The present study sought to explore the relationship of common cardiovascular disease risk factors and noncoding RNAs with essential hypertension (EH).A total of 402 EH patients and 402 gender- and age-frequency matched healthy controls were enrolled in this study. Each participant received a questionnaire survey, physical examination and laboratory tests. Quantitative real-time polymerase chain reaction (qPCR) was performed to assess relative expression levels of six noncoding RNAs  in peripheral blood leucocytes. Multiple logistic regression analysis was used to estimate the risk of having EH between hypertensive and non-hypertensive patients.P = 0.015) and NR_034083 (P = 0.004) were significantly reduced in EH patients compared with controls, whereas NR_104181 (P = 0.007), miR-143 (P = 0.005) and miR-145 (P = 0.015) were significantly elevated.Analysis showed that participants with anxiety, high body mass index, abdominal obesity and family history of hypertension had higher risk for EH, whereas those with bland diet and occupational physical activities had lower risk for EH. qPCR assays showed that NR_027032 (After controlling the cardiovascular risk factors, multivariate analysis showed that lower expression levels of NR_034083 and higher expression levels of NR_104181 and miR-143 were risk factors for EH.EH is a result of environmental and epigenetic factors. Strikingly, NR_034083, NR_104181 and miR-143 may be correlated with the risk for EH development; therefore, epigenetic markers could be used to measure hypertension levels to help elucidate the pathogenesis of EH. Hypertension, a leading risk factor for global cardiovascular disease, contributes to half of coronary heart disease and approximately two-thirds of cerebrovascular disease burdens . While t2+ and Ca2+ + Mg2+ and firm adhesion in Mg2+ and Mn2+, mimicking the two key steps in leucocyte accumulation in the inflamed vasculature [Currently, epigenetic regulators of hypertension mainly include long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and DNA methylation . LncRNAsculature .MiRNAs are involved in a variety of biological processes, including cellular proliferation, apoptosis and differentiation , 11. As Despite the important role of noncoding RNAs  in the development of hypertension, their relative contributions to hypertension remain largely unknown. Previous studies in humans have demonstrated that miRNAs  are differentially expressed in hypertensive patients and healthy individuals, though the expression levels of these miRNAs are not consistent among different reports . There hFrom November 2014 to June 2016, we performed a hospital-based case-control study on EH in Fujian Province, China. Participants were recruited from the First Affiliated Hospital of Fujian Medical University and the Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine. A total of 402 EH patients were included in the final analysis. Meanwhile, 402 healthy controls were randomly selected from the physical examination population in the same hospitals, and were frequency-matched by gender and age (±3 years) with cases. The disease-free status was ascertained according to the results of physical examination. Furthermore, 80 of the 402 EH patients and 80 of the 402 control individuals were selected by stratified random sampling method to donate venous blood samples for ncRNA expression analysis by quantitative real-time polymerase chain reaction (qPCR). Inclusion criteria for cases included patients with at least three consecutive records of systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or patients that have received antihypertensive medications for more than 3 months . Inclusion criteria for controls included healthy individuals that have systolic blood pressure and diastolic blood pressure < 140 and < 90 mmHg, respectively. Exclusion criteria included a known history of leucopenia, thrombocytopenia or severe hepatic or renal dysfunction and evidence of an inflammatory or malignant disease. The protocol was approved by the ethics committee of Fujian Medical University School. Written informed consent was obtained from all patients and controls.The participants completed the questionnaire themselves following instructions given by the researchers. The completed questionnaire was checked by the researchers to ensure that all questions have been answered appropriately. Questions covered demographic characteristics , lifestyle habits  and family history of hypertension. Smokers were defined as individuals who smoked cigarettes more than once a day consecutively for more than 6 months or smoked more than 100 cigarettes cumulatively . Alcohol2) and categorised into four scales: < 18.5 underweight, 18.5–24.0 normal, 24.0–28.0 overweight and ≥ 28.0 obesity [Systolic and diastolic blood pressure, height, weight and waist circumference (WC) were measured. Before blood pressure measurement, each subject was asked to not smoke, drink any beverage with caffeine or exercise for at least half an hour. After resting in a sitting position for 5 min, brachial blood pressure was measured three times with an interval of 2 min; the average of three readings was used for analysis . Body ma obesity . WC was  obesity .g for 10 min to remove plasma. According to the manufacturer’s instructions for the Lymphocyte Separation Medium , blood samples were carefully transferred into a new RNA-free tube for a second centrifugation at 400 g for 20 min to obtain the peripheral blood leucocytes and then stored at − 80 °C prior to RNA extraction. All blood samples were subjected to only one freeze-thaw cycle.Blood samples were collected in a K2-EDTA-coated tube  and centrifuged at 400 -△△CT method [Total RNA was extracted from peripheral blood leucocytes using TRIzol reagent  and dissolved in RNase-free water. RNA extracts were quantified using NanoDrop 2000 instrument . The integrity of the RNA was determined by agarose gel electrophoresis. Reverse transcription of quantified RNA was performed using PrimeScript RT Reagent Kit with gDNA Eraser (lncRNAs) or the PrimeScript RT Reagent Kit (miRNAs)  according to the manufacturer’s instructions. qPCR was performed on the LightCycler 480 real-time PCR system  with the SYBR® Premix Ex Taq™ II kit . Amplification curves were obtained by 40 cycles of 95 °C for 30 s, 95 °C for 5 s and 60 °C for 34 s, whereas dissolution curves were obtained by one cycle of 95 °C for 15 s, 60 °C for 1 min and 95 °C for 15 s. The Ct value was the fractional cycle number at which the fluorescence exceeded the given threshold. GAPDH and U6 were used as internal controls. The reverse primer used for miRNA was a universal downstream primer. LncRNA and miRNA expression levels were calculated using the 2T method . The pri-test or Chi-square analysis. Multiple factor logistic regression was used to analyse whether lncRNAs and miRNAs were influencing factors of EH. All tests were two sided and a P value < 0.05 was considered statistically significant.All data were analysed using SPSS 22.0 . Comparisons between the case and control groups were performed using a ZP > 0.05), indicating that the frequency matching was adequate. Associations between risk factors and EH are shown in Table χ2 test, P <  0.001), higher abdominal obesity rate  and higher family history of hypertension rate . Significant differences were found between cases and controls in the occupational physical activities, personality types, anxiety levels and body mass indices.Associations between demographic characteristics and EH are shown in Table Z-test = − 2.439, P = 0.015) and NR_034083  were significantly reduced, whereas NR_104181  was significantly elevated in hypertensive patients compared with controls  and miR-145  were up-regulated in hypertensive patients compared with controls, whereas miR-126 level  was not significantly different between hypertensive patients and controls  were a protective factor against hypertension, whereas higher expression levels of NR_104181  and miR-143  were risk factors  and bland diet, occupation physical activities, personality type, anxiety level, BMI, abdominal obesity and family history of hypertension as independent variables for multivariate logistic regression analysis , similar to some miRNAs, are differentially expressed in hypertensive patients and healthy individuals, supporting their roles in the pathogenesis of EH.


