment for C-reactive protein. eGFR (DOCX)Click here for additional data file.S2 Table≥90 ml/min/1.73m2 was taken as the reference category. *Due to the low number of events in the lowest category of eGFR further adjustment could not be performed.AR absolute risk, CI confidence interval, No number, py person years. Model 1: adjusted for the intervention with n-3 fatty acids, age, sex, diabetes, current smoking, ratio serum total cholesterol/HDL, statin-use, anti-hypertensive medication, systolic blood pressure, and diastolic blood pressure. Model 2: in addition to Model 1 additional adjustment for C-reactive protein. eGFR (DOCX)Click here for additional data file.S1 Fig2 was taken as the reference point (hazard ratio 1). The knots were chosen at the 5th, 35th, 65th and 95th percentile of the kidney function distribution, corresponding to creatinine-based eGFR of 43, 77, 94 and 110 ml/min/1.73m2.Hazard ratios for all-cause mortality depending on kidney function were modeled by separate restricted cubic splines for creatinine based-kidney function in a Cox-regression model. The model was adjusted for n-3 fatty acids treatment, age, sex, diabetes, current smoking, ratio serum cholesterol-HDL, statin-use, use of anti-hypertensive medication, systolic and diastolic blood pressure. An eGFR of 120 ml/min/1.73m(TIF)Click here for additional data file.S2 Fig2 was taken as the reference point (hazard ratio 1). The knots were chosen at the 5th, 35th, 65th and 95th percentile of the kidney function distribution, corresponding to cystatin C-creatinine-based eGFR of 41, 68, 86 and 104 ml/min/1.73m2.Hazard ratios for all-cause mortality depending on kidney function were modeled by restricted cubic splines for the combined cystatin C-creatinine based-kidney function in a Cox-regression model. The model was adjusted for n-3 fatty acids treatment, age, sex, diabetes, current smoking, ratio serum cholesterol-HDL, statin-use, use of anti-hypertensive medication, systolic and diastolic blood pressure. An eGFR of 120 ml/min/1.73m(TIF)Click here for additional data file.S3 Fig2 was taken as the reference point (hazard ratio 1).Hazard ratios for cardiovascular mortality depending on kidney function were modeled by separate restricted cubic splines for creatinine based-kidney function in a Cox-regression model. The model was adjusted for n-3 fatty acids treatment, age, sex, diabetes, current smoking, ratio serum cholesterol-HDL, statin-use, use of anti-hypertensive medication, systolic and diastolic blood pressure. An eGFR of 120 ml/min/1.73m(TIF)Click here for additional data file.S4 Fig2 was taken as the reference point (hazard ratio 1).Hazard ratios for cardiovascular mortality depending on kidney function were modeled by restricted cubic splines for the combined cystatin C-creatinine based-kidney function in a Cox-regression model. The model was adjusted for n-3 fatty acids treatment, age, sex, diabetes, current smoking, ratio serum cholesterol-HDL, statin-use, use of anti-hypertensive medication, systolic and diastolic blood pressure. An eGFR of 120 ml/min/1.73m(TIF)Click here for additional data file.S5 Fig2 was taken as the reference point (hazard ratio 1).Hazard ratios for non-cardiovascular-non-cancer causes of mortality depending on kidney function were modeled by separate restricted cubic splines for creatinine based-kidney function in a Cox-regression model. The model was adjusted for n-3 fatty acids treatment, age, sex, diabetes, current smoking, ratio serum cholesterol-HDL, statin-use, use of anti-hypertensive medication, systolic and diastolic blood pressure. An eGFR of 120 ml/min/1.73m(TIF)Click here for additional data file.S6 Fig2 was taken as the reference point (hazard ratio 1).Hazard ratios for non-cardiovascular-non-cancer causes of mortality depending on kidney function were modeled by restricted cubic splines for the combined cystatin C-creatinine based-kidney function in a Cox-regression model. The model was adjusted for n-3 fatty acids treatment, age, sex, diabetes, current smoking, ratio serum cholesterol-HDL, statin-use, use of anti-hypertensive medication, systolic and diastolic blood pressure. An eGFR of 120 ml/min/1.73m(TIF)Click here for additional data file.


