Background: The differential diagnosis in persistent airway limitation is sometimes not so clear in older adults. Airway eosinophilia and airway hyperresponsiveness may develop in some cases with chronic obstructive lung disease (COPD), independent of asthma. However, little is known about clinical significance of these phenotypes of COPD in detail.Aims and objectives: This clinical study was designed to examine prevalence of airway eosinophilia and airway hyperresponsiveness in COPD who have no symptom and no past history of asthma, and to examine involvement of these pathophysiological features of asthma in the management and therapy for COPD.Methods: Sputum examination via qualitative and quantitative procedures was performed in stable COPD (GOLD 1–3). When sputum eosinophils were qualitatively (≥+) or quantitatively assessed (≥3%), ciclesonide  was added on bronchodilators. In cases with FEV1 ≥ 70% of predicted values, acetylcholine provocation test was examined for assessment of airway hyperresponsiveness. Therapeutic effect was evaluated using spirometry and COPD assessment test (CAT).Results: Sputum eosinophils were observed in 65 (50.4%) of 129 subjects using qualitative analysis; in contrast, lower grade (>0%) and higher grade (≥3%) were observed in 15 (20.3%) and 25 (33.8%) of 74 subjects using quantitative analysis. Airway hyperresponsiveness developed in 46.9% of these subjects with sputum eosinophils. Exacerbations occurred much more frequently in lower-grade airway eosinophilia without ciclesonide than in higher-grade airway eosinophilia with ciclesonide. Airway hyperresponsiveness significantly increased frequency of exacerbations in COPD with both lower and higher grade in airway eosinophilia. Addition of ciclesonide to indacaterol markedly improved lung function , CAT score, and reliever use in these subjects with airway eosinophilia determined by qualitative analysis. However, ciclesonide was less effective in improving these values in subjects with airway hyperresponsiveness than in those without airway hyperresponsiveness.Conclusions: Airway eosinophilia and airway hyperresponsiveness are complicated with 25–50% of COPD that have no symptom and history for asthma. These phenotypes of COPD are closely related to symptom stability and reactivity to glucocorticosteroids. These phenotypes may play key roles for advancement of the management and therapy of this disease. COPD haal (LLN) .1 (200–400 ml), exhaled nitric oxide , and eosinophils in the peripheral blood (3–5% or 150–300 cells/ml) . To reduce a healthcare burden by these diseases, differential diagnosis should be needed to clarify them accurately by a potential biomarker  . Howeverells/ml) . This laells/ml)  and 13–6ells/ml) . Recentliomarker .The differential diagnosis among COPD, asthma, and ACO in patients with symptoms; eosinophils in the peripheral blood; and persistent airflow limitation is not always clear in older adults. Eosinophil counts in the peripheral blood may not always be consistent with eosinophil inflammation in the airways. Although it is generally considered that eosinophil inflammation and hyperresponsiveness in the airways are the major characteristic features of asthma, these pathophysiological conditions for asthma are complicated with some patients with COPD , even thIt may be meaningful to classify COPD according to eosinophilia and hyperresponsiveness in the airways as phenotypes of this disease. This retrospective clinical study was designed to determine whether airway eosinophilia and airway hyperresponsiveness are involved in severity and stability in the management of patients with COPD who have not been diagnosed with asthma by medical doctors, and to determine whether addition of inhaled glucocorticosteroid (ICS) is beneficial to COPD with this characteristic pathophysiology for asthma.1)/forced volume capacity (FVC) of <70% and their smoking history. Post-bronchodilator reversibility was not an exclusion criterion. None of the patients have a past history of asthma including previous doctor-diagnosed asthma, and none have characteristic features of asthma such as dyspnea and wheezing during nighttime. Moreover, none of the patients have a history of upper respiratory diseases such as allergic rhinitis and sinusitis; they have no clinical features of upper respiratory tract rhinorrhea and nasal congestion. Sputum collection and acetylcholine provocation test were approved by the research ethics committee of Rinku General Medical Center. These examinations were carried out after the consent was obtained in writing. This clinical study was approved by the research ethics committee of Rinku General Medical Center. The need for consent about the retrospective analysis of these results was waived by the committee. However, according to the committee’s suggestion, these patients were given the right to opt out this retrospective analysis by showing the contents on homepage and posters.Patients with COPD  admitted to the outpatient clinic in our hospitals  were enrolled in this retrospective study Table 1.−6/ml, and cytocentrifuge preparations were made. Cytospin slides were stained with Diff-Quick solution. A differential cell count was carried out on 400 nucleated nonsquamous cells, and the results were expressed as a percentage of the total nonsquamous cell count. Based on this quantitative analysis, enrolled cases were classified into three groups by percentages of eosinophils, i.e., 0% (Group A), 0% < eosinophils <3% (Group B), and ≥3% (Group C).Sputum samples were collected by the spontaneous act of coughing up. Sputum induction by inhalation of the normal or hypertonic saline was not performed for safety because lung function is essentially reduced in patients with COPD. Sputum eosinophils were evaluated qualitatively using cytological examination in the Department of Laboratory Medicine in our hospitals. Qualitative eosinophilia was defined as positive (+) when eosinophils existed in each of 10 high-power fields. As a quantitative analysis, these sputum samples were treated with dithiothreitol, and the suspension was filtered with gauze according to the methods of Pizzichini and co-workers . The sal1 ≥ 70% of predicted values, this provocation test was performed for assessment of airway hyperresponsiveness to avoid the risk of respiratory failure and false positives occurring (1 at each condition were not different from those of previous test (at least more than 90%), acetylcholine provocation test was started. Lung function test for flow–volume curves was cumulatively performed at each concentration after acetylcholine  was inhaled by tidal breathing for 2 min each concentration similar to the previous method  was not calculated, airway hyperresponsiveness was defined as threshold values of <4 mg/ml of acetylcholine to maximize the specificity of diagnose of asthma  and smoking history (≥20 pack-years). Management and therapy for COPD were carried out according to the guidelines of the Japanese Respiratory Society; on demand use of SABA and regular use of long-acting β2-adrenergic receptor agonists (LABA) or long-acting muscarinic receptor antagonists (LAMA) were prescribed to improve symptoms and lung function. Sputum collection was performed 8 weeks after long-acting bronchodilators were inhaled daily. ICS was added to cases with airway eosinophilia by sputum examination, which was diagnosed by qualitative (≥+) or quantitative assessment (≥3%). Inhalants (bronchodilators and glucocorticosteroids) that last for 24 h were used to reduce the number of inhalations. To assess the effects of addition of ICS on patients with airway eosinophilia and airway hyperresponsiveness, frequency of visits to the Emergency Department to improve exacerbation was investigated for 1 year in patients with COPD with sputum eosinophilia among Group A , Group B , and Group C . An exacerbation of COPD is defined as an acute event characterized by a worsening of respiratory symptoms  that are beyond daily variations and lead to change in medication (GOLD). In cases where sputum eosinophils were proven using this quantitative method, tiotropium (LAMA) was administered as a bronchodilator and ciclesonide (400 μg/day) was administered as ICS. Moreover, to assess the effect of indacaterol (LABA) and additional effects of ciclesonide (ICS) to a LABA on cases of GOLD 2–3 with sputum eosinophils determined by qualitative analysis (≥+), lung function test , COPD assessment test (CAT) score, and frequency of SABA for rescue use were investigated before and after regular inhalation of indacaterol once a day for 8 weeks and subsequently additional inhalation of ciclesonide once a day for an equivalent period  were excluded to distinguish from patients who could be judged as ACO.This clinical study was carried out to determine whether eosinophilic inflammation and hyperresponsiveness in the airways are latent in patients with stable COPD and to determine whether there are differences in severity and stability in these phenotypes of COPD. Sputum examination for airway eosinophilia and acetylcholine provocation test for airway hyperresponsiveness were performed against patients with COPD diagnosed based on persistent airflow limitation  was considered to be a significant difference.All data are expressed as the mean ± standard deviation (SD) with 95% confidence interval (CI). Statistical significance was assessed by unpaired Student’s 1 ≥ 80% of predicted values), 10 cases (40.0%) belonged to Stage 2 , and seven cases (28.0%) belonged to Stage 3 . The mean values of percentages of eosinophils in each stage of GOLD 1–3 were 7.9 ± 3.7 (n = 8) [95% CI: 4.80–11.00], 8.5 ± 3.4 (n = 10) [95% CI: 6.07–10.93], and 8.6 ± 3.4% (n = 7) [95% CI: 5.46–11.74], respectively  of 32 cases, > 20% reduction in FEV1 was observed at ≥5 mg/ml of acetylcholine. The values of threshold in acetylcholine concentration were 1.43 ± 1.29 [95% CI: 0.69–2.18] and 16.47 ± 4.78 mg/ml , respectively  of 32 cases, > 20% reduction in FEVP = 0.009, ICS was not inhaled in 34 patients without sputum eosinophils . Exacerbation occurred in one (0.03%) of these 34 cases during follow-up for one year  of six cases that have airway hyperresponsiveness; in contrast, exacerbation occurred in one (12.5%) of eight cases that have no airway hyperresponsiveness  and to 1802.3 ± 604.7 [95% CI: 1519.29–2085.31] ml , respectively (P = 0.011) and to 2523.5 ± 536.1 [95% CI: 2272.59–2774.41] ml , respectively (P = 0.007) and to 4.2 ± 1.6 [95% CI: 3.45–4.95] points (P = 0.004), respectively (P = 0.008) and to 0.3 ± 0.2 [95% CI: 0.21–0.39] puffs/week (P = 0.003), respectively . In these cases, after administration of indacaterol and indacaterol with ciclesonide, values of FEV1 were increased by 208.3 ± 180.4 [95% CI: 18.91–397.69] and 283.3 ± 219.7 [95% CI: 52.66–513.99] ml, respectively  by the former and 50.4% (≥+) by the latter. There was no significant difference between these two methods in an evaluation for sputum eosinophilia Figure 21 ≥ 70% predicted values not only to avoid false positives but also to secure safety in this examination (1 > 15% and >400 ml) concerning ACO; however, asthma may be latent in these patients with COPD.Airway hyperresponsiveness is also a characteristic feature of asthma. Acetylcholine provocation test is generally considered to be useful and reliable for diagnosis of asthma because this clinical examination has great sensitivity and specificity to diagnose asthma . On the mination . Althougmination . Sputum To determine the role of airway eosinophilia and airway hyperresponsiveness in the management of COPD, frequency of exacerbations of COPD was examined for a year. ICS was daily administered to these patients with ≥3% of sputum eosinophils (Group C). On the other hand, ICS was not administered to patients with 0% < sputum eosinophils < 3% (Group B). ICS was not administered to patients with 0% of sputum eosinophils (Group A). Exacerbations occurred much more frequently in Group B (lower-grade airway eosinophilia without ICS) than in Group A (no airway eosinophilia without ICS) . Therefo2-adrenergic agonist, the effects of this agonist are not so markedly reduced under the conditions the number and function of these receptors are attenuated by aging  and ciclesonide (ICS) were inhaled to COPD with sputum eosinophils determined by qualitative analysis Figure 1by aging . In thisaging  Figure 8HK, MH, and NH participated in research design. HK contributed to case registration. HK, MH, and NH discussed data analysis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This occurred despite a 20% reduction in anti-hypertensive medications. This novel and potentially highly effective dietary modification, done very cheaply alongside routine care, offers hope that should be tested in a large prospective trial.Hypertension is the second biggest known global risk factor for disease after poor diet; perhaps lifestyle interventions are underutilized? In a previous small pilot study, it was found that a low carbohydrate diet was associated with significant improvements in blood pressure, weight, ‘deprescribing’ of medications and lipid profiles. We were interested to investigate if these results would be replicated in a larger study based in ‘real world’ GP practice. 