The endothelial function plays key roles in both promoting and protecting against atherosclerotic disease. Several methods, including peripheral arterial tonometry (PAT), have been reported to be useful for investigating endothelial dysfunction. Furthermore, the level of thrombomodulin (TM) is assumed to reflect the endothelial dysfunction. In the present study, we investigated endothelial dysfunction in patients with peripheral arterial disease (PAD) by measuring their TM levels, and evaluated the correlation between TM and various parameters.We measured the TM levels and performed PAT in 17 patients with PAD. We also recorded the patients’ demographic information, including comorbidities, and investigated their hemodynamic status by measuring the ankle brachial pressure index (ABI). The PAT results were used to calculate the reactive hyperemia index (RHI), which reflected the patients’ level of endothelial dysfunction.The RHI and ABI values and the serum level of creatinine were found to be significantly correlated with the TM level . After setting an RHI value of 1.67 as the cut-off, the patients with RHI values of <1.67 were found to have significantly higher TM levels  than the patients with RHI values of ≥1.67  (P = 0.023).The degree of endothelial dysfunction, as calculated by the TM level, might influence the prognostic value of the RHI, which is determined by PAT. The measurement of the TM level and PAT might both be useful methods of measuring endothelial dysfunction in patients with PAD. The endothelium is a delicate monolayer of cells with whole blood vessels that plays an important role in the initiation and development of atherosclerotic diseases. Although the function of the endothelium is to protect against atherosclerotic disease, endothelial dysfunction can actually promote atherosclerotic diseases . FurtherEndothelial dysfunction has been established as an important early event in the pathogenesis of atherosclerosis, with changes in endothelial function occurring well before the onset of clinically apparent cardiovascular disease . We can Furthermore, several plasma markers have shown a significant correlation with endothelial dysfunction , 9. ThroWe conducted a pilot study to evaluate endothelial dysfunction in PAD patients by measuring their TM levels and performing PAT, and investigated the relationships between the TM level  and various parameters.We recruited consecutive 17 patients with PAD who had undergone PAT and whose serum TM levels had been measured at an outpatient clinic at Tokyo Medical and Dental University Hospital between May 2014 and March 2015. PAD was diagnosed based on the presence of > 50% vessel stenosis due to lesions in the lower limbs. We mainly assessed the vessel stenosis by computed tomography angiography. In the cases with contraindication of using contrast media, such as chronic kidney disease and allergy, we evaluated the stenosis using magnetic resonance angiography and/or duplex ultrasound sonography. All of the patients provided their written informed consent, then we enrolled. This study was approved by the ethics committee of Tokyo Medical and Dental University (No. 701), and we reviewed the patients’ medical examinations and records. In the present study, we excluded patients who had recently undergone interventions for PAD or coronary artery disease (CAD) (< 6 months), and patients with a recent history (< 3 months) of myocardial infarction, unstable angina, decompensated heart failure, or cerebrovascular disease (CVD). We also excluded the patients with systemic inflammatory and malignant diseases. The patients’ medical records were reviewed as described below, and we investigated the patients’ demographics, medications and medical histories using a questionnaire. Hypertension was defined as a systolic blood pressure of > 130 mmHg, a diastolic blood pressure of > 80 mmHg or a history of treatment for hypertension. Dyslipidemia was defined as a serum low-density lipoprotein cholesterol level of > 140 mg/dL, a high-density lipoprotein cholesterol level of < 40 mg/dL, a triglyceride level of > 150 mg/dL or a history of treatment for dyslipidemia. CAD was defined as the presence of angina pectoris, myocardial infarction or both, on coronary angiography, or based on a history of the patient having undergone coronary artery revascularization. CVD was defined as a history of stroke, transient ischemic attack, carotid artery revascularization or cerebral hemorrhage. Diabetes mellitus was defined as having a fasting blood glucose level of > 126 mg/dL, a hemoglobin A1c concentration of > 6.5%, or the use of antidiabetic drugs. The severity of PAD was assessed by the measurement of the ankle brachial pressure index (ABI). The ABI was measured using a VasoGuard P84™ system . We measured the systolic blood pressure on both sides of the brachial arteries in the upper limbs. In the lower extremities, both the posterior tibial arterial and dorsal pedis arterial pressures were measured if available. The ABI value was calculated based on the higher systolic blood pressure of the lower limbs divided by the higher brachial systolic blood pressure.To assess the endothelial function, pulse wave amplitude was assessed before and during reactive hyperemia, which is induced by occluding blood flow of brachial artery using inflatable cuff. The calculated index  between the flow in the upper arm with reactive hyperemia and the control upper arm represents a measure of the endothelial function . We usedAfter the patients had fasted for at least 12 hours, non-traumatic venipuncture was performed in a superficial vein of upper limb to collect blood samples. Complete blood cell counts were measured and biochemistry tests were performed using standard laboratory methods. Several plasma aliquots were withdrawn (from the blood samples) after centrifugation in a floor-standing centrifuge for 20 minutes at 2,500 rpm. The samples were stored until use at -80°C. We also measured the serum levels of TM using a Thrombomodulin Enzyme Immunoassay kit .U test for continuous variables. Correlations between the TM level and several parameters were assessed using Spearman’s correlation coefficient. P values of < 0.05 were considered to indicate statistical significance. The statistical analyses were performed using the Stat View software program .Categorical variables are expressed as frequencies and percentages, and continuous variables are expressed as median and interquartile range (IQR). The statistical significance was assessed using the Mann-Whitney 2 . The documented comorbidities included hypertension (82.4%), smoking history (70.6%), dyslipidemia (70.6%), DM (70.6%), CVD (29.4%) and CAD (17.6%). Ten patients (58.8%) were taking with Ca-blockers, and 3 patients (17.6%) were taking β-blockers. The laboratory test findings are shown in We evaluated 17  PAD patients in the present study. The median age was 71 years , and the median body mass index was 22.0 kg/mThe correlations between TM and each of the parameters are shown in An RHI value of < 1.67 was defined as cut-off value of endothelial dysfunction [TM is an endothelial membrane receptor for thrombin, which is an essential part of the protein C anticoagulant pathway. It has a large extracellular portion, in which most of its activity takes place . FurtherWe found a significant correlation between the TM level and the RHI value in the present study. The difference in blood flow, as measured by PAT, reflects microvascular dysfunction and might be useful for evaluating endothelial dysfunction at the microcirculation level  Several The present study is associated with several limitations. First, the small sample size might have affected the statistical significance. We should therefore conduct a further study to confirm the significance of the correlations in a larger population. Second, our study included the PAD patients with relatively mild symptoms. The presence of PAD patients with critical limb ischemia or asymptomatic PAD patients in our population might have affected our results. Despite the limitations of the present study, we demonstrated significant correlations between the TM level  and the RHI, as measured by PAT.We herein demonstrated that the TM level was significantly correlated with the RHI value, the ABI and the serum level of creatinine in PAD patients. Several factors might have affected our results. We should therefore perform a further study to confirm our findings. We used PAT as a novel method of evaluating the endothelial dysfunction of PAD patients. The results were confirmed based on the measurement of their TM levels, which showed the severity of endothelial dysfunction.S1 Table(DOCX)Click here for additional data file.


The global increase in Diabetes Mellitus (DM) has led to an increase in DM-Chronic Kidney Disease (DM-CKD). In this cross-sectional observational study we aimed to define phenotypes for patients with DM-CKD that in future may be used to individualise treatment We report 4 DM-CKD phenotypes in 220 patients recruited from Imperial College NHS Trust clinics from 2004–2012. A robust principal component analysis (PCA) was used to statistically determine clusters with phenotypically different patients. 163 patients with complete data sets were analysed: 77 with CKD and 86 with DM-CKD. Four different clusters were identified. Phenotypes 1 and 2 are entirely composed of patients with DM-CKD and phenotypes 3 and 4 are predominantly CKD (non-DM-CKD). Phenotype 1 depicts a cardiovascular phenotype; phenotype 2: microvascular complications with advanced DM-CKD; phenotype 3: advanced CKD with less anaemia, lower weight and HbA1c; phenotype 4: hypercholesteraemic, younger, less severe CKD. We are the first group to describe different phenotypes in DM-CKD using a PCA approach. Identification of phenotypic groups illustrates the differences and similarities that occur under the umbrella term of DM-CKD providing an opportunity to study phenotypes within these groups thereby facilitating development of precision/personalised targeted medicine. The introduction of renin-angiotensin-aldosterone system (RAAS) antagonists in the form of ACEi or ARB, has resulted in the regression of this surrogate marker and slowing of progression of renal dysfunction3. There is increasing appreciation that DN progression to end-stage kidney disease (ESKD) is not always a stepwise progression through albuminuria with different subgroups progressing at different rates and some progress in the absence of proteinuria, hence the need for us to redefine progression of DN4. Progression of the disease and response to the treatment varies in different patients, which may indicate heterogeneity of diabetes chronic kidney disease (DM-CKD). DM-CKD may consist of different sub-population and phenotypes which may require different treatment approaches. In doing so we should be able to identify personalised targeted therapies for people with this potentially devastating disease.Diabetes Mellitus (DM) is increasing worldwide and subsequently as people are treated for complications and enjoy longevity, it is inevitable that more people will develop Diabetic Nephropathy (DN). DN has been described since Egyptian times with the last century providing a classification of DN based on albuminuria5 with a set of reference clinical endpoints. These subgroups have been shown to have physiologically distinct underlying processes