P > 0.05). Logistic regression analyses showed a lower risk of pre-hypertension with higher dietary calcium intakes in women , but not in men; no association between dietary calcium intake and hypertensive risk was found in both genders . This study suggests that there are no conclusive associations of habitually low dietary calcium intake with blood pressure or hypertensive risk in Chinese individuals consuming predominantly plant-based diets.This study aimed to assess the association of habitually low dietary calcium intake with blood pressure or hypertensive risk using data from the China Health and Nutrition Survey (CHNS) in 2009. We included 6298 participants (2890 men and 3408 women) aged 18 years or older in this analysis. Food intakes were measured by 3-day 24-h individual recalls combined with a weighing and measuring of household food inventory. The participants were divided into normotensive, pre-hypertensive and hypertensive groups according to their mean blood pressure of three repeated measurements. Six intake levels were decided by percentiles of gender-specific dietary calcium intakes . Average dietary calcium intakes were 405 mg/day for men and 370 mg/day for women, 80% and 84% of which were derived from plant-based food in men and women, respectively. Multiple linear regression analyses showed that dietary calcium intakes were not related with blood pressure in both genders (all  A rising prevalence of hypertension worldwide has been well documented in the past two decades . StudiesFewer studies have documented this relationship among Chinese adults. Previous cross-sectional surveys conducted in Guangxi province, Tianjin province, and rural Henan province, China, found inverse associations between dietary calcium and blood pressure or hypertension among populations in both Han and minority nationalities ,23,24,25Cross-sectional data from the CHNS 2009 were used. This survey was conducted in nine provinces in China, with a multistage, randomized cluster design. The design and methods of this survey have been described in detail elsewhere . All of 2 or >45kg/m2, and nutrient intakes  out of the 99% range of the population, 6298 adults were included in the current analysis, among which 2890 were men and 3408 were women.In total, 8641 individuals aged 18 years and older from 218 communities were surveyed in the CHNS 2009. All participants were asked to finish a structured questionnaire, a dietary survey, physical examination and blood draw. The exclusion criteria include: those who had self-reported hypertension, diabetes, dyslipidemia; those who were currently taking antihypertensive, antidiabetic drugs; those who were diagnosed with severe diseases , and those who were pregnant and nursing. After excluding those with missing or implausible values, i.e., systolic blood pressure (SBP) <40 mmHg or >300 mmHg, diastolic blood pressure (DBP) <30 mmHg or >200 mmHg, energy intakes >5000 kcal/day or <500 kcal/day, BMI <14 kg/mBlood pressure was measured three times every 1–2 minutes following a standard procedure with a regularly calibrated mercury sphygmomanometer with appropriate-sized cuffs in the morning by trained physicians. Participants were required to avoid active exercises, smoking and talks, emptying the bladder within one hour, and keeping in a mental relaxed state for at least 10 minutes before measurements. In addition, they were asked to avoid taking foods, hot water or drugs that may affect blood pressure within 30 minutes. They could choose a sitting or horizontal position, but were asked to keep their arms and hearts at the same level. The average of the three readings was chosen as the corresponding BP values to reduce the effect of measurement errors. Blood pressure was recorded with mmHg as the unit. Subjects were classified into normotensive, pre-hypertensive, and hypertensive groups according to the classification of hypertension in Joint National Committee Report (JNC-Ш)  and 2010The individual diet was assessed by three consecutive day 24-h recalls including one weekend day and two weekdays, in combination with the consumption of condiments  recorded using household-based accounting method, adjusting for personal energy intake afterwards . Energy 2) = weight (kg)/height(m)2]. Waist circumference was measured under a standing posture with hands naturally sagging, then using a tape around the waist below the lowest rib margin and reading the measurement at minimum respiration. Body weight and height were measured after subjects had their shoes, hats and heavy out garments removed. All of them took a stand-up posture, with their chest and abdomen held up, shoulders flat, arms drooped