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Current guidelines recommend adrenal venous sampling (AVS) to identify unilateral primary aldosteronism (UPA) before offering adrenalectomy. However, AVS is costly and technically challenging, limiting its use to expert centres.To establish a model to predict UPA, and therefore, bypass the need for AVS prior to surgery.The model was developed in a Chinese cohort and validated in an Australian cohort. Previously published prediction models of UPA were also tested.primary aldosteronism patients with a definite subtyping diagnosis based on AVS and/or surgery.Diagnostic value of the model.In the development cohort (268 UPA and 88 bilateral primary aldosteronism), combinations of different levels of low serum potassium (≤3.0 or 3.5 mmol/l), high PAC (≥15-30 ng/dl), low PRC (≤2.5-10 μIU/ml) and presence of unilateral nodule on adrenal CT (8-15 mm in diameter) showed specificity of 1.00 and sensitivity of 0.16-0.52. The model of serum potassium 3.5 mmol/l or less, PAC at least 20 ng/dl, PRC 5 μIU/ml or less plus a unilateral nodule at least 10 mm had the highest sensitivity of 0.52 (0.45-0.58) and specificity of 1.00 (0.96-1.00). In the validation cohort (84 UPA and 117 bilateral primary aldosteronism), the sensitivity and specificity of the model were 0.13 (0.07-0.22) and 1.00 (0.97-1.00), respectively. Ten previous models were tested, and only one had a specificity of 1.00 in our cohorts but with a very low sensitivity [0.07 (0.04-0.10) and 0.01 (0.00-0.06) in our development and validation cohorts, respectively].A combination of high PAC, low PRC, low serum potassium and unilateral adrenal nodule could accurately determine primary aldosteronism subtype in 13-52% of patients with UPA and obviate the need for AVS before surgery.

BackgroundsEctopic fat deposition is closely related to chronic kidney disease (CKD). Currently, there are few population studies that have been conducted to determine the relationship between renal parenchyma fat deposition and the risk of CKD among patients with type 2 diabetes mellitus (T2DM). Therefore, we employed magnetic resonance imaging (MRI) to detect renal parenchyma fat content in individuals with T2DM, expressed as renal fat fraction (FF), to explore whether renal FF is an important risk factor for CKD in patients with T2DM.MethodsIn this cross-sectional study, 189 subjects with T2DM were enrolled. CKD was defined as the estimated glomerular filtration rate (eGFR)2. Measurement of the renal FF was performed on a 3.0-T MRI (MAGNETOM Skyra, Siemens, Erlangen, Germany). Binary logistic regression was used to determine the association between tertiles of renal FF and risk of CKD. Receiver-operator characteristic (ROC) curves were constructed to evaluate the sensitivity and specificity of renal FF in detecting CKD in T2DM patients.ResultsThe patients were divided into three groups according to tertiles of the renal FF level (2.498 - 7.434). As renal FF increases, patients tend to be older, and more abdominally obese, with a decreased eGFR (pConclusionsThe renal FF is significantly independently associated with CKD in patients with T2DM.

With the widespread use of advanced imaging technology, adrenal tumors are increasingly being identified.To investigate the prevalence and characteristics of adrenal tumors in an unselected screening population in China.Cross-sectional study. (ClinicalTrials.gov: NCT04682938).A health examination center in China.Adults having an annual checkup were invited to be screened for adrenal tumors by adrenal computed tomography.The participants with adrenal tumors had further evaluation for malignancy risk and adrenal function.A total of 25 356 participants were screened, 351 of whom were found to have adrenal tumors, for a prevalence of 1.4%. The prevalence increased with age, from 0.2% in participants aged 18 to 25 years to 3.2% in those older than 65 years. Among 351 participants with adrenal tumors, 337 were diagnosed with an adrenocortical adenoma, 14 with another benign nodule, and none with a malignant mass. In 212 participants with an adenoma who completed endocrine testing, 69.3% were diagnosed with a nonfunctioning adenoma, 18.9% with cortisol autonomy, 11.8% with primary aldosteronism, and none with pheochromocytoma. Proportions of nonfunctioning adenomas were similarly high in various age groups (72.2%, 67.8%, and 72.2% in those aged46, 46 to 65, and ≥66 years, respectively).Only 212 of 337 participants with an adrenocortical adenoma had endocrine testing.The prevalence of adrenal tumors in the general adult screening population is 1.4%, and most of these tumors are nonfunctioning regardless of patient age. Cortisol and aldosterone secretion are the main causes of functional adenomas.National Key Research and Development Program of China and National Natural Science Foundation of China.