that have facilitated the rational use of targeted therapy7. Targeted therapy can be used to specifically target pathways of the disease thereby avoiding the common clinical endpoint. This has led to a revolution in treatment for certain subgroups of this disease8. Clustering methods have been applied to the respiratory epidemiological field and perceived as ‘steps in the right direction’10 with the discovery of these subgroups.Appreciation of heterogeneous disease subgroups has previously been described in Asthma, with distinct subgroupset al.11, recently described non-proteinuric pathways in patients with type 2 DM (T2DM) associated with loss in renal function thereby illustrating phenotypic spectrum of DM that is independent of proteinuria. Given that patients with and without proteinuria with DM may develop ESKD, a new method looking at the spectrum of people with DM-CKD is needed12. The aims of this study were to 1) identify new phenotypes in DM-CKD and 2) compare this with CKD caused by other renal diseases using clinical variables and cytokines to ascertain whether there are more specific markers than albuminuria to determine who will progress to ESKD.Porrini, Determine whether clinical variables may identify heterogeneous subgroups within a cohort of patients with DM-CKD to facilitate further study of underlying mechanisms leading to progression to ESKD which may lead to novel treatment approaches for different sub-groups of DM-CKD.Define and characterise subgroups within the diabetic nephropathy cohort to act as a template for further studies.All methods were performed in accordance with current study guidance and regulations. Following ethics and research and development study approval (NRES Committee London-West London & GTAC 04/Q0406/25) participants with diabetic nephropathy or renal disease without diabetes mellitus were recruited prospectively from renal clinics at Imperial College Healthcare NHS Trust Hospitals London UK, between 2004 to 2012. In this study CKD is used to describe patients with renal disease without DM. Because of the risk/benefit balance, only a limited proportion of patients with DM-CKD had a kidney biopsy (5 patients) with CKD controls having 62 biopsy proven diagnosis. The remainder of the CKD group was diagnosed with imaging or ultrasound showing small kidneys not amenable to renal biopsy. The diagnosis of DN was made by an elevated uACR on at least two occasions or reduction in eGFR and the exclusion of other aetiologies for CKD by history, clinical, and laboratory examinations, including autoantibody screening, urine sediment and renal imaging. Patients with CKD without DM were classified as the control CKD group. The diagnoses of the non-diabetic CKD group are shown in Supplementary Table 13, C-Chemokine ligand-18 (CCL18)14 and macrophage migration inhibitory factor (MIF)15. All of these cytokines have been reported to be raised in DN and may play an important role in pathogenesis of the disease, hence they were chosen to determine whether these change in the different phenotypes and whether they are more specific to DM-CKD than CKD. These cytokines are immunomodulatory and may provide further insight as to whether there are specific changes in different phenotype. Exclusion criteria included: those receiving dialysis therapy or with kidney, pancreas or kidney pancreas transplants, those under 18 years old; and those unable to consent. See supplementary for details of ELISA protocols.Informed consent was obtained prior to any participants entering the study. Participants consenting to enter the prospective cohort study had their clinical and biochemistry data captured using questionnaires at baseline. Biochemistry data included MDRD GFR, serum albumin, urea, creatinine, haemoglobin, HbA1C, total cholesterol and C-reactive protein (CRP). Plasma and urinary samples were collected, processed and stored for cytokine analysis at baseline. Cytokines previously described in DN and studied by our group were analysed; monocyte chemoattractant protein-1 (MCP-1)All data analysed during this study are included in this published article and the Supplementary Information files.Participant selection was unbiased and reflects the widespread presentations of diabetic nephropathy to the renal clinic. However selection bias exists as these patients were already diagnosed with CKD or DM-CKD and hence referred to the specialist renal clinics.MCP-1, CCL18 and MIF levels were measured in plasma and urinary samples by ELISA. Details of antibodies used in Table We report cross-sectional analysis of baseline data in CKD and DM-CKD. We collected 43 variables to begin with and these were reduced to 30 in order to optimize the utility and exclude variables with predominantly missing data in the total dataset for principal component analysis  and derived four clusters or Phenotypes. The spatial distribution of patients across the PCs, are described in PCA plots  , reducing the original 30 variables into 3 high level variables , simultaneously creates equivalents of major traits or dimensions of the underlying dataset, in our case CKD and DM-CKD. The PC1, PC2 and PC3 establish a new coordinate system to describe the CKD and DM-CKD patients; the PCs can be considered as disease ‘forces’ that act on individual CKD and DM-CKD patients. In Agusti Closer examination of these diagrams reveals three traits in CKD and DM-CKD. The first trait/PC is aligned to traditional complications seen with long term diabetes such as insulin use, retinopathy, duration of diabetes, and peripheral vascular disease, with ethnicity also being one of the major variables in this domain. The second trait/PC has major variables determining the severity of CKD including: baseline GFR, Urea, Urine Albumin/Creatinine ratios. The third trait/PC with major variables of diastolic and systolic blood pressure may suggest a disease domain of a cardiovascular renal CKD type.As described in the methods section, the principal components were subjected to K-Means cluster analysis. The cluster analysis resulted in four clusters Fig.  with the2 compared with phenotype 2, whose GFR was 29.3mls/min/1.73 m2. Phenotypes 3 and 4 were predominantly CKD patients that showed a similar grouping of renal function as that seen in phenotypes 1 and 2. GFR for phenotype 3 and 4 was 27.3mls/min/1.73 m2 and 67.8mls/min/1.73 m2, respectively. The different phenotypes of patients with DM-CKD are evident as there were also DM-CKD patients in phenotypes 3 and 4. Urinary and serum MCP-1, CCL18 and MIF data did not reach significant differences between the phenotypes yet each group had a different cytokine profile that requires larger numbers to confirm these preliminary findings (see supplementary for cytokine profile graphs for the different DM-CKD phenotypes).Phenotype 1 consists of 34 patients all of whom have DM-CKD. This phenotype has a significantly higher systolic and diastolic blood pressure than the other phenotypes. The total cholesterol is high in this group compared with those in phenotype 2 despite a high use of statins. HbA1c levels were comparable to phenotype 2 and therefore cannot be the differentiating factor for the different phenotypes: 8.31% (67.3 mmol/mol) phenotype 1 and 8.06% (64.6 mmol/mol) phenotype 2. Albuminuria or proteinuria did not significantly affect the phenotyping of DM-CKD Table . The meaPhenotype 2 was entirely composed of DM-CKD patients, 40 in total with significantly worse GFR than phenotype 1. This group had a longer duration of diabetes compared with phenotype 1, mean 21.76 years compared to 17.59 years, respectively; however this was not significant and was not a determinant of the clustering. Those in phenotype 2 were more anaemic compared with those in phenotype 3, who had similar renal function Table .Phenotype 1 and 2 had more ischaemic heart disease (IHD) and stroke (CVA) than phenotypes 3 and 4 that were predominantly CKD. Angiotensin converting enzyme inhibitors and statins were used more in phenotypes 1 and 2 compared with 3 and 4.2, similar to phenotype 2 but without microvascular complications. The DM-CKD patients have a shorter duration of diabetes in phenotype 3 and anaemia was less prominent compared to phenotype 1 and 2. Patients in phenotypes 3 and 4 with CKD alone are also on immunosuppression unlike phenotypes 1 and 2. Urinary MIF and serum and urinary CCL18 were higher in this phenotype however this was not significantly different and a larger study is required to determine whether this profile is specific to this phenotype  in a well characterised population. To our knowledge this is the first time this approach has been used to establish the treatable traits and phenotypes in adults with DM-CKD. We are reporting preliminary results and suggest further exploration of both the treatable traits and the phenotypes to derive effective and high precision treatment modalities in DM-CKD.This study illustrates a novel approach to characterise DM-CKD patients in two ways. First, we introduce novel thinking on the variability of the disease using high level disease traits  and these alone may form a basis for treatable traits in DM-CKDThis was a predominantly male cohort with phenotypes 3 and 4 having more females than phenotypes 1 and 2. Phenotype 1 appears to have predominantly South Asian patients with phenotype 2 including a wide ethnic variety. Phenotypes 3 and 4 had predominantly more white people however this cohort had larger numbers of white people and thus with a larger cohort an ethnic and gender effect may be determined.Microvascular complications were more commonly seen in phenotype 2, where a longer duration of diabetes was reported. A prospective study is needed to determine whether individuals stay in these phenotypes or move from one phenotype to another with the progression of their disease. This will be established in the following study that will allow identification and recruitment of patients into these phenotypes with genetic and molecular mapping further characterising patients in these phenotypes. The follow-up will elucidate whether these phenotypes are fixed or whether people move between phenotypes allowing further mapping of the disease. The phenotypes, however, show that despite the similar GFRs in the DM-CKD and CKD population there are differences that arise in people with diabetes that are specific and individual to the person.The variability in the phenotype of patients with DM-CKD is illustrated by patients with DM-CKD found in all four phenotypes, albeit a predominance in phenotypes 1 and 2. The spectrum of phenotypes within this disease has been captured using the principal component analysis and as a concept this may explain the overlap we see between the traditional T1DM and T2DM classification, whilst also providing a possible explanation for people responding well to intensive glycaemic and blood pressure control whilst others with DM-CKD continue to progress to ESKD despite this. Access to increasing genome, molecular, cellular and tissue data will further allow specific pathways to be identified in different subgroups of patients with DM-CKD, similar to those seen in asthma. Further large cohorts are required to determine whether these phenotypes, based on predominantly clinical variables, are conceptually robust with a further overlay of genomic, molecular and proteomic data. This may lead to further elucidation of predominant signalling pathways