154 patients with type 2 diabetes or impaired glucose tolerance were recruited into an observational cohort study in primary care. The effects of a low carbohydrate diet sustained for an average of two years (interquartile range 10–32 months) on cardiovascular risk factors were examined. Results demonstrate significant and substantial reductions in blood pressure (mean reduction of systolic BP 10.9 mmHg (interquartile range 0–22 mmHg) ( The National Institute for Health and Care Excellence (NICE) defines hypertension as sustained clinic blood pressure of 140/90 mmHg or higher and either a subsequent ambulatory blood pressure monitoring daytime average or home blood pressure monitoring average of 135/85 mmHg or higher. According to a recent study on disease [Most individuals with hypertension have no readily identifiable cause and are termed “essential” hypertensives. Many health care professionals are unaware of what the causation may be beyond vague references to salt and obesity. Hypertension is likely caused by a combination of salt and volume retention , togethep < 0.005; and diastolic 91 ± 8 to 83 ± 11 mmHg, p < 0.05). This occurred despite discontinuing several antihypertensive drugs. In 2013 the authors started offering advice on a low carbohydrate diet (defined as <130 g carbs/day) to help people in the Norwood primary care (GP) practice with type 2 diabetes (T2D) and pre-diabetes or impaired glucose tolerance (IGT) [Our hypothesis for the 2013 pilot study was that a low carbohydrate diet may offer better diabetes control and weight management, compared to baseline results achieved with ‘standard care’. It is surprising now (in 2019) that in 2013 this was a controversial suggestion. Since 2013 this approach has gained wider acceptance ,5.p < 0.01).Improvements in features of the metabolic syndrome associated with a reduction in carbohydrate intake had been demonstrated as early as 2005 and considered to be mediated by an effect on insulin activity . A reducHyperinsulinaemia in people with T2D promotes renal sodium retention, a process not seen in non-diabetic people ,10,11. IDespite the wider acceptance mentioned above, questions remain about the low carb approach. For example the British Diabetic Association in their November 2018 policy statement  whilst aThe significant improvements in blood pressure in our initial pilot made us wonder firstly, if a larger cohort advised on a low carbohydrate diet for longer than six months would confirm our findings, and secondly what the possible mechanism for blood pressure (BP) improvement could be. Is it simply weight loss or something more?Outcomes to be studied:Primary, to examine the impact of dietary carbohydrate restriction on blood pressure and weight.Secondary, to examine the impact of dietary carbohydrate restriction on lipid profiles and antihypertensive drug prescribing.We performed a retrospective analysis of clinical data from routine work from the Norwood Surgery, a suburban GP practice with 9700 patients in the North of England.n = 6). Informed consent was obtained. Data was collected from March 2013 to November 2018 during which time we offered patients our study diet programme as part of ordinary appointments. Those who chose to enroll were given our diet sheet (2 and a weight of 95.2 Kg (IQR 82.5–105.5 Kg).A low carb diet was offered as part of routine care by GPs and practice nurses to practice patients with type 2 diabetes (T2D) or impaired glucose tolerance (IGT). Exclusion criteria were end of life patients, pregnancy, eating disorders, being underweight, type 1 diabetes or being under 18 years of age. People with type 2 diabetes on insulin were included . To help, we used our novel model based on a teaspoons of sugar equivalance system which represents the glycaemic load of various foods . For exaPatients also found it helpful to understand the physiological link between glucose, insulin and obesity, where insulin could be seen as ‘pushing’ excess glucose into fat cells. This advice was reiterated with our basic diet sheet  and a brA rough assessment of follow up would give an average review frequency of 6 per year, including the group sessions. One novel way to monitor compliance and help participants refine their diet was to ask them to use their mobile phone to photograph everything they ate and drank for the two days before their review. We used this particularly for those individuals who were disappointed with their weight loss. Others preferred to recount this information verbally. Because some of the patients were being followed up for to six years it was important to review the basic diet sheet with participants at least once a year rather than assume it had all been remembered. In addition to dietary measures, personal goal setting and the use of relevant patient feedback such as weight or blood tests results were emphasized as all participants were informed of their test results.Statistical methods. Non-normally distributed continuous variables  are shown as mean values with the associated inter-quartile range . Categorical variables (number of patients) are shown as absolute values with the percentage (%). Comparisons between continuous variables are made using the Wilcoxon Signed Rank test for paired samples. Baseline and follow-up distributions of patient data are presented visually using box and whisker charts, the upper and lower box lines on these charts indicate the inter-quartile range, the line in the middle of the box indicates the median value, the dot indicates the mean value and the upper and lower whiskers indicate either 1.5 times the interquartile range or the minimum/maximum value, whichever is the smaller distance from the box. Statistical analyses were performed with R version 3.4.0. In all cases a p-value < 0.05 was considered statistically significant.p < 0.0001) and a mean fall in diastolic BP of 6.3 mmHg (IQR 0–12.8 mmHg) (p < 0.0001), see The mean time spent on the diet was 24 months (IQR 10–32 months). This was associated with a mean unadjusted reduction of systolic BP of 10.9 mmHg (IQR 0–22 mmHg)  a 10% reduction.Mean weight fell overall by 9.5 kg (IQR 5–13) . She also lost 2 kg in weight. It is possible the physiology of insulin’s action on the kidneys to cause sodium retention holds a clue in cases like these. As mentioned in the introduction, a low carb diet may improve both hyperinsulinaemia and insulin resistance, promoting the loss of sodium in the urine so improving blood pressure. This may explain our (adjusted) average 1.6 mm Hg reduction in systolic blood pressure per 1 kg reduction in weight. An effect which is significantly larger than predicted by the average observed weight loss alone.In relation to the above theory around BP, insulin and sodium retention, by far the most convincing and tested theory is that seen in randomised controlled trials utilising the new SGLT2 inhibitor drugs which act on the renal sodium-glucose co-transport2 system . These aThe overall blood pressure reduction by 11/6 mmHg, if sustained over years would lower stroke risk by >30% and cardiovascular death by >20% . MoreoveCan a low carbohydrate diet be maintained long term? Many of the often-quoted studies about diet and health are surprisingly short term. Perhaps most notably, the widely cited DASH diet  to lowerLimitations of the study. We present a simple cohort study taken from the ‘real world’ of 10 min GP appointments. As such it has low internal validity as there were many variables we were not able to control. For example, these 154 people were not randomly generated. At the very least they all chose to take part rather than being randomly allocated. However, we hope that its basis in an ordinary GP practice gives at least the possibility of greater external validity in its potential to be replicated in other practices. In any case, dietary RCTs, particularly longer-term studies of over a year, may well suffer from the problem that diet is a very personal thing. It is unlikely that many people would be prepared to eat a diet long-term that they have not chosen for themselves. Another problem we faced, common to dietary research generally, is assessing adherence to the diet. What foods did participants actually consume? In part this was addressed by regular ‘revision’ of the physiological principles around insulin and the diet sheet itself. Our research grant totaled just £7000 for a study lasting six years. Even with a large grant we could never know with certainty what 154 people eat over a period of years. This problem was highlighted by the Observing Protein and Energy Nutrition (OPEN) Study . Doubly One of the striking features of our clinical work has been revealed by asking patients how they feel about long-term medication for blood pressure. When offered the choice of starting medication or buying in to lifestyle change with practice-based support, not a single patient opted to start the medication in six years. Similarly, we found patients were excited by the possibility of discontinuing medication they previously had assumed was ‘for life’. Our results may help clinicians uncertain how to best help a patient with type 2 diabetes, high blood pressure and a significantly raised triglyceride with a low HDL cholesterol level. A common scenario as our study shows. In this situation many clinicians may choose lifelong treatment with an SGLT2 inhibitor drug. From our work, it would seem reasonable to offer patients the alternative of a low carb diet which appears to offer similar benefits as well as cost savings and fewer side effects. For the low carb approach, the 32% improvements in serum triglyceride were particularly impressive. Indeed, emerging research from other sources is now associating improvements in cardiovascular health with a low carbohydrate diet. A recent systematic review and meta-analysis  concludeWe believe it is likely that the significant effect on blood pressure results was in part due to a reduction in insulin, together with improved insulin sensitivity. As discussed in the introduction, it is well known that high insulin levels elevate blood pressure, promote myocardial hypertrophy and increase sodium retention by the kidney. The marked and sustained improvements in our cohort could be explained by the effects of a low carbohydrate diet on insulin action in T2D and IGT patients, where insulin levels are high and insulin resistance marked. Sodium has been demonised as the cause of hypertension when perhaps insulin and insulin resistance may actually be the culprits. The improvements in blood pressure were despite 27 patients being able to reduce or discontinue antihypertensive therapy by a net total of 35 medications, a 21% reduction in prescribing of drugs for essential hypertension for the cohort. This raises the additional possibility of substantial drug budget savings from a lower carb approach to hypertension.Next steps:Our study, carried out in general practice in the UK, lacks data on changes in insulin sensitivity and resistance. We plan to address this in a further pilot study with accurate determination of insulin activity before and after a sustained period on the Norwood diet. We hypothesise that there will be a substantial improvement in insulin sensitivity and a reduction in post prandial insulin levels, and we look forward to this next investigation. Clearly, confirmation of our findings in a large prospective study is crucial.The Global Burden of Disease, Injuries and Risk Factor Study  looked aAdherence amongst people with T2D or glucose-intolerance to a low carbohydrate diet for an average of two years resulted in significant improvements in blood pressure, weight and lipid parameters despite ‘deprescribing’ of 21.5% of the total drugs for hypertension. The diet was well tolerated. These substantial benefits may translate into significant cardiovascular protection and drug budget savings that should be tested in a large prospective trial. Restricting dietary carbohydrates is now recognised as one way to help control the international epidemic of T2D [