Objective The saline suppression test (SST) and captopril challenge test (CCT) are commonly used confirmatory tests for primary aldosteronism (PA). Seated SST (SSST) has been reported to be superior to recumbent SST. Whether SSST is better than CCT remains unclear. We aimed to compare the diagnostic accuracy of SSST and CCT in a prospective study. Methods Hypertensive patients at a high risk of PA were consecutively included. Patients with an aldosterone-renin ratio of ≥1.0 ng/dL/μIU/mL were asked to complete SSST, CCT, and the fludrocortisone suppression test (FST). Using FST as a reference standard (plasma aldosterone concentration [PAC] post FST ≥ 6.0 ng/dL), area under the receiver-operating characteristic curve (AUC), sensitivity, and specificity of SSST and CCT were calculated, and multiple regression analyses were performed to identify potential factors leading to false diagnosis. Results A total of 196 patients diagnosed with PA and 73 with essential hypertension completed the study. Using PAC post SSST and PAC post CCT to confirm PA, SSST and CCT had comparable AUCs (AUCSSST 0.87 [95% CI 0.82-0.91] vs AUCCCT 0.88 [0.83-0.95], P = .646). When PAC post SSST and post CCT were set at 8.5 and 11 ng/dL, respectively, the sensitivity and specificity of SSST (0.72 [0.65, 0.78] and 0.86 [0.76, 0.93]) and CCT (0.73 [0.67, 0.80] and 0.85 [0.75, 0.92]) were not significantly different. In the multiple regression analyses, 1-SD increment of sodium intake resulted in a 40% lower risk of false diagnosis with SSST. Conclusion SSST and CCT have comparable diagnostic accuracy. Insufficient sodium intake decreases the diagnostic efficiency of SSST but not of CCT. Since CCT is simpler and cheaper, it is preferred over SSST.

Background and ObjectivesThe study aimed to evaluate the performance of a predictive model using the kidney failure risk equation (KFRE) for end-stage renal disease (ESRD) in diabetes and to investigate the impact of glomerular filtration rate (GFR) as estimated by different equations on the performance of the KFRE model in diabetes.Design, Setting, Participants, and MeasurementsA total of 18,928 individuals with diabetes without ESRD history from the UK Biobank, a prospective cohort study initiated in 2006–2010, were included in this study. Modification of diet in renal disease (MDRD), chronic kidney disease epidemiology collaboration (CKD-EPI) or revised Lund–Malmö (r-LM) were used to estimate GFR in the KFRE model. Cox proportional risk regression was used to determine the correlation coefficients between each variable and ESRD risk in each model. Harrell’s C-index and net reclassification improvement (NRI) index were used to evaluate the differentiation of the models. Analysis was repeated in subgroups based on albuminuria and hemoglobin A1C (HbA1c) levels.ResultsOverall, 132 of the 18,928 patients developed ESRD after a median follow-up of 12 years. The Harrell’s C-index based on GFR estimated by CKD-EPI, MDRD, and r-LM was 0.914 (95% CI = 0.8812–0.9459), 0.908 (95% CI = 0.8727–0.9423), and 0.917 (95% CI = 0.8837–0.9496), respectively. Subgroup analysis revealed that in diabetic patients with macroalbuminuria, the KFRE model based on GFR estimated by r-LM (KFRE-eGFRr-LM) had better differentiation compared to the KFRE model based on GFR estimated by CKD-EPI (KFRE-eGFRCKD-EPI) with a KFRE-eGFRr-LM C-index of 0.846 (95% CI = 0.797–0.894, p = 0.025), while the KFRE model based on GFR estimated by MDRD (KFRE-eGFRMDRD) showed no significant difference compared to the KFRE-eGFRCKD-EPI (KFRE-eGFRMDRD C-index of 0.837, 95% CI = 0.785–0.889, p = 0.765). Subgroup analysis of poor glycemic control (HbA1c >8.5%) demonstrated the same trend. Compared to KFRE-eGFRCKD-EPI (C-index = 0.925, 95% CI = 0.874–0.976), KFRE-eGFRr-LM had a C-index of 0.935 (95% CI = 0.888–0.982, p = 0.071), and KFRE-eGFRMDRD had a C-index of 0.925 (95% CI = 0.874–0.976, p = 0.498).ConclusionsIn adults with diabetes, the r-LM equation performs better than the CKD-EPI and MDRD equations in the KFRE model for predicting ESRD, especially for those with macroalbuminuria and poor glycemic control (HbA1c >8.5%).