that may subsequently be targeted more effectively in the right population.This study’s phenotypes were derived from 3 PCs/traits from the PCA that included the long term complications of diabetes (Trait 1), the severity of CKD (Trait 2) and the cardiovascular burden in CKD (Trait 3). Further clarification of these traits may reveal treatable traits (18) in CKD and DM-CKD that may lead the way in changing how we treat these patients.The limitations to this study include: the small number of T1DM patients (6 patients) recruited to the cohort and lack of long term follow up to determine whether these phenotypes are predictive of outcome or whether the phenotype changes with duration of the disease. The small proportion of T1DM in comparison to T2DM is a reflection of the common pattern in general nephrology clinics. Therefore, the main driver for identification of DM-CKD phenotypes were data from T2DM patients (80/86). T1DM patients have been included to suggest that a similar model and statistical approach can be used for a larger T1DM data set in future studies. At present no conclusion can be made to compare T1DM and T2DM patients because of the small size of T1DM patients A further study recruiting more T1DM will determine how similar or different the DM-CKD entity is between T1DM and T2DM and whether a common pathway really exists between the two or whether there is a T1DM DM-CKD and T2DM DM-CKD that do not share phenotypes. More patients are also needed in each phenotype to determine whether the high urinary MIF levels seen in phenotype 4 remains in view of the small sample size of DM-CKD in this group. A further limitation to this study is the lack of histopathology renal biopsies in patients within the different DM-CKD phenotypic groups which is limited by current clinical practice and concern on the risk/benefit ratio in patients with DM. DM-CKD has traditionally been a kidney disease that has been clinically diagnosed in view of the risk of renal biopsy however there is an increasing appreciation amongst the renal community of the important role of renal biopsy in further understanding the disease process and facilitating a more personalised medical treatment approach.In addition, many CKD patients are on immunosuppression that may have influenced the clusters and the cytokine biomarkers assessed in this study. The follow-up of this study is in progress and we hope to report our findings soon. A longer study is planned to increase number of patients with these characteristics to confirm these phenotypes.We believe that we are the first group to describe different phenotypes in DN using a PCA approach. Our results may form a platform to use a combination of clinical variables and cytokines to group patients with predominant phenotypes. This approach allows a structure to combine more clinical data and biological results to determine different endotypes within the phenotypes identified. A similar approach has been used in Asthma and has led to the discovery of specific phenotypes that have subsequently been amenable to more effective targeted personalised therapy. We hope this approach will help map further understanding of DN in a structured way whereby biomarkers may reflect disease progression within these groups.Supplementary Material


Although availability, cost, energy and lack of training are potential limitations for a wide use of HBPM in Sub-Saharan Africa (SSA), the method may add value for assessing efficacy and compliance in specific populations. We assessed the agreement between HBPM and ABPM in chronic kidney disease (CKD) patients in Douala, Cameroon.from March to August 2014, we conducted a cross sectional study in non-dialyzed CKD patients with hypertension. Using the same devices and methods, the mean of nine office and eighteen home (during three consecutive days) blood pressure readings were recorded. Each patient similarly had a 24-hour ABPM. Kappa statistic was used to assess qualitative agreement between measurement techniques.forty-six patients  were included. The prevalence of optimal blood pressure control was 26, 28 and 32% for OBPM, HBPM and ABPM respectively. Compared with ABPM, HBPM was more effective than OBPM, for the detection of non-optimal BP control (Kappa statistic: 0.49 (95% CI: 0.36 - 0.62) vs. 0.22 (95%CI: 0.21 - 0.35); sensitivity: 60 vs 40%; specificity: 87 vs. 81%).HBPM potentially averts some proportion of BP misclassification in non-dialyzed hypertensive CKD patients in Cameroon. Blood pressure (BP) control has been widely highlighted as a key component in decreasing the progression of Chronic Kidney disease (CKD)  and reduStudy design, setting and sampling: This was a cross sectional study carried out from March to August 2014 in the nephrology unit of the Douala General Hospital; a tertiary level, referral and teaching hospital located in Douala, the economic capital of Cameroon. Through consecutive sampling, consenting adult patients (age ≥ 18 years) with CKD and hypertension, receiving regular BP lowering medications for at least 14 consecutive days were included. Eligible patients who met the above criteria received explanations in simple terms, about the objectives and nature of the study. Those who freely provided written informed were included. Participants were free to withdraw from the study at any time without their decision influencing their care. We excluded data from patients with inability to obtain HBPM, incomplete HBPM or ABPM and invalid ABPM data. A trained investigator at the outpatient consultation using interviews and patient's record collected data. Sociodemographic and clinical characteristics collected were; sex, age, weight, height, abdominal circumference, smoking, alcohol use, physical activity status presumed aetiology and stage of CKD, duration and treatment of hypertension (number of drugs and their drug-classes), comorbidity such as dyslipidemia and diabetes. The study protocol was approved by the Universite des Montagnes Institutional Ethics Board and received administrative authorization from the Douala General Hospital, Cameroon. The study adhered to the declaration of Helsinki [Blood pressure measurements: Each patient had nine office blood pressure measurements, eighteen measures at home (six per day for three consecutive days) and an ABPM over 24 hours.Office blood pressure measurement (OBPM): After a rest of five minutes and patient in sitting position, three consecutive BP measurements were done on the left upper arm using an OMRON M2 basic sphygmomanometer device. An interval of five minutes was allowed between the different measurements. The mean of the three BP values was considered for the study.Home blood pressure measurement (HBPM): The procedure was explained to all patients and they were trained with the same sphygmomanometer used for the OBPM. After assessing the ability of each patient to accurately measure their own BP, they were required to record their home BP three times in the morning and likewise in the evening, with an interval of five minutes between the different measurements. This was done during three consecutive days and recorded the values in a diary. For each patient, the home BP value was defined by the mean of the eighteen values.Ambulatory blood pressure measurement (ABPM) : A twenty-four hour ambulatory BP monitoring was performed the day of the OBPM, using the “Eutherapie” device. The daytime and nighttime periods were pre-established; 6:00 am to 10:00 pm and 10:00pm to 6:00 am respectively. The monitor recorded every 15 minutes during the day and every 30 minutes during the night. This was done on a working day and patients were instructed to maintain their routine activities, but stop any movements and keep the arm extended at the time of cuff inflation. The success of the measurement was guaranteed when ≥ 70% of the recordings were valid with one or more valid value per hour.Operational definitions: CKD was defined as the presence of kidney damage of more than three months duration or estimated Glomerular Filtration Rate less than 60 mL/min/1.73m² via the Modified Diet on Renal Disease (MDRD) formula [ formula , with se formula . Office Statistical analysis: Data were analyzed using IBM SPSS statistical software v.16 for Windows . Qualitative variables were summarized as frequencies and percentages. Continuous variables were represented as means and standard deviations (SD). Chi square and analysis of the variance (ANOVA) tests  were used for categorical and continuous group comparisons respectively. Quantitative agreement of ambulatory BP with both office and home BP was assessed using Bland-Altman plots and by calculating bias and limits of agreements (± 2 SD). The qualitative agreement was analyzed using the Kappa statistic, calculation of sensitivity and specificity. Statistical significance was set at p-value less than 0.05.General and clinical characteristics of the study population: Of fifty patients included, four were excluded from the final analysis because of inability to conduct HBPM (one) and invalid HBPM (one) and ABPM (two). Among the remaining 46 patients included, 28 (61%) were men. The mean age was 56.2 ± 11.4 years. Their clinical characteristics are summarized in Blood pressure control: The mean office systolic BP (SBP) was 145.2 ± 11.7 mmHg and diastolic BP was 87.9 ± 11.3 mmHg. Isolated SBP control was achieved in 14 (30%) patients and in 27 (58%) patients for the diastolic, while in 12 (26%) patients both were optimal  was respectively 17.4 mmHg and 4.4 mmHg for systolic and diastolic BPs. According to the means of HBP, the SDDs were 15.8 mmHg and 1.6 mmHg for systolic and diastolic respectively ) whereas the HBPM was moderate (K = 0.49 (95% CI: 0.36-0.62)). Overall, the percentage of patients with optimal BP control was six (13%) with both clinic and ABPM and nine (19%) with both home and ABPM. Higher rates (25% for office and 58% for home) were observed for uncontrolled BP values. The prevalence of masked hypertension was 13% (n = 6) and 4% (n = 8) for office and home respectively, while white-coat effect was 19% (n = 9) and 13% (n = 6) for office and home measured BPs  compared to that of uncontrolled ones (54 % for OBPM and 58% for HBPM). This is in line with the observed high specificities (81% for OBPM and 87% for HBPM) than sensitivities (40% for OBPM and 60% for HBPM), suggesting that HBPM is more accurate when classifying a patient as uncontrolled and highlighting the use of ABPM when BP seems optimal. This is similar to the findings in children with CKD  and in cOur study suggests that HBPM is potentially a reliable alternative to ABPM for the assessment of BP control in Cameroonian patients with CKD. Its accuracy over clinic or office BP measurement is in line with reports from western countries. While we advocate for a possible wider application of HBPM in SSA settings, larger multicenter studies are warranted to confirm these findings.ABPM is the gold standard for assessment of BP control in non-dialyzed patients with hypertension;Its utilization is limited in SSA due to limited availability and cost;HBPM is a reliable and cheap alternative but in SSA, lack of training of patients and wide use of invalid devices are potential limitations.HBPM is a reliable alternative in Cameroon;Its accuracy is higher in case of non-optimal BP;Wider use of HBPM in SSA could potentially increase its accuracy.Authors declare no competing interests.