Total kidney volume (TKV) is a validated prognostic biomarker for risk assessment in autosomal dominant polycystic kidney disease (ADPKD). TKV by manual segmentation (MS) is the “gold standard” but is time-consuming and requires expertise. The purpose of this study was to compare TKV-based prognostic performance by ellipsoid (EL) vs. MS in a large cohort of patients. Cross-sectional study of 308 patients seen at a tertiary referral center; all had a standardized MRI with typical imaging of ADPKD. An experienced radiologist blinded to patient clinical results performed all TKV measurements by EL and MS. We assessed the agreement of TKV measurements by intraclass correlation(ICC) and Bland-Altman plot and also how the disagreement of the two methods impact the prognostic performance of the Mayo Clinic Imaging Classification (MCIC). We found a high ICC of TKV measurements  between EL vs. MS; however, 5.5% of the cases displayed disagreement of TKV measurements >20%. We also found a high degree of agreement of the individual MCIC risk classes (i.e. 1A to 1E) with a Cohen’s weighted-kappa of 0.89; but 42 cases (13.6%) were misclassified by EL with no misclassification spanning more than one risk class. The sensitivity and specificity of EL in distinguishing low-risk (1A-B) from high-risk (1C-E) MCIC prognostic grouping were 96.6% and 96.1%, respectively. Overall, we found an excellent agreement of TKV-based risk assessment between EL and MS. However, caution is warranted for patients with MCIC 1B and 1C, as misclassification can have therapeutic consequence. Mutations of two genes, PKD1 and PKD2, account for the majority of genetically resolved cases in ADPKD. Recent studies have delineated a strong genotype-phenotype correlation with the most severe kidney disease associated with PKD1 protein-truncating mutations, intermediate disease severity associated with PKD1 non-truncating mutations, and mild disease associated with PKD2 mutations5. Additionally, patients with complex biallelic or digenic mutations have more severe disease while those with no detectable mutations, mild disease6. At the clinical level, replacement of kidney parenchyma by increasing number and size of cysts with age is a typical feature of ADPKD, eventually leading to ESRD in a majority of patients. Kidney function measurements, such as serum creatinine, estimated glomerular filtration rate (eGFR) and creatinine clearance are not sensitive biomarkers for assessing disease severity or progression in ADPKD, as these measurements typically remain within or close to normal range until late in the clinical course7.Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder worldwide with a life-time risk of approximately 1:1,000 and the fourth leading cause of end stage renal disease (ESRD) in North America9. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have recently accepted TKV as a prognostic biomarker for enrichment of patients at high-risk for progression for clinical trials10. Using age- and height-adjusted TKV, the Mayo Clinic imaging classification (MCIC) provides a validated TKV-based risk assessment tool for selecting “high-risk” patients, defined as class 1C-1E, for clinical trials12. Moreover, with the approval of Tolvaptan as the first disease modifier drug for treatment of “high-risk” patients with ADPKD in multiple countries, TKV-based risk assessment assumes an increasingly important role for patient management in the clinical setting15.The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) have shown that total kidney volume (TKV) in ADPKD expands quasi-exponentially during adult life at an average rate of 5% per year albeit with considerable variability between patients and is a sensitive biomarker predicting kidney disease progression17. By contrast, TKV derived using an ellipsoid (EL) formula requires only measurement of the three orthogonal axes of each kidney and is much simpler but less accurate11. To encourage a more practical translation to the clinical setting, the MCIC uses EL-derived TKV for its risk assessment; however, this approach has not been well validated externally. In this study, we compared the agreement of TKV measurements by EL vs. MS in a large cohort of patients with ADPKD and evaluated how the disagreement of TKV measurements by the two methods impact on the prognostic performance of MCIC.Currently, TKV measurement with magnetic resonance (MR) or computed tomography (CT) images by manual segmentation (MS) is considered the “gold standard”. However, this method dictates manual tracing of each kidney outline slice by slice and thus, is labor-intensive and requires radiological expertise19 and/or genetic testing4, and underwent renal imaging by MRI or CT. Patients with atypical (i.e. MCIC Class 2) or non-ADPKD cystic kidney disease20 were excluded.The study cohort comprised 357 consecutive patients seen at a regional PKD center between April 1, 2011 and March 31, 2017; they were referred by more than 100 academic and community nephrologists from a metropolitan area with population of approximately 6.4 million. All except 3% of this cohort participated in the current study and provided informed consent according to a pre-specified research protocol approved by the institutional review board at the University Health Network in Toronto. All study patients were aged 18 years or older, diagnosed with ADPKD by renal imagingDemographic and clinical information including blood pressure, serum creatinine, estimated GFR by the CKD-EPI equation, mutation class, and height-adjusted TKV were collected from all study patients.All the research methods (i.e. genetic testing and imaging studies) used in this study were performed in accordance with guidelines and regulations at the Toronto General Hospital.11.All but 5 study patients underwent a standardized protocol using a 1.5-T MRI scanner . Coronal T2–weighted single–shot fast spin echo MR images with fat saturation were used for TKV calculation with the following parameters: 0.59- to 1.41-mm/pixel resolution in plane, 3-mm slice thickness, 90° flip angle, and 500–1491 ms/82–101 ms repetition time/echo time. Five patients with contraindication to MRI  had contrast enhanced CT (Canon (formerly Toshiba) Medical Systems Corporation, Otawara, Japan) imaging instead . All DICOM files from MRI and CT were downloaded into a workstation and inspected to confirm complete coverage of both kidneys and image quality. One experienced radiologist (M.P.) with over 10 years of experience, blinded to the patient clinical and genetic results performed all TKV measurements by MS and EL at two separate sittings. From each set of abdominal MR images, the boundary of each kidney was manually delineated slice by slice using a commercially available software . Kidney volume was calculated by summing the products of the renal area and slice thickness. Non-renal parenchymal tissue  were excluded from the measurements. TKV measurements by EL was performed as follows: for each kidney, length was measured as the average maximal longitudinal diameter measured in the coronal and sagittal planes, width, from the transversal image at maximum transverse diameter, and depth, from the same image perpendicular to the width measurement, all in millimeters. TKV was calculated by using the sum of the left and right kidney volumes, derived by the equation: π/6 * /2 * width * depth /1,000. Height-adjusted TKV and age were used to generate a MCIC risk class (i.e. 1A-1E) for all study patientsPKD1 and PKD221. All nonsense, frameshift, and canonical splice site mutations were grouped as protein-truncating mutations, and nonsynonymous missense or atypical splice site mutations were grouped as non-truncating mutations4. All non-truncating mutations and inframe insertions/deletions were evaluated for their potential pathogenicity using prediction algorithms , review of the PKD mutation database (http://pkdb.mayo.edu), and by segregation analysis with additional affected family members when possible4. We also screened all mutation-negative patients by multiplex ligation–dependent probe amplification to detect large gene rearrangements21.Genetic testing was performed in a single research laboratory in Toronto using a validated long range PCR protocol and bidirectional sequencing of coding region and splice junctions of Cohen’s Kappa value, specificity, sensitivity, positive predictive value, false positive rate, false negative rate, and accuracy were all calculated in Microsoft Office Excel 2016 for Windows. All other analyses were performed using the statistical package for the social sciences . Continuous variables are expressed as means ± standard deviation (SD), whereas non-normally distributed variables, as median with interquartile range (IQR). Categorical variables were expressed as percentages. Differences between MS and EL was tested using a 2-tail t-test for normally distributed and a chi-squared tests for categorical variables. Intra-class correlation coefficient of TKV measured by EL and MS was determined in the total cohort. The agreement of TKV measurements by EL and MS was assessed by Bland-Altman plots, with calculation of agreement limits . A 2-sided P < 0.05 was considered to indicate statistical significance.2. Overall, 69.5%, 21.4%, and 9.1% of our patients had chronic kidney disease (CKD) stages 1–2, 3, and 4–5, respectively; and approximately 1/3 of each had MCIC risk class 1A-1B, 1C, and 1D-1E, respectively. As expected, we found a positive correlation between TKV, age, blood pressure, serum creatinine, and a negative correlation between TKV and eGFR  that are typically associated with more rapid rate of ADPKD progression  and 8 cases of non-ADPKD renal cystic diseases  which show no significant percent differences in KV measurements by the two methods between the age strata (P = 0.15 by t-test).We found a high intraclass correlation coefficient of TKV measurements  between EL and MS. Figure S1To assess how TKV measurement errors by EL might impact the prognostic performance by MCIC, we tabulated the concordant and discordant cases across the five risk classes using the assignment by MS as the “gold standard” Fig.  and S2. 