The association between fat mass and mortality has been equivocally shown to be linear, J-shaped, and U-shaped. We aimed to clarify this relationship based on Mendelian randomization (MR) analysis and lifestyle modification.This prospective analysis included 449,831 participants from UK Biobank. Linear MR analysis was used to estimate the linear relationship between fat mass and mortality. We assessed whole body fat mass by bioimpedance analysis at baseline and categorized subjects into five equal groups based on fat mass index (FMI). The association between FMI and mortality were investigated among whole population and in subgroups stratified by individual lifestyle factors, including diet, physical activity, smoking, alcohol, sleep and psychological health.Linear MR analyses indicated a positive association between genetically predicted fat mass and all-cause mortality (HR 1.10, 95 % CI 1.08-1.12, P 0.001). The association between FMI and all-cause mortality was manifested as J-shaped (HRs across FMI categories: 1.04, 1.00, 1.07, 1.21, 1.54), which was significantly modified by the number of low-risk lifestyle factors (P for interaction0.001). When evaluating individual lifestyle factors, we observed a nonlinear relationship between FMI and all-cause mortality among participants who had high-risk lifestyle factors, while a linear relationship was observed among participants who had low-risk lifestyle factors, especially for those with adequate physical activity (HRs across FMI categories: 0.95, 1.00, 1.05, 1.17, 1.44) and who never smoked (0.96, 1.00, 1.03, 1.14, 1.51).Genetically determined fat mass is causally and linearly associated with mortality. The J-shape association between anthropometric FMI and mortality is caused by high-risk lifestyle factors.

Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves podocyte injury in type 1 DKD mice. However, the direct molecular target of puerarin and its underlying mechanisms in DKD remain unknown. In this study, we confirmed that puerarin also improved DKD in type 2 diabetic db/db mice. Through RNA-sequencing odf isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability method combined with mass spectrometry analysis, we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and mouse diabetic kidney in vivo. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. Inhibition of PKA by Rp-cAMP also diminished the effects of puerarin on high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.

Neutrophil-related chronic inflammation (NRCI) may contribute to the pathogenesis of diabetic kidney disease (DKD). We evaluated whether blocking NRCI with low-dose colchicine prevents DKD.A double-blind, randomized, placebo-controlled study was conducted. A total of 160 patients with type 2 diabetes (T2D) and microalbuminuria (urinary albumin creatinine ratio [UACR] 30 to 300 mg/g Cr) who received angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) for at least 3 months were included. Subjects were 1:1 randomized to a placebo or colchicine group (0.5 mg/day).The primary end point was the incidence of overt nephropathy (UACR 300 mg/g Cr). During the 36 months, 38 patients (51.4%) in colchicine group and 39 (54.1%) in the control group developed overt nephropathy (hazard ratio, 1.066; 95% confidence interval, 0.679-1.673; P = .78). Compared with placebo, colchicine modestly lowered levels of NRCI parameters (P values.05 for high-sensitivity C-reactive protein, white blood cell counts, neutrophil counts, and neutrophil-to-lymphocyte ratio), whereas the changes of UACR and estimated glomerular filtration rate (eGFR) were similar between the two groups. There were no significant differences between the two groups in drug-related adverse events, including infection, gastrointestinal symptoms, and limb numbness.In patients with T2D with microalbuminuria, low-dose colchicine effectively and safely lowered NRCI but did not prevent the incidence of overt nephropathy.背景: 中性粒细胞相关性慢性炎症(NRCI)可能与糖尿病肾病(DKD)的发生有关。我们用低剂量秋水仙碱抑制NRCI并评估其是否能延缓DKD的发生。 方法: 本研究为一项双盲、随机、安慰剂对照临床试验。研究共纳入2型糖尿病合并微量白蛋白尿(肌酐比 [UACR] 30-300mg/g Cr)的患者共160名, 所有患者均接受血管紧张素转换酶抑制剂(ACEi)或血管紧张素受体拮抗剂(ARBs)类药物至少3个月。患者按1:1随机分为安慰剂组或秋水仙碱组(接受秋水仙碱0.5mg/d)。 结果: 本研究的主要终点为显著肾病(UACR300mg/g Cr)的发生率。在随访的36个月中, 秋水仙碱组的38名患者(51.4%)以及安慰剂组的39名患者(54.1%)发展成为了显著肾病(危险比1.066; 95%置信区间 0.679-1.673; p=0.78)。秋水仙碱组与安慰剂组相比, NRCI水平有所下降(高灵敏C-反应蛋白、白细胞总数、中性粒细胞总数、中性粒细胞-淋巴细胞比值等指标, 两组有显著性差异, p0.05), 但两组的UACR变化率、估算肾小球滤过率变化率无显著差异。两组的药物相关不良反应, 包括感染、胃肠道症状、肢体麻木等症状无显著差异。 结论: 在2型糖尿病合并微量白蛋白尿的患者中, 低剂量秋水仙碱能有效且安全地降低NRCI, 但是不能延缓DKD的发生。.