Inferior outcomes for black kidney transplant recipients in the USA may not be generalisable elsewhere. In this population cohort analysis, we compared outcomes for black kidney transplant patients in England versus New York State.Retrospective, comparative, population cohort study utilising administrative data registries.English data were derived from Hospital Episode Statistics, while New York State data were derived from Statewide Planning and Research Cooperative System. All adults receiving their first kidney-alone allograft between 2003 and 2013 were eligible for inclusion.The primary outcome measure was mortality post kidney transplantation . Secondary outcome measures included postoperative admission length of stay, risk of rehospitalisation, development of cardiac events, stroke, cancer or fracture and finally transplant rejection/failure. Cox proportional hazards regression was used to investigate relationship between ethnicity, country and outcome.Black patients comprised 6.5% of the English cohort (n=1215/18 493) and 23.0% of the New York State cohort (n=2660/11 602). Compared with New York State, black kidney transplant recipients in England were more likely younger, male, living-donor kidney recipients and had dissimilar medical comorbidities. Inpatient mortality was not statistically different, but death within 30 days, 1 year or kidney transplant rejection/failure was lower among black patients in England versus black patients in New York State. In adjusted regression analysis, with black ethnicity the reference group, white patients had reduced risk for 30-day mortality (OR 0.62 (95% CI 0.44 to 0.86)) and 1-year mortality (OR 0.79 (95% CI 0.63 to 0.99)) in New York State but no difference was observed in England. Compared with England, black kidney transplant patients in New York State had increased HR for kidney transplant rejection rejection/failure by median follow-up .Outcomes after kidney transplantation for black patients may not be translatable between countries. Large population-cohort study of two datasets.Data linkage to mortality data for accuracy.Use of administration rather than registry data.Kidney allograft survival data not well defined.Numerous confounders unavailable to robustly probe this question.Black patients are significantly more likely to develop end-stage kidney disease (ESKD), which is likely secondary to increased risk of chronic kidney disease progressing to kidney failure.While kidney transplantation is recognised as the preferred modality of renal replacement therapy for patients with ESKD, disparate post-transplant outcomes are reported for black recipients of a kidney allograft. For example, black kidney transplant patients in the USA have previously been shown to have worse kidney allograft survival compared with white recipients,No comparative analysis has ever been conducted to specifically compare post-transplant outcomes for black kidney transplant patients between countries across distinct geographical regions like the UK and the USA. This is of interest as healthcare systems differ significantly between the two countries, with the possibility that black people in the UK may not share the same post-transplant outcomes observed in the USA. Therefore, it is unclear if the counselling of black kidney transplant candidates in one country can be adequately made utilising data translated from black patients in another country. The aim of this analysis was to undertake a comparative population-based cohort analysis exploring outcomes after kidney transplantation for black patients in England versus New York State.We obtained data from every patient’s first kidney-alone transplant procedure performed in England and New York State between 2003 and 2013, collecting patient demographics that included age, gender, donor type (living or deceased), transplant year, medical comorbidities  codes) and ethnicity. English data were obtained from Hospital Episode Statistics,This study included all patients’ first kidney transplant procedures ) performed in England and New York State between the years 2003–2013. With regards to outcome analysis, both Hospital Episode Statistics (HES) and SPARCS data sets have the limitation of only capturing deaths occurring in a hospital setting. To obtain the complete mortality list, the study cohort was cross-referenced with mortality data from the Office for National Statistics and New York State/New York City Vital Statistics, respectively, which collects information on all registered deaths in the UK and New York State, respectively. Death data were available from 1 January 2013 up until 31 December 2014. Combining sources via this data linkage process creates a comprehensive data set with regards to mortality, which was the endpoint of interest in this analysis. In addition, we extracted data for kidney transplant rejection/failure (ICD-10: T861 or ICD-9: 99 681), which is derived from the administrative data and substituted for lack of data linkage to transplant registry records. Formal ethical approval was not required due to the pseudonymised nature of the data retrieved; data were linked by NHS Informatics utilising a special HES ID code and avoided any patient identifiable information. Thus, the study was registered as an audit with University Hospitals Birmingham NHS Trust .We extracted data on all adult kidney allograft recipients’ first procedure between the dates of 1 January 2003 and 31 December 2013, who underwent their kidney transplant procedure in a transplant centre in either England or New York State. From our original cohorts of 21 371 and 12 373 patients in England and New York States, respectively, we excluded from analysis 2582 and 771 patients from both data sets, respectively, as shown in online 10.1136/bmjopen-2016-014069.supp1The primary outcome measure was all-cause mortality post kidney transplantation . In addition, we looked at various secondary outcome measures including postoperative admission length of stay, risk of re-hospitalisation, development of cardiac events (ICD-10: I2(01234), ICD-9: 410,411,413,429), stroke (ICD-10: I6(0 12 3456), ICD-9: 430–436), cancer  or fracture (ICD-10: S(0123456789)2, T02, T07, T10, T12, ICD-9: 800–829) and finally kidney transplant rejection/failure . Rehospitalisation was defined as whether a patient was readmitted to hospital as an emergency at any time postdischarge of their transplant admission. All other secondary outcomes were captured with use of ICD-10 and ICD-9 codes (as defined above), at any time post-transplant.2 tests for categorical variables two-sample t-test for normal continuous variables or Mann-Whitney tests for all non-normal continuous variables. Multivariate logistic regression was used to measure 30-day and 12-month mortality. All patients were included in these models to see if there was a difference in mortality outcomes for the different ethnic groups, within the two populations. Variables included in the models were age, sex, admission method (emergency vs elective), number of emergency readmissions and ethnic group. Survival analyses were performed, combining all black patients in the two countries, for the outcome of graft failure/rejection (defined using ICD-10: T861 or ICD-9: 99681 at any time post-transplant) using Cox’s proportional hazards model and the generation of Kaplan-Meier plots. The proportional hazard assumption was checked and satisfied by examination of the scaled Schoenfeld residual plots. Variables included in the Cox model were ethnicity, age, gender, donor type (living vs deceased), year of transplant, geography (England vs New York State) and selected medical comorbidities at the time of transplant . Sensitivity analyses, stratified by ethnicity and donor type, were further conducted for both English and New York State. A p value less than 0.05 was considered statistically significant in the analysis. All statistical analyses were conducted using Stata V.14.Differences between groups were compared using χBetween 2003 and 2013, there were 21 371 patients in England and 12 373 patients in New York State who had their first kidney transplant. After exclusions due to missing age or sex, and those who had multiorgan transplants, data were analysed for 18 493 and 11 602 patients between 2003 and 2013 from England and New York State, respectively, with median follow-up in England and New York State of 6.3 years and 5.5 years, respectively. Black patients comprised 6.5% of the English cohort (n=1215) and 23.0% of the New York State cohort (n=2660), forming the basis of all comparative analyses.There were significant differences in the post-transplantation course for black kidney transplant patients in England versus New York State see . Black pWhile our analyses revealed significant mortality differences between black patients in England versus New York State, we were keen to understand if black ethnicity itself was a risk factor for mortality in each population cohort. In a logistic regression model, accounting for variables associated with mortality after kidney transplantation , we analysed whether black ethnicity was an independent predictor for death in England or New York State. With black ethnicity utilised as the reference group, 10.1136/bmjopen-2016-014069.supp3A significant difference was observed in unadjusted Kaplan-Meier plots of kidney transplant rejection/failure for black kidney transplant patients in England versus New York State see . After a10.1136/bmjopen-2016-014069.supp2Our comparative analysis of two large population-based cohort data sets demonstrates that black kidney transplant patients have different baseline characteristics and post-transplant outcomes in England compared with New York State. Most importantly, black patients in England have lower mortality than their New York State counterparts, where black ethnicity in the latter cohort was found to be independently associated with increased 30-day and 1-year mortality. Our analysis, to our knowledge, is the first comparative study comparing black kidney allograft outcomes in contemporaneous population cohorts. Our study highlights significant differences between black kidney transplant patients in England versus New York State and suggests caution in translating outcomes for black transplant patients between different countries.The strengths and weaknesses of this study must be appreciated for the correct interpretation of our results. There are likely to be numerous confounders that have an impact on black mortality post kidney transplantation that we were unable to factor in . It should be acknowledged that New York State data may not be completely representative of other states in the USA, and we are crudely inferring that data from New York State is broadly representative of the USA. Missing data (and misclassification bias) also have an implication on the analyses performed, and this limitation is inherent with all epidemiological studies of this type. Unfortunately, while the majority of data obtainable was matched between the two cohorts, we were unable to extract any information regarding socioeconomic deprivation status or cause of death from the SPARCS data set. Our utilisation of the composite for kidney transplant rejection/failure from administration records is an inferior surrogate compared with registry-derived data regarding kidney allograft rejection and graft failure. The ability to extract more data, and to link data sets to create more comprehensive databases, allows the minimisation of confounding and provides a more robust platform from which to conduct meaningful epidemiological analysis. Further work in this area is clearly warranted and should be undertaken using more robust renal data including registry data from both the USA  and the UK . Finally, mortality data are readily available and were the sole analytical endpoint of this analysis. However, absence of recorded death may not necessarily translate to assumption that a recipient remains alive .Current literature suggests that black kidney transplant patients in the USA have inferior kidney allograft survival compared with white recipients,By contrast, no mortality difference between black and white patients has been observed in the few limited publications within European transplant centres.et al in their exploration of racial disparities using kidney transplant cohorts, which included patients receiving healthcare within versus outside the Department of Veterans Affairs (VA).Perhaps the most fundamental difference between countries is the infrastructure delivering and providing healthcare. Black kidney transplant patients in England have universal health coverage as part of the taxpayer-funded NHS. This ensures complete financial access to immunosuppressive medications and other aspects of care including allied medications  and long-term medical follow-up to support post-transplant care. Compared with the USA, countries such as England, Canada and France that demonstrate similar mortality outcomes after transplantation for black versus white patients share elements of universal health coverage,et al, analysing data from the United Network for Organ Sharing and the Collaborative Transplant Study, compared kidney transplant outcomes in the USA versus Europe, respectively.This raises the question as to what underlies poor outcomes among black kidney transplant patients in the USA while acknowledging disparate outcomes appears to be narrowing between black and white patients’ post kidney transplantation.all black patients on dialysis have reduced risk for death on dialysis may be incorrect when interpreting large population cohorts in the context of competing factors. For example, Kucirka  et al conducted an observational cohort study of 1 330 007 incident end-stage renal disease patients in the USRDS and showed black patients have lower mortality on dialysis than white patients .higher mortality than their white counterparts on dialysis. Teasing out the differences that help explain our disparate mortality outcomes between black patients in England versus New York State will likely prove more challenging than just a simple explanation. Caution must also be exercised in the interpretation of epidemiological data to ensure false inferences are not made from statistical analyses. For example, Yeates et al found black kidney transplant patients in Canada had significantly lower post-transplantation mortality compared with white patients .Our analysis should be interpreted in the context of the well-recognised observation of reduced risk for death for black versus white ESKD patients after commencement of dialysis, and this phenomenon has been noted in both the USATo conclude, this is the first comparative study examining mortality for black kidney transplant patients between two different countries and found black kidney transplant patients in New York State have a greater hazard for death and kidney transplant failure/rejection compared with their black counterparts in England. Our results suggest that further work is essential to investigate poor outcomes for black patients after kidney transplantation in the USA to aid our inadequate understanding of their social, environmental and/or biological pressures. While macro-level factors like universal health coverage may be an important factor contributing to post-transplantation mortality and allograft loss for black patients, our study suggests additional micro-level factors are likely to be concomitantly important and are in need of deeper evaluation.