15. Using these two broad prognostic groupings (i.e. 1A-1B vs. 1C-E) as an outcome, we found a sensitivity and specificity for correct risk assignment by EL  to be 96.6%, of 96.1%, respectively. By contrast, both the sensitivity (0.894 vs. 0.987) and specificity (0.900 vs. 0.968) for correct risk assignment by EL were respectively reduced in the younger (aged 18–30 years) as compared to older (aged 31–79 years) patients  based on individual MCIC classes have been proposed to separate “low-risk” from “high-risk” patients15. Misclassification of class 1B or 1C by EL potentially may have the greatest negative impact on clinical management including the use of a disease-modifier drug. Caution may be warranted for patients with these two risk classes; additional risk factors such as ADPKD mutation class5, family history of PKD disease severity24, rate of loss of eGFR25, or repeat TKV measurement after 12 months may help to improve the confidence of assessment for patients in class 1C, while repeat TKV assessment after 12 months may identify high-risk patients misclassified as class 1B. The issue of MCIC misclassification is further exacerbated by a narrower TKV range that defines each MCIC class in the younger patients11. Thus, measurement errors in TKVs by EL had a greater negative impact on the accuracy of MCIC risk classification in the younger (aged 18–30 years) compared to older (aged 31–79 years) patients.TKV measurement by MS in ADPKD is currently time-consuming, requires radiological expertise including the use of specialized computer software, and remains challenging outside specialized centers. While this is essential in clinical trials to provide accurate assessment of the therapeutic effects, exact TKV measurement may not be necessary for risk assessment. In this regard, the use of EL-derived TKV by the MCIC significantly reduces the technical complexity and time required, and allows for wider clinical translation27. Thus, TKV by MS may eventually become the standard option, where additional information from MR images such as texture analyses to delineate and quantify the functional kidney mass may also be added to improve risk assessment in ADPKD28. However, TKV via EL may still be attractive in centers that would not have the technology or expertise to use machine learning technologies.The strengths of our study include a large cohort of well-characterized patients who underwent a standardized MRI protocol and their TKV measured using MS and EL by a single experienced radiologist. However, this study has several limitations. First, since our study involved a single center with only one radiology reader, we are unable to evaluate the impact of TKV measurement by different readers and multiple sites. We expect that there may be more disagreement in the TKV measurements under these latter scenarios which can be minimized by standardization of the MRI protocol and training of the readers. Second, we are unable to evaluate the validity of serial EL TKV measurements for risk assessment over time given that our study was cross-sectional. Lastly, the challenge of TKV measurements by MS may be overcome in the near future by recent innovations, such as semi- to full-automation by specialized computer software and the “deep learning” technologiesIn conclusion, TKV-based risk assessment is now an integral component of clinical management for ADPKD. We found that TKV by EL performed well with low bias, and high precision and accuracy when compared to MS. Although TKV measurement errors also resulted in the discordance of MCIC in 13.6% of our patients, their impact on MCIC is clinically most relevant in the misclassified patients with risk classes 1B and 1C. In the latter patients, incorporation of additional risk factors such as ADPKD mutation class, family history of PKD disease severity, rate of loss of eGFR, or repeat TKV measurement after 12 months may help to improve the confidence of their risk assessment. Moreover, younger patients aged 18–30 years are susceptible to a higher MCIC misclassification rate which may be minimized by using TKV derived from MS, rather than EL.Supplementary Information


In summary, the BP and LDL-C goal achievement rates in Chinese dyslipidemia outpatients with hypertension were low, especially in endocrine departments. Combination therapies were not associated with improvement of the goal achievement rates.The present study comprised 17,096 Chinese hypertensive dyslipidemia patients who received lipid-lowering treatment for > 3 months in order to investigate blood pressure (BP) as well as low-density lipoprotein cholesterol (LDL-C) goal attainment rates in Chinese hypertensive dyslipidemia patients on antidyslipidemia drugs. The factors that interfered with BP, or BP and LDL-C goal attainment rates and antihypertensive treatment patterns, were analyzed. In total, 89.9% of the 17,096 hypertensive dyslipidemia patients received antihypertensive medications mainly consisting of a calcium channel blocker (CCB) (48.7%), an angiotensin receptor antagonist (ARB) (25.4%) and an angiotensin-converting enzyme inhibitor (ACEI) (15.1%). In cardiology departments, usage rates of β-blockers (19.2%) were unusually high compared to other departments (4.0–8.3%), whereas thiazide diuretics were prescribed at the lowest rate (0.3% vs 1.2–3.6%). The overall goal attainment rates for combined BP and LDL-C as well as BP or LDL-C targets were 22.9, 31.9 and 60.1%, respectively. The lowest BP, LDL-C and BP combined with LDL-C goal attainment rates were achieved in endocrine departments . Combination therapies showed no benefit particularly for BP goal achievement. A multivariate logistic regression analysis showed that age < 65 years, alcohol consumption, diabetes, coronary heart disease (CHD), cerebrovascular disease (CVD), chronic kidney disease (CKD), body mass index (BMI) ≥ 28 kg/mNCT01732952Clinical trial registration number The online version of this article (10.1186/s12944-019-0974-y) contains supplementary material, which is available to authorized users. The China Hypertension Survey of 2012–2015 revealed that 23.2% of adult Chinese people were hypertensive . The cumDYSIS-China is one part of a DYSIS series of epidemiological studies, which is a cross-sectional observational study when the clinical data of enrolled patients are collected and recorded but the treatments and clinical evaluations are unaffected. The patients’ data were collected from departments of cardiology, endocrinology, geriatrics, internal medicine and neurology as well as other departments  in Tier 1, Tier 2 and Tier 3 hospitals. For the DYSIS-China study, data from 25,311 dyslipidemia patients who were treated with lipid lowering drugs, including a large percentage of patients with hypertension, were collected from 122 hospitals in 6 geographic regions of China between April 2012 and October 2012. Patients were consecutively enrolled in the study if they were older than 45 years and had accepted lipid lowering drug therapy for ≥ three months. Demographic data, cardiovascular risk factors, a history of cardiovascular disease and corresponding treatments were recorded through a disease history inquiry, and laboratory test results were also collected. Laboratory measurements included the fasting lipid profile , fasting blood-glucose, glycosylated-hemoglobin and serum creatinine. In addition, each patient’s hospital Tier and the treating department were noted.For this study, 17,096 (67.5%) patients with concomitant hypertension from the DYSIS-China database were selected and we analyzed their antihypertensive treatments, LDL-C and BP goal attainments. Hypertension was defined as patients with a previous diagnosis of hypertension according to the criteria devised by Liu et al. 2011) [ [11], inThe BP and LDL-C target values were based on the 2010 Chinese hypertension management guidelines  and the Patients who were taking part in other clinical research trials were excluded from the DYSIS-China study. Each patient signed an informed consent form. The ethical committee of each research center involved in the DYSIS-China survey approved the research project and the contents of the informed consent form.2, diabetes mellitus (DM), coronary artery disease (CAD), cerebrovascular disease (stroke), ≥ stage 3 chronic kidney disease (CKD), TC not at goal, LDL-C not at goal, and combination therapy vs monotherapy; backward elimination (α = 0.05) was performed. Statistical significance was accepted at the two-sided 0.05 level and all confidence intervals were computed at the 95% level. Statistical analyses were performed using SAS .Categorical variables are presented as frequencies and percentages, and continuous variables as the mean ± standard deviation (SD). Intergroup differences in categorical variables were evaluated using a chi-squared analysis or Fisher’s exact test, depending on the number of patients in each group. Intergroup differences in continuous variables were determined using analysis of variance. Multiple logistic regression analysis was performed to determine the independent predictors of lipid parameters. The variables included in the model were: age ≥ 65 years, gender, smoker, alcohol drinker, cardiovascular family history, BMI ≥ 28 kg/m2 in 2658 (15.6%) cases. Hypertension treatment modalities were 50.5% monotherapy and 39.4% combination therapy. Statins were used as medication for 15, 363 (89.9%) and antiplatelet therapies for 11,989 (70.1%) hypertensive dyslipidemia patients , CHD in 6958 (40.7%) and BMIs ≥28 kg/mP < 0.001). These data revealed that the BP achievements under monotherapy correlated with specific drugs, but the most efficient drugs were not the most frequently prescribed ones.First, we investigated the antihypertensive treatment rates in different hospital departments and found that the antihypertensive drug treatment rates were lowest in neurology 80.1%) and highest in cardiology (93.9%) departments  and β-blockers (19.2%) were most frequently given in cardiology, and CCB was most widely used in neurology (65.1%), a value that is unusually high compared to other departments. All hypertensive dyslipidemia patients received lipid-lowering medication, with a statin being the most frequently prescribed drug (82.8–95.4%) in all departments  compared to those who received combination therapy (32.4%) . The use of statins and the lack of attention to LDL-C or adopting small doses for fear of side effects may be the reasons for the low LDL-C achievement rate.Similarly, a recent study showed that cardiologists were more likely to prescribe combination antihypertensive therapy than endocrinologists . Thus fiAccording to the hypertension guidelines, the majority of patients need combination therapy to reach their BP goal. Early and aggressive combination treatment, particularly for patients with comorbidities, is an effective method to help patients achieve their goals, as the combination of different classes of antihypertensive drugs with various mechanisms of action produce synergistic BP lowering effects –23. In fP = 0.001), and the more the number of antihypertensive drugs, the lower the BP control rate. Possible explanations for this strange phenomenon could be poor treatment compliances with the increment of drug-tablets [In present study, a strange finding was that the monotherapy was associated with a higher BP control rate (36.2%) than combination therapies (32.4%)  may in part account for the low BP attainment rate in our study population, especially in patients receiving combination therapy. In China, it has been reported that 58.7% of hypertension patients were salt-sensitive, a percentage that may even be higher in diabetic and/or elderly patients. In these patients, it is difficult to control BP without a diuretic in their antihypertensive drug regimen, particularly in the north of China where salt intake is as high as 12–18 g/day . TherefoOur multivariate logistic regression analysis showed that obesity, diabetes, coronary heart disease, cerebrovascular disease and chronic kidney disease were independent risk factors