Context The Endocrine Society Guidelines for the diagnosis of primary aldosteronism (PA) suggest that confirmatory tests (CFT) are not required when the following criteria are met: plasma aldosterone concentration (PAC) is >20 ng/dL, plasma renin is below detection levels, and hypokalemia is present. The evidence for the applicability of the guideline criteria is limited. Objective To develop and validate optimized criteria for sparing CFT in the diagnosis of PA. Design and Setting The optimized criteria were developed in a Chinese cohort using the captopril challenge test, verified by saline infusion test (SIT) and fludrocortisone suppression test (FST), and validated in an Australian cohort. Participants Hypertensive patients who completed PA screening and CFT. Main Outcome Measure Diagnostic value of the optimized criteria. Results In the development cohort (518 PA and 266 non-PA), hypokalemia, PAC, and plasma renin concentration (PRC) were selected as diagnostic indicators by multivariate logistic analyses. The combination of PAC >20 ng/dL plus PRC Conclusions Hypertensive patients with PAC >20 ng/dL, PRC

Objective: To investigate whether serum bisphenol A (BPA) concentration is related to the occurrence of dyslipidemia. Methods: A total of 574 adults were enrolled at baseline and followed up for 5 years. Concentrations of serum BPA, triglycerides (TGs), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured. Dyslipidemia was defined as the existence of one or more of the following conditions: high-LDL-cholesterolemia (LDL ≥140 mg/dL), hypertriglyceridemia (TGs ≥150 mg/dL), or low-HDL-cholesterolemia (HDL

Background A total of 44.7% adults in China have hypertension, but the prevalence of primary aldosteronism (PA) in Chinese hypertensive patients is unknown. Objectives This study prospectively investigated the prevalence, characteristics, and outcomes of PA in newly diagnosed hypertensive patients. Methods In a large community health center, consecutive hypertensive patients with an aldosterone-renin ratio >20 ng/mIU and plasma aldosterone concentration >10 ng/dl underwent captopril challenge test and/or saline infusion test for confirmation of PA. Adrenal computed tomography scan and adrenal vein sampling were used for subtyping. PA patients treated with surgery or medication were followed up for 1 year, and outcomes after treatment were evaluated. Results In total, 1,020 newly diagnosed hypertensive patients were screened over 16 months, of whom 40 were diagnosed with PA, 948 with non-PA, 32 with probable PA, resulting in a prevalence of more than 4.0%. Compared with non-PA, PA patients more frequently displayed microalbuminuria (p = 0.031), but the incidence of cardiovascular events was not different (p = 0.927). For surgically treated patients (n = 7), a complete biochemical success rate was 100% and a complete clinical success rate was 85.7%. For medically treated patients (n = 29), the proportion with optimal blood pressure control was 79%, and among them, 91% (21 of 23) only needed 1 antihypertensive drug: the mineralocorticoid receptor antagonist. Conclusions The prevalence of PA in patients with newly diagnosed hypertension in China was at least 4%. PA screening in newly diagnosed hypertensive patients leads to good clinical outcomes. (Primary Aldosteronism In Hypertensive Patients in China [PA-China]; NCT03155139)

Context The saline infusion test (SIT) is a common confirmatory test for primary aldosteronism (PA). According to the guideline, a postinfusion plasma aldosterone concentration (PAC) of 5-10 ng/dL is considered indeterminate, and recommendations for diagnostic strategies are currently limited in this situation. Objective To explore whether an addition of the captopril challenge test (CCT) could improve the diagnostic accuracy in patients with indeterminate SIT. Methods A total of 280 hypertensive patients with high risk of PA completed this study. Subjects were defined as SIT indeterminate based on their PAC post-SIT. These patients then underwent the CCT where PACs post-CCT >11 ng/dL were considered positive. Using fludrocortisone suppression test (FST) as the reference standard, diagnostic parameters including area under the receiver-operator characteristic curves (AUC), sensitivity and specificity were calculated. Results There were 65 subjects (23.2%) diagnosed as PA indeterminate after SIT. With the addition of CCT, true-positive numbers increased from 134 to 147, and false-negative numbers decreased from 27 to 14. Compared to SIT alone, a combination of SIT and CCT showed a higher AUC (0.91 [0.87,0.94] vs 0.87 [0.83,0.91], P = .041) and an increased sensitivity for the diagnosis of PA (0.91 [0.86,0.95] vs 0.83 [0.76,0.89], P = .028), while the specificity remained similar. In the subgroup with indeterminate SIT results, using PAC post-CCT resulted in a 36% higher AUC than using PAC post-SIT alone for the diagnosis of PA. Conclusion For patients under investigation for possible PA who have indeterminate SIT results, an addition of CCT improves the diagnostic accuracy.