Postoperative pulmonary complications (PPC) in patients with pulmonary diseases remain to be resolved clinical issue. However, most evidence regarding PPC has been established more than 10 years ago. Therefore, it is necessary to evaluate perioperative management using new inhalant drugs in patients with obstructive pulmonary diseases.April 2014 through March 2015, 346 adult patients with pulmonary diseases ) underwent non-pulmonary surgery except cataract surgery in our university hospital. To analyze the risk factors for PPC, we retrospectively evaluated physiological backgrounds, surgical factors and perioperative specific treatment for asthma and COPD.3) and severity  STEP ≥ 3) were significantly associated with PPC in the multivariate logistic regression analysis . In patients with COPD, age, introducing treatment for COPD, upper abdominal surgery and operation time (≥ 5 h) were significantly associated with PPC .Finally, 29 patients with pulmonary diseases  had PPC. In patients with asthma, smoking index (≥ 20 pack-years), peripheral blood eosinophil count (≥ 200/mmHistory of smoking or severe asthma is a risk factor of PPC in patients with asthma, and age, upper abdominal surgery, or long operation time is a risk factor of PPC in patients with COPD. Adequate inhaled corticosteroids treatment in patients with eosinophilic asthma and introducing treatment for COPD in patients with COPD could reduce PPCs. Postoperative pulmonary complications (PPCs) and their management are clinically important in patients with asthma and chronic obstructive pulmonary disease (COPD). PPCs include bronchospasm, atelectasis, pulmonary infection, respiratory failure and exacerbation of chronic pulmonary disease . The preAlthough Global INitiative for Asthma (GINA)  and GlobTo reduce PPC, we implemented the preoperative pulmonary management program in our hospital over 10 years ago. In our management program, all surgical patients with an abnormal pulmonary function test undergo a medical examination performed by pulmonologists and are administered medical treatment and evaluated for risk factors for PPC development. However, most evidence regarding the risk factors for PPC was established more than 10 years ago, and recent advances in inhalant drugs have changed the clinical course in affected patients, especially those with asthma and COPD. It is therefore critically important to precisely evaluate the risk factors for PPC development during perioperative management and to use recently available inhalant drugs in patients with both asthma and COPD.All patients with asthma were diagnosed by physicians or self-reported, when the patients had past medical histories of asthma, typical symptoms  and pulmonary function compatible with asthma. Severity at baseline and during exacerbation was defined according to the GINA document . Recentl1)/ forced volume capacity(FVC)] < 0.7 and the exclusion of other diseases , GINA STEP ≥3 . However, there was no significant difference between former and current smokers in the incidence of PPCs in the univariate analysis .We performed a univariate analysis to assess PPC risk factors in asthma Table  and COPDp = 0.046], the introduction of COPD treatment , upper abdominal surgery , and an operation time ≥ 5 h  , 9.5, 1.2–7.4, p = In the present study, we show that treating asthma with perioperative systemic corticosteroids seemed to significantly increase the risk of PPCs in the univariate analysis. However, no significant risk of PPCs was detected for systemic corticosteroids in the multivariate logistic analysis. Does treatment with systemic corticosteroids increase the risk of PPCs? Previous studies reported that the incidence of PPCs in untreated patients with asthma was 24% , whereas3 decreased the risk of PPCs to one-third. There are several phenotypes of bronchial asthma [3 was correlated with both sputum eosinophil count and the efficacy of ICS [According to the multivariate logistic analysis of patients with asthma, peripheral blood eosinophilia and a history of heavy smoking were significantly associated with PPCs. Both of these variables are implicated in steroid responsiveness. Interestingly, the result of the present study demonstrated that a peripheral blood eosinophil count ≥200/mml asthma . The eosl asthma –16. Hency of ICS , 16, 17.A smoking history of ≥20 pack-years was associated a five-fold increased risk of PPCs. However, Chaudhuri et al.  demonstr1/FVC < 0.7 and a peripheral blood eosinophil count >400/mm3, was proposed [Patients with ACO were included in the asthma group in the present study. There were three reasons for this. First, no standardized definition has yet been established for ACO. Recently, a new definition, including a post-bronchodilator FEVproposed  that reqproposed . Becauseproposed . Third, p < 0.01, Mann-Whitney U test, data not shown). The merit of using laparoscopic surgery to reduce the risk of PPC was masked by its intrinsically longer operation time. In addition to these risk factors, in the present study, we provide the newly evidence demonstrating that introducing treatment for COPD, including LAMA and LABA, reduced the risk of PPC. These inhaled drugs were recently developed and are much more effective in preventing COPD exacerbation. The mechanisms underlying their actions involve their ability to decrease hyperinflation and mechanical stress, to modulate mucus production and mucociliary clearance and to improve symptoms [Next, regarding patients with COPD, previous studies have found that aging, upper abdominal surgery and operation time are risk factors for PPCs , 8. Canesymptoms . Low pulThe present study has some limitations. First, this study is a retrospective case-control study performed at a single institution. Because early reports have demonstrated that systemic corticosteroid is effective as a precaution against PPC in patients with asthma, we believe that it may not be ethical to perform a prospective study using a control group consisting of untreated patients. The number of patients with asthma or COPD analyzed in the present study may depend on the proportion of surgical cases per department. Otolaryngology patients comprised approximately 20% of all patients treated with general anesthesia, and these patients often had asthma. However, the number of cases in which cardiovascular diseases, esophageal cancer or laryngopharyngeal cancer coexisted with COPD was small. Hence, multicenter cohort studies are desirable for collecting balanced data.Second, although the total number of patients was 346, it would be preferable to register more patients. In addition, fewer PPC events in patients with COPD were observed than expected in this study. However, the reason for the small number of PPC events could be that we managed our patients in a manner aimed at reducing PPCs. Third, we excluded patients who underwent lung resection, because it is a direct risk factor for pulmonary complications. In the future, these concerns should be addressed in separate studies.In summary, our results demonstrate that asthma patients with a history of smoking or severe asthma had an increased risk of PPCs. Sufficiently and aggressively increasing ICS can reduce the risk of PPCs in asthma patients with eosinophilia. Although aging, upper abdominal surgery and long operation times are risk factors for pneumonia and respiratory failure in COPD patients, introducing treatment for COPD significantly reduces the risk of PPC by improving pulmonary function.