associated with BP target attainment failure. The combined goal attainment rate for both BP and LDL-C was very low (22.9%) in our hypertensive dyslipidemia patients. For those with diabetes, CHD and/or CKD, the lower BP target (< 130/80 mmHg) in the 2010 Chinese Hypertension Guideline may partially account for the disappointing BP attainment rates. However, the BP target rate in patients with obesity or cerebrovascular disease were also very low, though these patients shared the same BP target value (SBP/DBP < 140/90 mmHg) as uncomplicated hypertensives. Moreover, the analysis of dyslipidemia management in DYSIS-China also revealed that diabetes was a strong predictor of failure in attaining LDL-C and non-HDL-C goals [Though in “Other Departments” the percentages of treated patients (55.9% for hypertension and 62.4% for lipid lowering drugs) was not the highest  and the treatment rate of statins in this patient population was as high as 89.7%. If DYSIS-China would have enrolled dyslipidemia subjects consecutively and not eliminated patients without previous antidyslipidemia treatment, the statins’ treatment rate would have certainly been much lower than 89.7%, and the combined BP and LDL-C targets attainment rates even worse than those in the present study.Although the prevalence of hypertension in Chinese dyslipidemia patients was high, a considerable proportion of patients failed to achieve the BP target, as well as both BP and LDL-C targets. An incomplete management system, improper monotherapy, inappropriate diuretic prescription and poor treatment compliance may account for the unsatisfactory goal attainment rates in Chinese patients with both hypertension and dyslipidemia. The data from our study clearly suggest that the establishment of a sound management system for the treatment of hypertension and dyslipidemia should become an important healthcare strategy in China.Additional file 1:Table S1. Distribution of study patients treated with antihypertensive and lipid lowering drug treatment in different departments. (DOC 45 kb)Additional file 2:Table S2. Blood pressure goal attainment rates of study patients based on different antihypertensive or lipid-lowering treatments in different departments. (DOC 49 kb)Additional file 3:Table S3. Both blood pressure and LDL-C goal attainment rates of study patients based on different antihypertensive or lipid-lowering treatments in different departments. (DOC 50 kb)


The invasive method for intracranial pressure measurement is ‘gold standard’ but not always feasible because the intraventricular catheter/ intraparenchymal micro transducer used in the measurement of intracranial pressure measurement may cause complications. Imaging modalities with clinical examination protocol have a lack of specificity and accuracy. The objective of the study was to compare the accuracy of diagnostic parameters of ultrasound measurements in patients with brain injury underwent invasive intracranial pressure measurement method.Data of invasive intracranial pressure measurement method and ultrasound measurements of 185 patients with brain injury who required admission diagnosis were included in the analysis. Pearson correlation was tested for diagnostic parameters. Logistical regression analysis was performed for diagnostic parameters of death patients to evaluate independent parameter of mortality.p < 0.0001 for all). Arterial blood pressure (p = 0.127) and middle cerebral artery pulsatility index (p = 0.06) were not correlated with intracranial pressure. A total of 47 patients died during the study period. Intracranial pressure (p = 0.015) and optic nerve sheath diameter (p = 0.035) were found to be independent predictor of mortality.Straight sinus flow velocities, middle cerebral artery flow velocities, and optic nerve sheath diameter were correlated with intracranial pressure (Ultrasound measurement especially optic nerve sheath diameter can be successfully used instead of invasive intracranial pressure measurement method in patients with brain injury.III. Intracranial hypertension is a deadly complication and one of the contributing factor in secondary brain injury because its intensity and duration are associated with a fatal outcome .Imaging modalities with clinical examination protocol have a lack of specificity  and insuThe use of an intraventricular catheter/ intraparenchymal micro transducer may cause complications like infection or hemorrhage . TherefoThe primary aim of the retrospective study was to compare the accuracy of diagnostic parameters of ultrasound measurements in patients with brain injury underwent invasive intracranial pressure measurement method. The secondary endpoint of the study was to evaluate independent diagnostic parameters for mortality of patients in a Chinese setting.Patients age 18 years or older with severe traumatic brain injury, intraparenchymal hemorrhage, aneurysmal subarachnoid hemorrhage, or stroke (decision of neurosurgeon) were included in the analysis. Among these patients, who required sedation, intracranial pressure monitoring or mechanical ventilation with an admission diagnosis were included in the analysis.Patients were excluded from the analysis who had optic nerve injuries, skull base fracture , an ocular pathology, inaccessible ultrasound windows, and no radiological or clinical susceptibility of cerebral venous vasospasm or thrombosis. Patients whose intracranial pressure mean values changed > 2 mmHg during ultrasound measurements and who had a history of glaucoma were not included in the analysis.Patients were put on propofol (a continuous infusion) and the muscle relaxant (atracurium) was given when necessary. Mechanical ventilation was adjusted to maintain normocapnia  and adequate oxygenation . The adequate cerebral perfusion pressure had been maintained ≥61 mmHg by norepinephrine, vasopressors, and normal saline . As per Intracranial pressure had been measured by intensive care physician (minimum 10-years of experience) of institutes using 1.3 mm Tunnelling intraparenchymal probe  or a catheter inserted into the ventricles of brain and was connected to an external drainage and pressure transducer and system . Admission Glasgow Coma Scale, demographical characteristics, comorbidities, severity and mechanism of brain injuries, and discharge Glasgow Outcome Scale were recorded for each patient .Ultrasound measurements had been performed by ultrasound equipment  by ultra-sonographers of the institutes . The mean values of five individual measurements were considered in the analysis. Venous transcranial Doppler measurements, optic nerve sheath diameter, and arterial transcranial doppler had been measured twice in a day from day 1–5 at 50–80 mm optic nerve blood pressure (as accessible ultrasound windows).d), mean (FVm), and systolic (FVs) middle cerebral artery flow velocities, FVd, FVm, and FVs straight sinus flow velocities were recorded by 2 MHz linear probes  on the straight sinus through an occipital and transforaminal bone window .Fig.Fig0 on 2 MHz linear probe  was used to measure arterial transcranial Doppler measurement in the same supine position of the patients. It was performed bilaterally on middle cerebral artery using temporal window .Events of mortality were collected from institutional records.InStat GraphPad Software, San Diego, IL, USA was used for statistical analysis. Pearson correlation was tested for diagnostic parameters. Logistical regression analysis was performed for diagnostic parameters among the data of death patients. Inter-rater reliability was evaluated by intraclass correlation coefficient , calculated by a two-way random effects model in Stata 12.1 software  . The resData of patients who required intracranial pressure monitoring or mechanical ventilation with an admission diagnosis from 12 February 2017 to 1 January 2019 of the Beijing Luhe Hospital, Affiliated to Capital Medical University, Beijing, China, and referring hospitals were reviewed. Among the available patients’ records, 15 patients had optic nerve injuries, 41 had skull base fracture, 13 had a known history of ocular pathology, 40 had inaccessible ultrasound windows, 11 had no radiological susceptibility of cerebral venous thrombosis, and 12 had no clinical susceptibility of cerebral thrombosis. Therefore, these data were excluded from the analysis. Also, 8 patients were on treatment that might affect cerebrospinal fluid pressure, so excluded from the analysis. Even, 15 patients had reported more than ±2 mmHg changes in mean values of intracranial pressure during ultrasound measurements. Therefore, these data were also excluded from the analysis. Data of invasive intracranial pressure measurement method and ultrasound measurements of 185 patients were included in the analysis. Flow chart of the study is presented in Fig. The minimum admission Glasgow Coma Scale of the enrolled patients was 4. The other demographical and clinical characteristics of enrolled patients are presented in Table p < 0.0001 for all). Arterial blood pressure (p = 0.127) and middle cerebral artery pulsatility index (p = 0.06) were not correlated with intracranial pressure  and optic nerve sheath diameter (p = 0.035) were found to be independent predictor of mortality  and no association between intracranial pressure and neuropsychological outcome during follow-up period among survivors. The results of the study were consistent with prospective cohort studies [In the study, all the enrolled patients required admission diagnosis and subjected to measure intracranial pressure. Also, elevated intracranial pressure was found a significant parameter of death p = 0.05 and no  studies . The pat studies . IntracrStraight sinus flow velocities and middle cerebral artery flow velocities had a correlation with intracranial pressure, those were measured invasively but failed to predict mortality. The results of the study were consistent with the clinical study , 17 and p = 0.035) as well as had correlation (p < 0.0001) with intracranial pressure, those were measured invasively. The results of the study were consistent with prospective observational studies [Optic nerve sheath diameter was found an individual parameter of death p = 0.03 as well  studies , 9, 18 a studies . The opt studies . If cerep = 0.06) with intracranial pressure and was not independent parameter of death (p = 0.095). The results of the study were consistent with the clinical studies [Middle cerebral artery pulsatility index had no correlation ( p = 0.09. The res studies  but not  studies . The pos studies  while in studies . Even, i studies  and it iDuring the study, besides the invasive intracranial pressure measurement method, optic nerve sheath diameter and arterial and venous transcranial Doppler measurements were performed for all patients who required measurements of intracranial pressure. Invasive intracranial pressure measurement devices are ‘gold standard’ modalities  but due Several limitations of the study have reported for examples, different types of brain injury patients were enrolled. Type of brain injury also has an effect on mortality. Effects of type of brain injury on mortality is not evaluated in multivariate analysis. There is a need for specialized training for image analysis of ultrasound. The threshold values for intracranial pressure and optic nerve sheath diameter are not well-defined for brain injuries . Unlike Non-invasively measured straight sinus flow velocities, middle cerebral artery flow velocities, and optic nerve sheath diameter were correlated with invasively measured intracranial pressure. Optic nerve sheath diameter and intracranial pressure were independent parameters for mortality. Ultrasound measurement can be successfully used instead of invasive intracranial pressure measurement method in patients with brain injury. The large human trial is recommended to validate non-invasive techniques.