Background While both renin‐dependent and renin‐independent aldosterone secretion contribute to aldosteronism, their relative associations with cardiovascular disease (CVD) risk has not been investigated. Methods and Results A total of 2909 participants from the FOS (Framingham Offspring Study) with baseline, serum aldosterone concentration, and plasma renin concentration who attended the sixth examination cycle and were followed up until 2014 and who were free of CVD were included. We further recruited 2612 hypertensive participants from the CONPASS (Chongqing Primary Aldosteronism Study). Captopril challenge test was performed to confirm renin‐dependent or ‐independent aldosteronism in CONPASS. Among 1433 hypertensive subjects of FOS, when compared with those with serum aldosterone concentration −1 (normal aldosterone), participants who had serum aldosterone concentration ≥10 ng dL −1 and plasma renin concentration ≤15 mIU L −1 (identified as renin‐independent aldosteronism) showed a higher risk of CVD (hazard ratio, 1.40 [95% CI, 1.08–1.82]), while those who had serum aldosterone concentration ≥10 ng dL −1 and plasma renin concentration >15 mIU L −1 (identified as renin‐dependent aldosteronism) showed an unchanged CVD risk. In CONPASS, renin‐independent aldosteronism carried a significantly higher risk of CVD than normal aldosterone (odds ratio, 2.57 [95% CI, 1.13–5.86]), while the CVD risk remained unchanged in renin‐dependent aldosteronism. Elevation of the urinary potassium‐to‐sodium excretion ratio, reflective of mineralocorticoid receptor activity, was only observed in participants with renin‐independent aldosteronism. Conclusions Among patients with hypertension, renin‐independent aldosteronism is more closely associated with CVD risk than renin‐dependent aldosteronism.

BackgroundAdrenocorticotropic hormone (ACTH) is widely used in adrenal vein sampling (AVS) and can be administered as a bolus injection or continuous infusion. The optimal administration method has not been determined. We aimed to compare the effects of ACTH bolus with infusion on cannulation success, lateralization assessment and adverse events (AEs).MethodsRetrospectively collected data from patients with primary aldosteronism who underwent AVS with ACTH at a tertiary hospital in China. Rate of successful cannulation, lateralization index (LI), complete biochemical remission and AEs related to AVS were analyzed.ResultsThe study included 80 patients receiving ACTH bolus and 94 receiving infusions. The rate of successful cannulation was comparable between bolus and infusion groups (75/80, 93.4% vs 88/94, 93.6%). In those with successful cannulation, the bolus group had a higher selectivity index than the infusion group, while LI [6.4(1.8-17.5) vs. 7.6(2.0-27.8), P=0.48] and rate of complete biochemical remission (43/44, 97.7% vs 53/53, 100%, P=0.45) did not significantly differ between the two groups. One in the bolus and one patient in the infusion group had adrenal vein rupture but they recovered with conservative treatment. The bolus group reported more transient AEs such as palpitation (52.9% vs 2.2%) and abdominal discomfort (40.0% vs 2.2%) than the infusion group.ConclusionsDue to their similar effects on cannulation success and lateralization, but a lower rate of transient AEs in the infusion group, the continuous infusion method should be recommended for ACTH stimulation in AVS.

ObjectivesPrimary aldosteronism (PA) is characterized by the autonomous excessive production of aldosterone in the adrenal cortex. Aldosterone is associated with damages to heart muscle and skeletal muscle. The purpose of this study was to evaluate serum levels of muscle injury markers and their associated factors in patients with primary aldosteronism.MethodsWe retrospectively enrolled subjects with PA and essential hypertension (EH) who had completed testing for serum high sensitivity troponin T (hs-TnT), creatine kinase isoenzyme MB (CK-MB) and myoglobin from the database of the Chongqing Primary Aldosteronism Study (CONPASS). Univariate and multivariate linear regression analyses were performed to analyze the influencing factors of myocardial injury markers.ResultsIn total, 278 patients with PA and 445 patients with EH were enrolled in this study. Compared with EH patients, serum concentrations of hs-TnT [7.0 (4.0–12.0) vs. 6.0 (3.0–11.0) ng/L; p=0.005] and myoglobin [24.2 (21.0–38.1) vs. 21.8 (21.0–31.9) μg/L; p=0.023] were significantly higher among PA patients, while no significant difference of CK-MB was found between two groups [1.4 (1.0–2.0) vs. 1.3 (0.9–1.9) μg/L; p=0.154]. Univariate linear regression analysis showed that myoglobin was negatively correlated with serum potassium (β=-0.31; ppppConclusionsThe serum level of myoglobin was significantly increased in PA patients, and myoglobin was independently correlated with plasma aldosterone concentration.

Angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renoprotective effects remains unclear. Here, we conducted single-cell RNA sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARBs, SGLT2i, or ARBs plus SGLT2i, using db/m mice as control. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARBs had more anti-inflammatory and anti-fibrotic effects, while SGLT2i affected more mitochondrial function in PT. We also identified a new PT subcluster, was increased in DKD, but reversed by the treatments. This new subcluster was also confirmed by immunostaining of mouse and human kidneys with DKD. Together, our study reveals kidney cell-specific gene signatures in response to ARBs and SGLT2i and identifies a new PT subcluster, which provides new insight into the pathogenesis of DKD.

To assess the diagnostic performance of the H-score of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) in the histopathological diagnosis of adrenocortical tumors (ACT). We retrospectively evaluated 199 cases of ACT, of which 85 were diagnosed as aldosterone-producing adenoma (APA), 66 as cortisol-producing adenoma (CPA), 9 as aldosterone–cortisol co-secreting adenoma, 30 as nonhyperfunctioning adenoma, and 9 as adrenocortical carcinoma (ACC). Immunohistochemical staining was performed using anti-CYP11B1 and anti-CYP11B2 monoclonal antibodies. The staining was quantified by the McCarty’s H-score system. The diagnostic performance was assessed by the receiver operating characteristic curve (ROC). The H-score of CYP11B1 is highest in the CPA group and lowest in the ACC group. The H-score of CYP11B2 in the APA group is significantly higher than other ACT groups. The area under ROC (AUC) of an increased H-score of CYP11B2 (>65) for the diagnosis of APA was 0.971 (95%CI 0.937–0.990). The AUC of an increased H-score of CYP11B1 (>204) for the diagnosis of CPA was 0.725 (95%CI 0.658–0.786). The AUC of a decreased H-score of CYP11B1 (

Objective Saline infusion test (SIT), captopril challenge test (CCT), fludrocortisone suppression test (FST) and oral sodium loading test (SLT) are recommended by the Endocrine Society's Clinical Practice Guidelines to diagnose primary aldosteronism, but which one is the best remains controversial. We aimed to summarize the available comparative data and evaluate the diagnostic accuracy of these four tests. Design We searched PubMed, Embase and the Cochrane Library for relevant studies published between January 1980 and January 2018. Patients Eligible studies reported on the accuracy of one or more of the four confirmatory tests in patients suspected of PA. Measurements Two reviewers independently conducted the data extraction of all selected studies, which consisted of study characteristics and data to estimate the summary receiver operating characteristic (SROC) curve and the corresponding summary area under the curve (SAUC), pooled sensitivity and specificity, diagnostic odds ratios (DOR) with 95% confidence interval (CI). Results We identified 26 articles including 3686 patients. Fifteen articles evaluated the diagnostic accuracy of CCT, 10 of SIT, 1 of FST and none of SLT. For CCT, the SAUC was 0.9207, and the pooled sensitivity and specificity were 0.87 (95% CI: 0.84-0.89) and 0.84 (95% CI: 0.81-0.86), respectively. For SIT, the SAUC was 0.9232, and the pooled sensitivity and specificity were 0.85 (95% CI: 0.82-0.87) and 0.87 (95% CI: 0.85-0.89), respectively. For FST, the pooled sensitivity and specificity were 0.87 (95% CI: 0.66-0.97) and 0.95 (95% CI: 0.82-0.99), respectively. Overall, we found no significant differences in the diagnostic accuracy of CCT and SIT. Conclusions CCT and SIT exhibit high and comparable accuracy for diagnosing PA. CCT may be a more feasible alternative as it is safe and much easier to perform.

Summary Objective The euglycemic‐hyperinsulinemic clamp is the gold standard to evaluate insulin resistance (IR), but there are only a few studies on the prevalence of IR in Chinese Han women with polycystic ovary syndrome (PCOS). This study investigated: (a) the prevalence of IR in Chinese Han women with PCOS by clamp, (b) the degree of reduction in insulin sensitivity (IS) and the contribution of body mass index (BMI). Design Retrospective cross‐sectional analysis. Patients Chinese Han women with PCOS (n = 448) visiting the Department of Endocrinology or the Department of Obstetrics and Gynaecology of the First Affiliated Hospital of Chongqing Medical University. Chinese Han women without PCOS (controls) from the same area (n = 40). Measurements Clamp‐measured IS, age, BMI, and total testosterone. Results The prevalence of IR and reduction in IS were 56.3% and 30.3%, respectively, in Chinese Han women with PCOS (both P 0.05). Conclusions 56.3% of Chinese Han women with PCOS had IR and their reduction in IS was 30.3%. Obesity exacerbated the reduction in IS. When being evaluated by HOMA, the prevalence and the risk factors of IR in Chinese women with PCOS were underestimated.