Acute kidney injury (AKI) is associated with increased morbidity and mortality. Although there are many causes of AKI, it is known that patients undergoing high-risk surgery are known to be at significant risk. Although much effort has centred on the minimum arterial pressure needed to maintain renal perfusion, this tends to be based on relatively crude measures such as the mean arterial pressure (MAP), which is widely used as an index for the optimal blood pressure. The rationale behind maintaining MAP is to provide adequate organ perfusion, although this is difficult to assess other than by applying crude end-points. Recent studies have examined the progression of AKI as defined by the KDIGO criteria in terms of time-weighted average values for premorbid and within-ICU haemodynamic pressure-related parameters. Although principally performed on patients who had undergone cardiovascular surgery and who were on vasopressor support, some interesting results were obtained suggesting that crude MAP may not be an adequate target in AKI. In patients with AKI progression, greater observed deficits in mean perfusion pressure, diastolic arterial perfusion, and diastolic perfusion pressures were observed. This study may highlight potential modifiable risk factors for the prevention of progression of AKI, and hopefully translate into improved outcomes. The kidneys account for less than 5% of our total body weight and yet receive about 25% of our cardiac output. It is of no surprise, therefore, that targeting adequate renal perfusion is considered a potential factor for modifying the risk of acute kidney injury (AKI). The risk of AKI varies depending on aetiology, but it is well established that high-risk surgery, in particular cardiovascular surgery, is associated with an increased threat of AKI. Therefore, protective strategies may be instigated prior to, or during, insult in order to minimize this potentially devastating outcome.The preservation or improvement of renal perfusion may be achieved through increasing cardiac output by fluid resuscitation, inotropic drugs, renal vasodilators, or systemic vasopressors that all “redirect” blood flow to the kidney. The optimal target mean arterial pressure (MAP) remains an area of debate, although several studies have examined this including a multicentre randomised controlled trial (RCT) which randomized patients with septic shock to resuscitation with a MAP target of either 80–85 mmHg or 65–70 mmHg . This stTo date, most studies have examined the MAP rather than specific components of the derived MAP. However, Saito and colleagues have examined patients on vasopressors who had undergone cardiovascular surgery with regard to the progression of AKI as defined by the KDIGO criteria . They meWhen considering alterations to the systemic blood pressure and effects on the renal circulation, however, several features must be borne in mind. Firstly, the renal circulation can be viewed as two circulations in series: that to the glomerular capillaries through the afferent arteriolar system, and that to the tubular network via the efferent arterioles. Secondly, in order to maintain adequate pressure within the glomerular and distal capillaries, these systems are under intimate local control. This balance between the afferent and efferent systems, termed auto-regulation, is a fundamental component of renal function.both tubular and vascular function, and together these mechanisms adjust the tone of the pre-glomerular vessels in the face of a changing RPP. Local mediators also govern these responses; these include angiotensin II, arachidonate metabolites, and NO. Thus, auto-regulation is intrinsic to the kidney and largely independent of extrinsic nerves or circulating hormones [function of RBF and is specifically dependent on the GFR and the amount of sodium that is to be actively re-absorbed [Autoregulation stabilizes renal blood flow (RBF) and the glomerular filtration rate (GFR) during variations in renal perfusion pressure (RPP) over a defined range, implying that renal vascular resistance (RVR) changes in proportion to the RPP. The major pre-glomerular resistance vessels whose tone mediates most of this pressure-induced auto-regulation includes the afferent and cortical radial arteries. The efferent arterioles only play a minor role in RBF auto-regulation, principally under conditions of low RPP. Auto-regulation occurs through two major mechanisms: the myogenic response and the macula densa tubuloglomerular feedback (TGF) response, which are outlined in Fig. hormones . Such auabsorbed , 10. Thep = 0.027, 0.023, and 0.002, respectively). The AKI+ group had consistently greater deficits of all three perfusion pressures in the first 24 h of vasopressor support compared with the AKI– group, with 21.7% and 23.8% of the percentage MPP and DPP deficits, respectively, due to an increase in CVP, with no difference between the AKI+ and AKI– groups. Also of note is that the median MAP of 74 was similar in both groups. Although this study has several limitations , the results are still intriguing. The suggestion that DPP or indeed MPP may be viewed as haemodynamic targets in this high-risk group would fit with the recent consensus regarding blood pressure targets in ICU patients being targeted to the individual, with evidence from studies in sepsis supporting this view [So, what did Saito and colleagues observe? In terms of measured haemodynamic parameters there was no difference in percentage SAP or MAP deficit between the AKI+ (AKI progression group) and the AKI– (those who did not progress). However, DAP, MPP, and DPP were all significantly different, with the greatest difference observed in the diastolic perfusion pressure  during cardiopulmonary bypass (CPB) and in the first 3 h after surgery in the ICU examined real-time monitoring of cerebral blood flow (CBF). This allowed derivation of the correlation flow index (CFx) which was calculated as a moving, linear correlation coefficient between cerebral flow index measured using UT-NIRS and MAP . This isIn conclusion, we may be entering an era where the application of non-individualised haemodynamic targets based on empiric blood pressure may be a practice of the past. In similar fashion to the use of intra-operative monitoring of volume response to guide fluid therapy, real-time monitoring of blood flow coupled with attention to previously ignored parameters may well guide intra-operative blood pressure management as well as that on the ICU. Hopefully this will translate to improved outcomes.


Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality. Although morbidity of AKI after off-pump coronary artery bypass grafting (OPCAB) has been investigated, little is known about risk factors for AKI after OPCAB. To identify risk factors for AKI, we examined the association between perioperative variables and AKI after OPCAB.We reviewed the medical records of consecutive adult patients who underwent isolated OPCAB between January 2010 and February 2013 in a single institute, retrospectively. The primary outcome was the incidence of AKI evaluated using Acute Kidney Injury Network classifications during the first 48 h postoperatively. We investigated preoperative and intraoperative variables, including hemodynamic parameters, as potential risk factors for AKI. The relationship between candidates of AKI and incidence of AKI was examined by multivariate logistic regression analysis.P < 0.001] and diabetes mellitus  were significantly associated with AKI.A total of 298 patients were enrolled in this study. Acute kidney injury occurred in 47 patients (15.7%). Multivariate logistic regression analysis showed that intraoperative furosemide administration (odds ratio [OR], 5.163; 95% confidence interval, 2.171 to 12.185; Intraoperative furosemide administration and diabetes mellitus were significantly associated with AKI in patients who had received OPCAB. Acute kidney injury (AKI) is a highly prevalent and serious complication after cardiac surgery. Depending on the various definitions of AKI, 5 to 40% of patients who have undergone cardiac surgery developed AKI, and 1 to 5% of patients required dialysis . The morOff-pump CABG (OPCAB) has been expected to have a lower incidence of AKI than on-pump CABG (ONCAB), as CPB has been proven to cause an inflammatory response, lack of pulsatile flow, hemodilution, atheroembolism, hemolysis, low output syndrome, and global hypoperfusion, which may lead to postoperative complications. However, the benefit of OPCAB for AKI remains controversial. Several studies have reported that patients with OPCAB have a lower incidence of AKI than those with ONCAB –14; yet,In this retrospective study, we examined the association between AKI after OPCAB with perioperative variables, including intraoperative parameters related to hemodynamic instability, such as the cardiac index and lactate levels.2 or requiring dialysis, a history of previous cardiac surgery, congenital heart disease, and minimally invasive cardiac surgery. We focused on patients with AKI after OPCAB as a primary outcome. The incidence of AKI was diagnosed until 48 h postoperatively, and the staging of AKI was evaluated until 7 days postoperatively, according to the criteria proposed by Acute Kidney Injury Network (AKIN) classifications . Categorical variables are expressed as a number and percentage. Initially, all preoperative variables and intraoperative variables, except continuous variables in the arterial blood gas analysis during surgery, were divided into dichotomous data according to a clinically significant cut point. To identify which variables were associated with AKI, data were examined using the chi-square test or Fisher’s exact test for dichotomous data, or univariate logistic regression analysis for intraoperative continuous data. Among the variables with a 2, required dialysis (n = 23), or had a history of cardiac surgery (n = 10), minimally invasive cardiac surgery (n = 2), or OPCAB with another surgery (n = 6). Two hundred ninety-eight patients remained in this study. Approximately 16% of patients had AKI, and most of them were classified as stage 1 according to the AKIN criteria : diabetes mellitus, perioperative IABP, and intraoperative furosemide administration. Besides these three variables, preoperative hypoalbuminemia , the highest intraoperative lactate level, and total urine output during surgery  were likely to increase the incidence of AKI (P < 0.20). However, since urine output itself was involved in the diagnosis of AKI after surgery from the end of surgery to 48 h after surgery, we thought intraoperative urine output as clearly inappropriate for a risk factor to be analyzed by multivariate analysis. We entered the five variables with a P value < 0.20 except total urine output  into multivariable logistic regression analysis, because five covariates were within permissible range to avoid overfitting the model based on occurrence of 47 outcomes in this study. Multivariable logistic regression analysis identified intraoperative furosemide administration and diabetes mellitus as independent risk factors for AKI (Table P = 0.914).Results of univariate analysis of preoperative demographic characteristics and intraoperative variables are shown in Table We further reviewed the patients who were administered furosemide based on the above results. In all 28 patients with furosemide, only single injection, not continuous infusion, was used to administer furosemide, and the average dosage of furosemide was 10 ± 4.90 mg. Although this retrospective study could not clearly specify the reason why furosemide was used for oliguria, hyperkalemia, or hypervolemia during surgery, only four patients (14.2%) experienced continued oliguria during surgery . Since diuretics were usually used to treat oliguria, it was difficult to interpret the exact relationship between furosemide and postoperative AKI, whether the furosemide was either risk factor, or simply risk marker. Therefore, we also investigated the preoperative kidney function and intraoperative urine output in the patients given the furosemide or carperitide, the another diuretic commonly used for oliguria as well as furosemide Table , suggestIn this retrospective study, multivariable logistic regression analysis identified intraoperative furosemide administration and diabetes mellitus as independent risk factors for AKI. Intraoperative hemodynamic parameters, CI, BE, lactate, and hemoglobin levels were not associated with AKI.P = 0.049). This result was consistent with previous studies [Diabetes mellitus is well known as a systemic disease, which frequently causes the diabetic nephropathy, neuropathy, retinopathy, and increased the cardiovascular events and mortality , 27. Dia studies , 30–32.We also identified the use of furosemide during surgery as an independent risk factor for postoperative AKI. Furosemide is a loop diuretic that inhibits the Na-K-2Cl cotransporter system in the luminal membrane of the ascending limb of the loop of Henle , 34. FurHowever, prior studies have failed to demonstrate a clinical benefit of furosemide in terms of mortality and renal recovery of AKI and suggested a possible harmful effect of furosemide when used to prevent or treat AKI. –45 A preAlthough most previous studies did not focus on the effect of furosemide on postoperative AKI, several studies have implied a deleterious effect of furosemide in cardiac operation , 44, 45.P = 0.0007) [Although we aimed to investigate whether intraoperative hemodynamic instability during OPCAB affected postoperative AKI, we were unable to identify anything regarding an association between intraoperative hemodynamic parameters and postoperative AKI. Intraoperative hemodynamic instability can cause the impairment of renal perfusion, resulting in postoperative AKI. A recent meta-analysis involving data of 4220 surgical patients in 20 studies examined whether perioperative hemodynamic optimization improved renal outcome and found that postoperative AKI was significantly reduced by perioperative hemodynamic optimization compared with that in the control group (OR 0.64; confidence interval 0.50 to 0.83; There were several limitations in this study. First, the number of patients was small and derived from a single center. Even though many preoperative factors including age, anemia, hypoalbuminemia, DM, chronic kidney disease, chronic heart failure, and IABP have been reported as the independent risk factors for AKI in early studies, we could not identify the only two independent factors , 21, 22.In conclusion, we found that intraoperative furosemide administration and diabetes mellitus were independently associated with AKI in patients undergoing OPCAB. However, our findings in this retrospective study represent only the possibility that furosemide during surgery affects postoperative AKI. Further prospective randomized trials are needed to investigate the effect of intraoperative furosemide administration on renal function, and whether intraoperative hemodynamic variables are associated with the incidence of AKI.