The long-term management of patients with resistant hypertension has been made even more difficult by a “moving target” goal blood pressure (BP). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines defined resistant hypertension as the failure to achieve goal BP in patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic. The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) guidelines laid out more lenient target BP goals, without addressing the definition of resistant hypertension directly. The present scenario is a state of confusion, with providers selectively adopting recommendations from different guidelines. The Systolic Blood Pressure Intervention Trial (SPRINT) trial contributed to the confusion with further evidence supporting the strict control of hypertension. In addition, the failure of another trial on renal denervation in the US has essentially put an end to six long years of experimentation with catheter ablation in patients with resistant hypertension. Other therapies are still experimental. Adding a new dimension of medical management, spironolactone has made a comeback in resistant hypertension, with reports of better responsiveness when added to existing anti-hypertensive therapy. The present review discusses the current state and management options for patients with resistant hypertension considering the new evidence. Newer advances in pharmacological and device therapy are also discussed to improve understanding and quality in the management of resistant hypertension. Resistant hypertension has been historically defined as a blood pressure (BP) measurement that exceeds 140/90 millimeters of mercury (mmHg)  despite the regular use of three or more antihypertensive drugs of different classes that should include one diuretic at the maximum (or maximum tolerated) dose unchanged for at least one month without interruption as per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines .The latest definition according to the 2017 AHA/American College of Cardiology (ACC) taskforce emphasizes strict control with a target BP <130/80 mmHg and has defined resistant hypertension as uncontrolled BP ≥130/80 mm Hg while on optimal doses of at least three antihypertensives with one being a diuretic. Office blood pressures have been defined as BP <130/80 mmHg with the patient requiring more than four anti-hypertensive medications .Prevalence and prognosisReliable estimates of the prevalence of resistant hypertension are not available. However, estimates based on large clinical trials suggest a recent prevalence of 13% unlike the previously reported rate of 20%-30% amongst all hypertensive patients under treatment -10. WithResistant hypertension may be caused by the identified factors, as seen in Table Pseudo-resistant hypertensionPseudo-resistant hypertension is a condition where the patient does not have resistant hypertension but will present with uncontrolled BP despite undergoing the appropriate treatment. The following factors may result in this condition -16 as seEvaluation and managementPhysicians will be able to effectively manage resistant hypertension using the following step-by-step principles and management.1. Physicians must have knowledge of and adhere to the most recent guidelines of resistant hypertension management .2. They must identify and reverse the causes of pseudo-resistance ,3.3. They must identify and reverse the causes of true resistance: a) Have prior knowledge that pharmacological agents like non-steroidal anti-inflammatory drugs (NSAIDS) increase BP and, therefore, discontinue or minimize their use ,3. b) Evaluate the amount of alcohol intake in the patient and try to discontinue the intake ,3. c) Decrease salt intake to less than 2-3 grams (gm) per day ,3. d) Assess the degree of abdominal obesity and increase daily physical activity to 40 minutes per day for a minimum of three to four days/week ,3. e) Evaluate renal function and modify treatment if necessary ,3. f) Identify and manage any potential causes of secondary hypertension ,3. 4. Use combinations of anti-hypertensive drugs for the definitive management of the condition ,3.Non-pharmacological approachSimilar to many conditions, resistant hypertension can be managed with a non-pharmacological approach. This may require certain lifestyle changes done by the patient and an understanding of factors that can worsen the condition.1. Daily alcohol intake should be restricted to 1 oz in men and 0.5 oz in women or individuals of lower weight classification .2. Excessive dietary intake of salt is seen in many patients with resistant hypertension, which leads to an expanded plasma volume as identified in 90% of patients. Taking less than 3 gm/day of salt is associated with the modest reduction in BP largely seen in African Americans and elderly patients ,3.3. Discontinue NSAIDS, as they lead to reduced renal prostaglandin production followed by sodium and water retention. They increase BP by 5 mmHg. Stop anabolic steroids, glucocorticoids, nasal decongestants, and amphetamine-like stimulants ,3.4. Identify kidney disease if present, both parenchymal and vascular, in order to select proper antihypertensives, particularly diuretics ,3.5. Obese patients have insulin resistance and are associated with increased sympathetic activity and obstructive sleep apnea, all of which contribute to resistant hypertension. Weight loss and a reduced-calorie diet are associated with a modest BP reduction in obese hypertensive patients ,3.6. Age greater than 65 years is associated with a higher prevalence of resistant hypertension ,3.Pharmacological approachResistant hypertension patients may require pharmacological treatment for the effective management of their condition. The following approach is recommended.1. The present rationale in the treatment of resistant hypertension is to ensure that all possible mechanisms responsible for BP elevations are blocked at all levels .2. Suboptimal dosing regimens or inappropriate antihypertensive drug combinations are the most common causes of resistant hypertension. They should be targeted and modified with three or more antihypertensive drugs used ,3.3. In resistant hypertension patients, volume expansion is the most frequently seen pathologic finding. In more than 60% of patients, altering the diuretic therapy either by changing the drug, the dose, or the drug class reduced the prevalence of this finding. It has been shown that switching from the same dose of hydrochlorothiazide to chlorthalidone was associated with an additional drop of 8 mmHg in systolic BP, which leads to more patients achieving their goal BP ,3.4. The currently recommended combination of medication is a renin-angiotensin-aldosterone system (RAAS) blocker with a calcium channel blocker (CCB) and a diuretic ,3.5. If the BP goal is still not achieved, beta-blockers should be chosen if the pulse rate is more than 60 beats per minute ,3.6. Peripheral alpha-blockers are well-tolerated and can be used if beta-blockers do not have alpha-blocking activity. Combining angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) has been shown to be less effective in BP reduction. Thus, the drug combination of ACE inhibitors and ARBs are not recommended for resistant hypertension ,3.7. Studies suggested that using spironolactone or eplerenone with the existing three-drug treatment in resistant hypertension patients who are obese or have sleep apnea syndrome provides significant BP reduction as seen in Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which showed a BP drop of 21.9/9.5 mmHg that was not affected by age, sex, smoking, and diabetic status . The Pre8. If the goal BP is still not achieved with a combination of four drugs then the use of other agents, such as centrally acting alpha agonists (methyldopa/clonidine) or vasodilators  will be needed ,3.9. Endothelin receptors antagonists are not currently recommended. However, darusentan, a selective endothelin receptor antagonist (ERA) demonstrated a dose-dependent decrease in the BP of resistant hypertension patients ,3.2017 ACC/AHA task force guidelines for resistant hypertensionThere are seven steps for the management of resistant hypertension according to the 2017 AHA/ACC. The steps range from the confirmation of the diagnosis to definitive treatment.1. The resistance needs to be confirmed with measured systolic blood pressure (SBP) ≥130 mmHg and diastolic blood pressure (DBP) ≥80 mmHg along with the patient being on three different antihypertensive drugs at their optimal dose (including one diuretic). An alternative would be a confirmed systolic blood pressure (SBP)/diastolic blood pressure (DBP) <130/80 mmHg and a patient taking more than four antihypertensive medications [2. Pseudo resistance in patients needs to be excluded by double-checking the patients' BP. This would be done during the patient’s outpatient visit. In order to rule out white coat hypertension, BP readings could be done at the patient’s home and work as well. The patient should also be evaluated for nonadherence to antihypertensive medication therapy .3. Identify and reverse lifestyle factors that contribute to resistant hypertension [4. The physician will need to stop or lessen the patient’s use of interfering substances (that contribute to resistant hypertension). These will include NSAIDs, sympathomimetic drugs, stimulants, oral contraceptives, licorice, and ephedra .5. Screen the patient for secondary causes of hypertension. Potential causes would include primary aldosteronism, chronic kidney disease, renal artery stenosis, pheochromocytoma, and obstructive sleep apnea .6. Start pharmacological therapy. The patient is placed on optimized diuretic therapy, mineralocorticoid receptor antagonist, loop diuretics (if he or she has chronic kidney disease and/or is on vasodilators), and other medications with different mechanisms of action .7. Refer the patient to a specialist if the patient’s goal BP has still not been achieved even after six months of consistent therapy. Another reason would be to treat or find a potential cause of secondary hypertension .JNC 8 guidelines over JNC 7 guidelines for patients with resistant hypertensionStudies have demonstrated the failure to achieve target blood pressure in most hypertension patients based on the more stringent JNC 7 guidelines, especially among patients with diabetes and chronic kidney disease. JNC 7 can be envisioned as a set of more idealistic expert recommendations whereas JNC 8 has guidelines based on evidence and the practicality of hypertension management. JNC 8 came in 2014 with lots of controversial issues, as it was a big change from the JNC 7 guidelines. The following changes were seen.1. JNC 8 raised the target BP to 140/90 in all patients, irrespective of the presence of diabetes mellitus and chronic kidney disease [2.  Diuretics were not the first drug of choice in non-resistant hypertension, but they are a definite part of the treatment regimen for resistant hypertension ,4.3. Chlorthalidone or indapamide are considered superior therapies over hydrochlorothiazide due to better evidence of benefit ,4. 