Cancer immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), represents a breakthrough in cancer treatment, resulting in unprecedented results in terms of overall and progression-free survival. Discovery and development of novel anti PD-1 inhibitors remains a field of intense investigation, where novel monoclonal antibodies (mAbs) and novel antibody formats (e.g., novel isotype, bispecific mAb and low-molecular-weight compounds) are major source of future therapeutic candidates. HLX10, a fully humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T-cells and showed in vitro, and anti-tumor activity in several tumor models. The combined inhibition of PD-1/PDL-1 and angiogenesis pathways using anti-VEGF antibody may enhance a sustained suppression of cancer-related angiogenesis and tumor elimination. To elucidate HLX10’s mode of action, we solved the structure of HLX10 in complex with PD-1 receptor. Detailed epitope analysis showed that HLX10 has a unique mode of recognition compared to the clinically approved PD1 antibodies Pembrolizumab and Nivolumab. Notably, HLX10’s epitope was closer to Pembrolizumab’s epitope than Nivolumab’s epitope. However, HLX10 and Pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage, which recognizes several overlapping amino acid residues on PD-1. We compared HLX10 to Nivolumab and Pembrolizumab and it showed similar or better bioactivity in vitro and in vivo, providing a rationale for clinical evaluation in cancer immunotherapy.

Perirenal fat is adjacent to kidneys and active in metabolism and adipokine secretion. We aimed to investigate whether perirenal fat is an independent predictor for chronic kidney disease (CKD) and compared it with total, subcutaneous, or visceral fat in patients with diabetes. Perirenal fat thickness (PRFT) was measured by computed tomography, and total body fat (TBF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were assessed by DEXA. In cross-sectional analysis, patients with higher PRFT had a lower estimated glomerular filtration rate (eGFR). Multiple linear regression analysis showed a negative correlation between PRFT and eGFR after confounders adjustment. No association between eGFR and TBF, SAT, or VAT was observed. Longitudinally, 190 patients with type 2 diabetes mellitus (T2DM) without CKD at baseline were followed for 2 years. A total of 29 participants developed CKD. After VAT-based multivariate adjustment, each SD (per-SD) increment in baseline PRFT was associated with a higher incidence of CKD (hazard ratio 1.67, 95% CI 1.04–2.68), while TBF, SAT, and VAT were not. Furthermore, PRFT predicted CKD, with a C-statistic (95% CI) of 0.668 (0.562, 0.774), which was higher than that of TPF [0.535 (0.433, 0.637)], SAT [0.526 (0.434, 0.618)], and VAT [0.602 (0.506, 0.698)]. In conclusion, with perirenal fat there was a higher predictive value for CKD than with total, subcutaneous, or visceral fat in T2DM.

Aldosterone-producing adenoma (APA) is a main cause of primary aldosteronism (PA). Given that a large benign-appearing unilateral masse (>1 cm in diameter) may represent an aldosterone and cortisol-co-secreting adenoma, dexamethasone suppression testing is required in such patients to exclude or confirm the diagnosis of hypercortisolism. Tuberculosis is highly prevalent in China, and rifamycins are often used in these patients. Rifapentine belongs to the rifamycin family, and we herein for the first time report a case of misdiagnosis of hypercortisolism due to rifapentine use in a patient with APA. Thus, in patients treated with rifapentine, diagnosis of hypercortisolism based on dexamethasone suppression tests can be very misleading.

Introduction Compared with the typical onset of type 2 diabetes in middle age or older, type 2 diabetes with early age of onset has a higher risk of diabetes-related complications. It is unclear whether the early age of diabetes diagnosis would affect the development of end-stage renal disease (ESRD) in patients with diabetic kidney disease (DKD) who are at higher risk of ESRD. Methods We enrolled 1,111 type 2 diabetes patients with DKD in this study. We used the age at diabetes diagnosis of younger than 40 years to define early-onset diabetes and 40 years or older to define late-onset diabetes. Medical history, anthropometry, and laboratory indicators were documented. ESRD was defined by estimated glomerular filtration rate (eGFR) of less than 15 mL/min/1.73 m2 or dialysis. Logistic regression analysis was used to explore the association between early-onset diabetes and ESRD. Results Early-onset diabetes patients had a longer diabetes duration, higher body mass index, and worse blood lipid metabolism profile. Compared with late-onset diabetes patients, patients with early-onset diabetes had a prevalence of ESRD that was twofold higher (9.2% vs 4.3%; P = .009). Univariate analysis showed that early-onset diabetes was a risk factor for ESRD in patients with DKD (P < .05). In multivariate logistic regression analysis, even after adjusting for sex, traditional metabolic factors, drug factors, and diabetes duration, the risk of ESRD in patients with early-onset diabetes was still 3.58-fold higher than in subjects with late-onset (95% CI, 1.47–8.74; P = .005). Conclusions In patients with DKD, early-onset type 2 diabetes is an independent risk factor of ESRD.