naturally, eyes flat front and head upright. Body weight was measured to the nearest 0.1 kg and height was measured to the nearest 0.1 cm. Body mass index (BMI) was calculated by weight in kg by the square of height in meter , smoking status , alcohol drinking and physical activity were obtained through questionnaire interview. The average daily alcohol consumption was calculated based on frequency and amount of alcohol consumed by the drinkers in the past year. Physical activity levels(PAL) was quantified into multiples of basal metabolic rate (BMR) on the basis of the Chinese Dietary Reference Intakes (2000 edition) : in men,χ2 tests with linear-by-linear tests for categorical variables. Multiple linear regression models were used to investigate the association between dietary calcium intake and blood pressure. Demographic variables consisting of age, education level, ethnicity, residence, urbanization index were included in model 1. Total energy intake and BMI were included in each model for adjusting individual differences. Model 2 adjusted variables cited above in model 1 and further adjusted life behavior factors  [Continuous variables were presented as means and standard deviations for normal distribution, medians and interquartile range for skewed distribution; and categorical variables were presented as numbers and proportions. Participants were divided into six intake levels  according to the percentiles of gender-specific dietary calcium intake. Differences across dietary calcium intake levels were analyzed by using one-way ANOVA  or Kruskal–Wallis test (skewed distribution) for continuous variables with tests for linear trend, and by using and PAL) . Resultsand PAL) , and dieand PAL) ,42, so wand PAL)  were furP < 0.05 was considered as the significant level for all analyses. Due to the significant gender differences in blood pressure and calcium intake, and the gender differences that were observed in previous studies for assessing the association of calcium and blood pressure or the risk of hypertension , men andThe baseline characteristics of men and women are, respectively, shown in P > 0.05, P > 0.05).The associations between dietary calcium intake and blood pressure for men and women are shown in Pfor trend = 0.001); and 0.65, 0.71, 0.71, 0.63, 0.33 in model 4 (Pfor trend = 0.001). However, we did not find similar associations in men . No associations were observed between dietary calcium intakes and the risk of hypertension in men or women .The associations between dietary calcium intake and risk of hypertension and pre-hypertension are presented in This cross-sectional study showed that there was no significant or consistent association between low dietary calcium intake and blood pressure in Chinese adults with predominantly plant-based diets, whose mean dietary calcium intake was below 400 mg/day. Although such a low intake of dietary calcium was reported as a risk factor for hypertension in western populations , our finInconsistent associations were found between dietary calcium intake and hypertension in previous studies. Some studies reported that lower calcium intake was associated with blood pressure or hypertension ,47,48,49A study from the United States suggested that a calcium intake of less than 700–800 mg/day was associated with a higher risk of hypertension . In the Strengths of our study are the relatively large sample size and good representativeness with participants recruited from nine provinces in China. In this study, pre-hypertension and hypertension were analyzed as outcome variables, and biochemical indicators were also included as confounding factors. Beyond all of the above, we divided calcium intake into six intake levels to make the highest level close to average dietary calcium intakes in western countries, so as to make better comparison with the findings from Europe and the United States. This study also has several limitations. First, this is a cross-sectional investigation, longitudinal changes of blood pressure of this population cannot be observed in this analysis. Second, some confounding factors such as family history of hypertension and other possible covariates were not included. Third, there is a lack of information on calcium supplementation in this survey, although the proportion of Chinese individuals using dietary supplements was quite low . Fourth,In conclusion, this study based on data from the CHNS 2009, suggested no conclusive associations between habitually low dietary calcium intake and blood pressure or hypertensive risk in Chinese adults with a predominantly plant-based diet containing a relatively low dietary calcium intake of 400 mg/day on average.