4. African Americans have a high risk for strokes. Calcium channel blockers (CCBs) have better risk and blood pressure reduction in African Americans vs ACE inhibitors ,4.5. Thiazides produce better cardiovascular outcomes (including reduced stroke risk) than ACE inhibitors in African Americans who are “salt-sensitive” ,4.6. With the JNC 8 guidelines, patients older than 60 years had target blood pressures of 150/90, making it more lenient for the elderly patients .American society for hypertension guidelines for resistant hypertensionThe American Society for Hypertension (ASH) guidelines for patients with resistant hypertension have different but validated guidelines for antihypertensives.1. Patients <80 years of age should start pharmacotherapy at 140/90 mmHg and patients /90 mmHg .2. As advised by JNC 8, patients with diabetes or chronic kidney disease should have a target blood pressure of <140/90 mmHg .3. For patients 18-55 years of age, it was advised to consider lower BP target , per prescriber discretion, if treatment is tolerated. However, evidence of additional benefit with a lower BP target versus BP goal of <140/90 mmHg is lacking .4. It was recommended to blood pressure <130/80 mm Hg in patients with chronic kidney disease with albuminuria .Systolic blood pressure intervention trial studyThe Systolic Blood Pressure Intervention Trial (SPRINT) study examined the effects of more intensive antihypertensive therapy than currently recommended in United States adults of age over 50 years who have hypertension and the additional risk for cardiovascular disease . After tRole of interventions in the treatment of resistant hypertensionDevice TherapyRecently, a novel implantable device  has been developed, which works by electrical stimulation of the carotid sinus. The device enhances afferent nerve traffic from the baroreceptors to the cardiovascular control centers in the brain that reduce the sympathetic outflow and BP. The device consists of a pulse generator and a two-lead system, which are tunneled subcutaneously to each carotid sinus. This is then used as either a unilateral or a bilateral stimulation system. This device provides baroreflex activation based on an algorithm or response of the patient.In one of the earliest large scale trials, the Rheos Pivotal Trial, there was a mean reduction of 35 mmHg in SBP seen 12 months after baroreflex activation therapy (BAT) . AdditioIn one study by Scheffers et al., 45 patients with BP more than 160/90 despite three antihypertensive drugs were enrolled and subjected to Rheos Therapy and followed up for a period of two years . After tRenal Artery Angioplasty/Stenting in Patients with Renal Artery StenosisMost cases of renal artery stenosis are asymptomatic. Deterioration in renal function may develop if both kidneys are poorly supplied or when treatment with ACE inhibitors is initiated. Some patients present with episodes of flash pulmonary edema.Atherosclerotic Renal Artery StenosisThis is initially treated with optimal medical management, including statins, antiplatelet agents, and drugs for the control of blood pressure. When high-grade renal artery stenosis is demonstrated by renal angiography and blood pressure cannot be controlled with medications, or if renal function deteriorates, invasive procedures (angioplasty with or without stenting) can be considered. A 2003 meta-analysis found that angioplasty was safe and effective; however, randomized, controlled trials have not shown any clinical benefit to improve blood pressure or renal function .Fibromuscular DysplasiaAngioplasty with or without stenting is the best treatment of renal artery stenosis due to fibromuscular dysplasia. Sympathetic Denervation by Radio Frequency AblationSympathetic overactivity is thought to be a major contributor to the pathogenesis and progression of hypertension ,21. RenaRenal sympathetic nerves contribute to the development and perpetuation of hypertension, and sympathetic outflow to the kidneys is activated in patients with hypertension. Efferent sympathetic outflow stimulates renin release, increases tubular sodium reabsorption, and reduces renal blood flow. Afferent signals from the kidneys modulate central sympathetic outflow and thereby directly contribute to neurogenic hypertension.Catheter technology utilizing radiofrequency energy enables selective denervation of the kidney inside the wall of renal arteries . The firDue to the occasional inadequacy of medical treatment for resistant hypertension, more non-drug treatments like radiofrequency ablation have been created. As a result, a few trials have been conducted to demonstrate the utility of radiofrequency ablation in resistant hypertension patients. One of the earliest studies done was a study by Krum and Schlaich using radiofrequency ablation in 50 patients . In thisIn the Simplicity-2 trial, Murray de Esler conducted a study using 106 patients. Patients were randomly assigned to undergo renal denervation . The femImpressed with the results of both Simplicity-1 and Simplicity-2, a prospective, single-blind, randomized, sham-controlled trial called Simplicity-3 was created . A totalSurgical TreatmentNon-selective surgical sympathectomy was effectively used as a treatment of severe hypertension before antihypertensive drugs became easily available -34. AddiBoth JNC 8 and ASH have recommended target goals that are evidence-based, practical, and achievable, despite some variations in guidelines between the two. Although the number of patients who cannot achieve BP goals on multiple drug combinations according to guidelines is growing, resistant hypertension can and should be stringently treated with appropriate and maximum drug therapy after excluding the factors associated with pseudo-resistant hypertension. Unfortunately, so far, there has been no proven benefit of device therapy and radiofrequency ablation techniques in the major trials, and further studies are required in these areas. Although guidelines and recommendations are adequate to meet the requirements of most patients, these are not a substitute for clinical judgment. A multidisciplinary, patient-centered approach is the optimal solution for adequate blood pressure control in the present world.


Several studies examining the association and discriminative ability of adiposity measures for prehypertension and hypertension among adolescents have reported varying outcomes. We aimed to determine the discriminative ability of the Body Mass index (BMI), Waist Circumference (WC), and Waist-to-Height Ratio (WHtR) adiposity measures for elevated blood pressure (prehypertension and hypertension combined) among adolescents in Gombe, northeast Nigeria.This cross-sectional study used a multi-stage sampling technique and involved 367 secondary school adolescent (10–18 years) boys and girls in Gombe Local Government Area, Gombe State, northeast Nigeria from January to September 2015. We examined and compared the associations and discriminative ability of the BMI, WC and the WHtR for elevated blood pressure using multiple logistic regression and receiver operating characteristics (ROC) curves. Area under the curves (AUC), odds ratio (OR) and 95% confidence intervals (CI) are reported.All three measures of adiposity were strongly and positively associated with elevated blood pressure. The BMI obesity showed the strongest association with elevated blood pressure with odds that was double the odds of WC and triple that of WHtR . The discriminative ability of adiposity measures for elevated blood pressure using AUC was comparable .We provide evidence, here on the BMI, WC and WHtR to support the use of simple indirect measures of adiposity in evaluating adiposity-related risk including prehypertension and hypertension among Nigerian adolescents.The online version of this article (10.1186/s40608-018-0211-7) contains supplementary material, which is available to authorized users. Childhood overweight and obesity currently pose major public health challenges, with associated increase in adiposity-related health risk including hypertension . AlthougEmpirical evidence from longitudinal studies shows that a significant proportion of primary hypertension is associated with the epidemic of overweight and obesity, even in the adolescent age group , 6. For Epidemiological studies evaluating the relationship between excess adiposity and the development of hypertension in adolescents have traditionally used the measures of general, or truncal adiposity. However, the BMI, a measure of general adiposity is considered not discriminatory of the distribution of body fat in the abdominal region, which is now considered the critical factor in the development of obesity-related hypertension , 9. MeasSeveral empirical studies –15 whichThere is limited literature on the relationship between obesity that is determined by the WHtR and risk of elevated blood pressure in Nigerian children and adolescents. The WHtR, is a measure of truncal adiposity that is relatively easy to obtain, does not require the use of reference tables to determine categories (unlike the WC or BMI), and uses a single cut-off value of 0.5 to define obesity in both adults and children –23. Our We conducted a cross-sectional analytical study involving apparently healthy secondary school adolescents in Gombe Local Government Area (LGA) of Gombe State between January 2015 and September 2015. Gombe State which is mainly populated by the Fulani, Hausa, Bolewa, Waja, Tera and Tangale ethnic groups is located in the northeast of Nigeria and shares borders with Yobe, Borno, Adamawa, Bauchi, and Taraba States .Gombe LGA which also includes Gombe town, the capital of the State is the largest among 11 other LGAs and has a population of 302,674 with children aged 18 years and below being approximately 50% of the population .Among study participants, five ethnic groups accounted for more than 70% of study participants: Fulani 90 (24.5%), Hausa 75 (20.4%), Tangale 61 (16.6%), Waja 20 (5.5%), and Yoruba 15 (4.1%). However, there were 25 ethnic nationalities among the study participants  was used and the participants were selected using a systematic sampling technique. The sampling interval was determined by dividing the total number of students in each grade by the number of participants selected from that grade. A number was randomly selected from a list of random numbers and was considered the initial point for sampling. Participants who did not fit the inclusion criteria were omitted and the next student on the list was subsequently selected.Secondary school adolescents aged 10–18 years from the selected schools whose parents/guardians had consented to their participation in the study and who themselves have assented to the study were included. Participants excluded from the study include; those with any form of chronic disease based on participant volunteered information, available school records, or evidence from physical examination. Other exclusion criteria were presence of haematuria and glucosuria on urinalysis, participants who actively consumed alcohol or cigarette within the past 3 months to the date of the study and participants who were on any mediction known to affect blood pressure such as steroids, and diuretics.Pre-tested questionnaires . Height was measured to the nearest 0.1 cm using a potable, collapsible stadiometer (Seca® Leicester portable height measure). Waist circumference were measured according to standard procedures with a non-stretch tape rule (Seca® 2011) placed horizontally, once, midway between the lower border of the 10th rib and the top of the iliac crest, at normal expiration .Blood pressure measurements were done per the recommendations of the 4th report criteria of the National High Blood Pressure Education Programme . Measure2.BMI was derived from the formula: BMI = weight (kg)/height (m)WHtR was derived using the formula: WHtR = waist circumference (cm)/height (cm) .Prehypertension was any blood pressure ≥90th percentile but < the 95th percentile or any blood pressure >120/180 mmHg [Hypertension was any blood pressure ≥95th percentile [Elevated blood pressure was any blood pressure ≥90th percentile  .Adult cut-off values of blood pressure ≥140/90 mmHg for hypertension, systolic blod pressure = 120–139 mmHg, and diastolic blood pressure = 80–89 mmHg for prehypertension, were used for participants, 18 years old .WC ≥ 75th percentile but <90th percentile .BMI ≥ 85th percentile but <97th percentile .Overweight was defined as:WC ≥90th percentile .BMI ≥97th percentile .WHtR ≥0.5 .Obesity was defined as:All data generated were processed and analysed using the IBM Corp SPSS statistics for windows version 24.0 . To determine which measures of adiposity (the independent variables) was strongly associated with or discriminative of elevated blood pressure (the dependent variable), multiple logistic regression models were fitted. The