Introduction. Lactate is an important indicator of tissue perfusion. The objective of this study is to evaluate if there are significant differences between the arterial and central venous measurement of lactate in pediatric patients with sepsis and/or septic shock. Methods. Longitudinal retrospective observational study. Forty-two patients were included between the age of 1 month and 17 years, with a diagnosis of sepsis and septic shock, who were admitted to the intensive care unit of a university referral hospital. The lactate value obtained from an arterial blood sample and a central venous blood sample drawn simultaneously, and within 24 hours of admission to the unit, was recorded. Results. The median age was 2.3 years , with a predominance of males (71.4%), having a 2.5 : 1 ratio to females. Most of the patients had septic shock (78.5%) of pulmonary origin (50.0%), followed by those of gastrointestinal origin (26.1%). Using Spearman's Rho, a 0.872 (p < 0.001) correlation was found between arterial and venous lactate, which did not vary when adjusted for age (p < 0.05) and the use of vasoactive drugs (p < 0.05). Conclusion. There is a good correlation between arterial and venous lactate in pediatric patients with sepsis and septic shock, which is not affected by demographic variables or type of vasoactive support. Sepsis is a disease characterized by a hypercatabolic state, with an increased tissue oxygen demand. When there is an imbalance between the supply and demand of oxygen, both tissue hypoperfusion and hypoxia lead to anaerobic metabolism with the ultimate production of lactate .Under critical conditions homeostasis is altered, producing reversible or irreversible multiple organ injury. The length of exposure to the damaging stimulus determines the reversibility of the organ dysfunction 2-3). Therefore, early detection of sepsis and organ dysfunction is important in critically ill patients in order to begin appropriate therapeutic measures , 2.-3. ThereTraditionally, identification of organ dysfunction in patients was made based on clinical signs and symptoms  and identification of circulatory failure and consequent tissue hypoperfusion, with the presence of persistent and refractory hypotension (4-5). This approach is complicated due to the lack of sensitivity of the clinical findings to predict the presence or absence of an organ lesion or tissue hypoperfusion, especially in the pediatric population with physiological variables changing and complementary tests are typically needed .Serum lactate is a biomarker which estimates the probability and extent of tissue hypoperfusion and also evaluates the therapeutic response and prognosis . A valueIn light of the difficulty in drawing an arterial sample in patients, especially in the pediatric age group, the need to employ another, more accessible, type of sample for its measurement is proposed, in order to determine this pathological condition. For this reason, a correlation between arterial and venous lactate in children with sepsis and/or septic shock is sought; considering that there are no existing studies in the pediatric population the objective of our study was to assess whether there was a correlation between arterial and venous lactate in children with sepsis , 5.A longitudinal retrospective observational study diagnostic test was carried out on Pediatric Intensive Care Unit patients at the Fundación Cardioinfantil-Instituto de Cardiología, a quaternary care institution in Bogotá, Colombia, South America, where there is electronic chart review. The study was previously analyzed and approved by this institution's Ethics Committee and all requirements were met including informed consent.Patients admitted to the Pediatric Intensive Care Unit of the Fundación Cardioinfantil between January 1, 2009, and May 31, 2012, with a diagnosis of sepsis and/or septic shock, according to the 2005 International Pediatric Sepsis Consensus were included  Figure .The electronic medical records were reviewed, and the required information was recorded on a questionnaire developed for this purpose. The recorded arterial and central venous gas samples corresponded to the first sample taken simultaneously within the first 24 hours following admission as is usual protocol in the Pediatric Intensive Care Unit. The information recorded in the medical records was verified with the institution's clinical laboratory's official data base. The blood drawing technique was reviewed with the PICU nursing staff; the technique is standardized for drawing arterial and venous blood samples simultaneously by two staff members. The arterial blood was obtained from a radial or femoral arterial line, while the venous blood was extracted through a central venous catheter located in the subclavian, internal jugular vein  or femoral vein. All samples were collected in heparinized syringes, leaving no spaces or bubbles in them. For the arterial blood draw, 5 mL of blood was extracted through the arterial line, and then 1 mL was collected in the heparinized syringe; following this, the initially extracted 5 mL was returned through the arterial line, thus avoiding the anemization of patients. For the venous sample, 10 mL of blood was extracted through the central venous catheter, and then 1 mL was collected in the heparinized syringe, and the original 10 mL of blood was returned to the patient. The samples were immediately sent through the pneumatic tube system, guaranteeing their processing in the least amount of time possible, not greater than 5 minutes by institutional standards. All blood samples were analyzed on the Siemens Rapidlab® 1265 series blood gas machine, which performed an analysis of arterial and central venous gases, reporting the lactate levels of each sample type. The time elapsed between blood samples draws and processing in the laboratory was a maximum of 15 minutes as part of a standardized protocol at our institution. A data base was created with the variables of interest, and statistical analysis was performed. U test. The normality of the arterial and central venous lactate was evaluated with the Kolmogorov-Smirnov test, finding that the lactates did not fulfill the assumption of normal distribution [All the information was collected in a database whose source was the electronic medical record. The SPSS version 15.0® program was used for data analysis. A descriptive analysis of the variables was carried out, using means, medians, and standard deviation (SD) for continuous variables and proportions in categorical variables. A comparison of the means, medians, and SD of the lactate from the arterial and central venous samples was performed using Mann–Whitneyribution . Therefon = 33) and 21,4% was sepsis (n = 9); the main source was pulmonary origin, 50%, followed by gastrointestinal, 26.1% (mainly gastroenteritis) . There were 12 females (28.5%) and 30 males (71.4%), with a male to female ratio of 2.5 : 1. The main diagnosis found was septic shock in 78.6% of cases (teritis) . There wp < 0.001), with Spearman's index of 0.897. There was no correlation between arterial lactate and venous lactate with the weight and age variables   during hospitalization and potentially increase lactate values with the different numerical variables, without finding any difference ( = 0.53) . U test, the behavior of the blood lactate and central venous according to gender, type of sepsis, and vasoactive drugs was determined  .p < 0.001). When we analyzed the results we found no statistically significant differences between arterial lactate and central venous lactate with respect to age, weight, and diagnosis, keeping in mind that the severity and stages of illness can vary rapidly [p = 0.14) and weight (p = 0.74), significant differences were not found either, which makes lactate a reliable indicator, not influenced by these variables [p = 0.068). This finding is very important in critically ill patients in whom it is sometimes difficult to obtain arterial access due to their state of shock or the high vasopressor support, which makes the procedure difficult. In addition, the consideration that arterial and venous lactate results are correlated, regardless of how compromised their removal mechanism may be (due to lactate dehydrogenase or to the oxidative capacity of the tissues), has a significant added value because it provides the clinician with more tools with which to evaluate the critical patient when an arterial or central venous line is not available. In other words, regardless of the origin of lactate analysis both production and the arterial and venous elimination behave uniformly.Our study found a good correlation between arterial and central venous lactate in pediatric patients with sepsis and/or septic shock who are in intensive care  between these values. More recently, Nascente et al. [p < 0.00001).No pediatric studies were found in the reviewed literature which would allow a comparison of the central venous and arterial lactate results in septic patients with our findings. Our study suggests conclusions which have been concordant with findings obtained in adult patients, in whom few studies have been carried out on this particular aspect. Bucuvalas et al.  comparede et al.  evaluateOne of the limitations of our study is that simultaneous measurement of arterial and central venous lactate was not always performed. In addition, in spite of the fact that the sample size was calculated according to the findings in previous studies, it corresponds to the experience of a single reference site, which should be corroborated with prospective studies in the pediatric population which would also determine the sensitivity and specificity of these tests as clinical determinants in patients being treated for sepsis or septic shock.Within the reviewed literature, our study is the first research to compare arterial and central venous lactate in critically ill children with a potentially lethal pathology such as sepsis and septic shock. Likewise, although lactate is analyzed at a specific point in time, having central venous lactate as a reliable alternative to arterial lactate provides a monitoring tool and, above all, can serve as another tool to help determine the severity of the illness. A goal-guided approach, according to the studies by Nguyen et al. , has shoTechnical difficulties in obtaining an arterial line in pediatrics are very common, especially when the patient is in shock, but also for all those cases where an arterial vascular access is not necessary or during the initial phase of stabilization before an arterial vascular access can be obtained. These are why being able to assume that lactate obtained from a central vein is just as reliable as arterial lactate provides alternatives when establishing therapeutic goals on the admission of our patients.We recommend carrying out prospective studies that will evaluate the behavior of lactate over time, its clearance, and its relationship to the clinical course of the patient.There is a good correlation between arterial and central venous lactate in children with septic shock, after statistically adjusting the different variables inherent to the critically ill patient, such as the use of vasoactive support, medications, and demographic variables, serving as a good indicator of tissue perfusion in critically ill children.