regression models were adjusted for known confounders of blood pressure in children such as age, gender, height, parental socioeconomic status and school type of participants.The adjusted odds ratio (AOR), and 95% CI  were subsequently reported and compared to the odds using other measures of adiposity.Receiver operating characteristics (ROC) curves and associated area under the curves (AUCs) were generated for all three measures of adiposity to further estimate the discriminatory ability for elevated blood pressure. Furthermore, the overall discriminatory ability for elevated blood pressure was determined by combining all three measures of adiposity.The AUC is a measure of overall discriminatory ability of each adiposity measure, with a value of 0.5 representing no discriminative ability and 1.0 representing perfect discrimination of elevated blood pressure. The AUCs were compared using a non-parametric approach for comparison of multiple AUCs from ROC curves .p = 0.780).A total of 377 adolescents were recruited to participate in this study. Of these, 370 participants who fulfilled the study criteria eventually completed the study. Data for 367 participants were analysed, because three participants were excluded due to incomplete or missing data at the time of data analysis. There were 191 (52%) boys and 176 (48%) girls, making a boys to girls ratio of 1.1:1, with the mean age of study participants being 14.9 ± 1.9 years. There was no significant difference in the mean age of boys and girls , the use of WC and WHtR may however also be sufficient in clinical settings for determining associated elevated blood pressure. The WHtR as a measure of truncal adiposity for example is an easy to use , non-invAlthough the WHtR is easy to use in clinical and population settings, does not require complex calculations and reference to age, gender, and race-specific tables, data on WHtR is still limited in Nigerian adolescents . FurtherThere are limitations to our study. Firstly, due to the cross-sectional nature of our study, causal and temporal inferences between the measures of adiposity and elevated blood pressure may not be made for the associations reported. However, the largely causal relationship between excess adiposity and elevated blood pressure is well-established , 45, andWe provide evidence, here on the BMI, WC and WHtR to support the use of simple measures of adiposity in evaluating adiposity-related risk among Nigerian adolescents. The BMI, a measure of general adiposity showed the strongest association or discriminatory ability for the presence of elevated blood pressure compared to the measures of truncal adiposity. Although the WC and WHtR showed lesser discriminatory ability for elevated blood pressure, they may still have important clinical implication for risk-stratification in adolescent population in resource limited settings where determination of more complex adiposity measures like the BMI may not be feasible.Additional file 1:Study questionnaire developed specifically for use in this study. (DOCX 16 kb)


The performance of various equations for estimated glomerular filtration rate (eGFR) in patients with diabetes remains controversial. We aimed to evaluate the performance of equations for eGFR in Chinese patients with diabetic nephropathy (DN). CKD-EPI-Cr), cystatin C (eGFRCKD-EPI-CysC), and joint equations (eGFRCKD-EPI-Cr-CysC), respectively. End-stage kidney disease was defined by initiation of renal replacement therapy. The eGFR concordance between equations was assessed by Bland-Altman plots. Log-rank and multivariable logistic regression were employed to evaluate the performance of equations.  This is a retrospective study included in 308 patients with type 2 diabetes and biopsy-proven DN who were followed up at least one year. eGFR was calculated using chronic kidney disease epidemiology (CKD-EPI) equations based on serum creatinine  from CKD 1-2 stages to CKD 3-5 stages by eGFRCKD-EPI-CysC and they presented significantly longer diabetic duration, heavier proteinuria, advanced pathological lesions, and poorer kidney outcomes. Multivariable logistic regression indicated cystatin C was independently associated with advanced glomerular classifications.  Overall, the proportion of patients with eGFR < 60 mL/min/1.73m eGFR equations incorporating cystatin C are superior to eGFR based on creatinine alone for detecting kidney injury in the early stage. The independent association between cystatin C and glomerular classifications might contribute to it. The past few decades have witnessed a marked increasing prevalence of type 2 diabetes, especially in China, and the global prevalence of microvascular and macrovascular complications associated with diabetes increases dramatically , 2. DiabCKD-EPI-Cr) instead of the Modification of Diet in Renal Disease equation. They also suggest use of the 2012 CKD-EPI equations  to confirm kidney function when cystatin C has been measured, particularly for patients with eGFRCr of 45–59 mL/min/1.73 m2 who do not have markers of kidney damage. However, the performance of various equations in CKD cohorts remains controversial due to serum creatinine is influenced by age, muscle mass, sex, and race; cystatin C level is affected by ages, body mass index, diabetes, and inflammation. Patients with DN are recognized as a special community in CKD. Also, the implications and predictive potential of different equations in patients with DN have yet to be elucidated. The objective of the study was to compare the performance for detecting kidney injury of equations of eGFRCKD-EPI-Cr, eGFRCKD-EPI-CysC, and eGFRCKD-EPI-Cr-CysC in patients with DN in a single center in Southwest China.The Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of CKD  recommenThis is a retrospective cohort study. From November 2003 to March 2018, a total of 308 Chinese patients with type 2 diabetes mellitus (T2DM) and biopsy-proven DN in West China Hospital of Sichuan University were recruited and followed up for at least one year by routine clinical visits. Patients with T2DM and proteinuria > 0.5 g/24 h or eGFR decline were indicated to receive kidney biopsy in our hospital. The diagnoses of T2DM and DN were based upon the criteria recommended by the American Diabetes Association (ADA) in 2018 . The ESKThe protocol of study was approved by the ethics committee of West China Hospital of Sichuan University and conducted based on the principles of the Declaration of Helsinki; written informed consents were obtained at the time of biopsy from all the patients.Diabetic history, data including physical examinations  and laboratory tests , were collected at the time of kidney biopsy from the hospital information system. Creatinine was measured using Jaffe's assay. Serum creatinine value was calibrated to isotope dilution mass spectrometry (IDMS). Serum cystatin C was measured using an automated particle-enhanced immunoturbidimetric method. Blood samples were collected after 12 hours of fasting in all the patients . PatholoCKD-EPI-Cr, eGFRCKD-EPI-CysC, and eGFRCKD-EPI-Cr-CysC, respectively. The CKD stages 1, 2, 3a, 3b, 4, and 5 were categorized by eGFR  , higher level of cystatin C , lower free triiodothyronine 3 , advanced glomerular classifications (P < 0.001), IFTA scores (P < 0.001), and interstitial inflammation (P < 0.001). In addition, during the follow-up, 11 (12.5%) patients reached the end point in the not reclassified group, while 21 (36.8%) patients reached the end point in the reclassified group; the kidney survival was significantly poorer by the log-rank test in the reclassified group  and cystatin C  were independently associated with advanced glomerular lesions. Serum creatinine  was not independently associated with advanced glomerular lesions. However, total cholesterol  and serum creatinine  were independently associated with advanced tubular and interstitial injury.We then investigated the association between serum creatinine and cystatin C and pathological lesions. For glomerular classification, we defined class of III and IV as advanced lesion, and for tubular and interstitial lesions, we defined scores of 2 and 3 of IFTA as advanced lesions. We adjusted essential clinical variables including gender, age, blood pressure, diabetic duration, triglyceride, total cholesterol, and proteinuria for multivariable logistic regression. As shown in CKD-EPI-Cr) were reclassified into advanced CKD stages (by eGFRCKD-EPI-CysC) and they had longer diabetic duration, heavier proteinuria, advanced pathological lesions, and poorer prognosis. In addition, cystatin C, not creatinine, was independently associated with more severe glomerular classifications. Those findings suggest that equations incorporate cystatin C would improve the performance of detect glomerular lesions in the early stage in patients with DN.Despite decades of research and heavy public health burden associated with DN, few new biomarkers have been applied to clinical practice in recent years . AlbuminBoth serum creatinine and cystatin C are endogenous molecules. Serum creatinine is unstable and easily influenced by daily diet , secretiCr and eGFRCysC, respectively. And patients with diabetes were more likely to be reclassified from preserved kidney function calculated by eGFRCr to reduced kidney function calculated by eGFRCysC [MDRD and eGFRCKD-EPI-Cr equations underestimated measured GFR (>90 mL/min/1.73 m2) [CKD-EPI-Cr while 70% of which using eGFRCKD-EPI-CysC. Interestingly, patients who were reclassified by eGFRCKD-EPI-CysC have significantly heavier proteinuria, advanced pathological lesions, and faster progression of kidney disease than not reclassified patients, which suggested that eGFRCKD-EPI-CysC was more sensitive to detect kidney injury and predict kidney outcomes.In the U.S. population of noninstitutionalized civilian, the prevalence of reduced kidney function was 6.5% when estimated using equations based on creatinine, compared with 8.7% when incorporated with cystatin C . SimilareGFRCysC . However1.73 m2) . Moreove1.73 m2) . In the CysC failed to improve the area under the curve for the diagnosis of reduced kidney function in patients with diabetes [2) and older (>55 years old). Higher BMI is associated with increased fat mass which is a primary determinant of cystatin C generation [2) on the performance of eGFRCysC is limited. Third, we aimed to explore the performance of equations to detect kidney injury, not the accuracy in estimating measured GFR.However, several studies questioned the improved performance of equations based on cystatin C. A latest study with 882 patients reported the misclassification was approximately 50% for creatinine-based equations and still 35% for cystatin C-based equations, and equations combined creatinine and cystatin C were not outperform equation only based on cystatin C . In addidiabetes . In the diabetes , 27. Secneration . And theneration . In the CysC is more sensitive to detect kidney injury in the early stage. Therefore, eGFRCysC should be considered, rather than eGFRCr alone, for clinical decision-making, especially when eGFRCr > 60 mL/min/1.73 m2.These findings suggest that eGFRThere are several limitations of the current study that should be discussed. First, the sample size was limited due to that we only enrolled patients with biopsy-proven DN. Second, all the patients were ethnic Han in Southwest China; the performance of equations may be influenced by multiethnic setting such as muscle mass and meat intake. The results should be verified in more ethnic cohorts. Third, it was a retrospective cohort study; we did not have data of measured GFR to evaluate accuracy of different equations. Fourth, creatinine and cystatin C could be fluctuated; repeated measurements should be applied.eGFR equations incorporating cystatin C is superior to eGFR based on creatine alone for detecting kidney injury in the early stage. The independent association between cystatin C and glomerular classifications might contribute to it.