Objective: This study aimed to investigate the effect of anti-osteoporosis therapy on plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the aldosterone/renin ratio (ARR) in patients with postmenopausal osteoporosis. Methods: In 60 patients with postmenopausal osteoporosis, bone mineral density (BMD), PAC and PRC were measured before and after treatment with alendronate (70 mg/week, n=22) or recombinant human parathyroid hormone (20 μg/day, n=35) for 48 weeks. Results: PAC was negatively correlated with the T-score of lumbar spine BMD and femoral neck BMD (lumbar r=−0.386, p37 pg/μIU, and the proportion decreased to 8% (5/57) after treatment. Conclusion: Treatment with alendronate or parathyroid hormone causes decreased PAC and increased PRC, resulting in a decreased ARR in postmenopausal women with osteoporosis.

IntroductionAldosterone is a mediator of progressive renal disease, but the mechanisms for aldosterone-mediated renal impairment in mice with diabetes are not fully defined.MethodsAldosterone and/or mineralocorticoid receptor antagonist eplerenone were used to treat the db/db mice with diabetes. Proximal tubule epithelial cells (PTECs) and fibroblasts were cultured. Blood and kidney samples from patients with diabetes with or without diabetic kidney disease (DKD) were used to verify the findings from animals and cultured cells.ResultsWe found that aldosterone promoted proteinuria and tubulointerstitial extracellular matrix (ECM) accumulation in db/db mice with diabetes while eplerenone mitigated the adverse effect of aldosterone. However, coculture of PTECs and fibroblasts found that when PTECs-derived extracellular vesicles (EVs) were taken up by fibroblasts, ECM production increased remarkably. Moreover, C57BL/6 mice injected with EVs from renal cortex of aldosterone-treated db/db mice showed increased ECM accumulation. Function of the ingredients of PTECs-derived EVs were analyzed, and RNAs were identified to be responsible for the EVs-induced fibroblast dysfunction. Furthermore, microRNA (miRNA) array analysis revealed that miR-196b-5p was the most remarkably increased miRNA in PTECs-derived EVs with aldosterone stimulation. Overexpression of miR-196b-5p in fibroblasts increased ECM production, accompanied by inhibition of the SOCS2 expression and enhanced STAT3 phosphorylation. In addition, plasma levels of miR-196b-5p was higher in patients with DKD as compared with patients without DKD and miR-196b-5p levels positively correlated with the albuminuria concentration. In kidney specimens from patients with diabetes, expression of miR-196b-5p, located mainly in PTECs, increased in patients with DKD as compared with the non-DKD.ConclusionThis study demonstrates the involvement of miR-196b-5p-EVs pathway as a novel mechanism in aldosterone-induced renal fibrosis in diabetes. EVs rich in miR-196b-5p mediate the crosstalk between PTECs and fibroblast during the development of renal fibrosis, which might be associated with STAT3/SOCO2 signaling pathway.

Background The prevalence of primary aldosteronism concurrent with subclinical Cushing’s syndrome was higher than previously thought. Through analyzing a rare clinical case, we summarized the diagnosis and management of primary aldosteronism with subclinical Cushing’s syndrome. Case presentation A 54-year-old Chinese man of Han nationality was diagnosed as having primary aldosteronism with subclinical Cushing’s syndrome. An abdominal computed tomography scan revealed a mass in his left adrenal gland and a mass in his right adrenal gland. After finishing sequential adrenal venous sampling without adrenocorticotropic hormone, the result reminded us that the left and right nodules were responsible for hypercortisolism and aldosterone hypersecretion, respectively. Right and left adrenalectomy were performed successively. The pathological diagnosis was adrenocortical adenoma for both. Histological findings revealed that the right one had positive immunostaining for CYP11B2 and the left one had positive immunostaining for CYP11B1. The immunohistochemistry result helped us to confirm the diagnosis. Somatic KCNJ5 mutation (Leu168Arg) was found in the right tumor; there was no KCNJ5 mutation in the left adrenal tumor. Conclusions We suggest that patients with primary aldosteronism should have a low-dose overnight dexamethasone suppression test to screen for hypercortisolism. It can help avoid misdiagnoses and contribute to proper understanding of the adrenal vein sampling result. Making sure of the nidus of aldosterone and cortisol secretion is crucial for the therapy of patients with primary aldosteronism and subclinical Cushing’s syndrome.

Context More than half of patients diagnosed with unilateral primary aldosteronism (UPA) suffer from persisting hypertension after unilateral adrenalectomy. Objective The objective of this work is to develop and validate a nomogram-based preoperative score (NBPS) to predict clinical outcomes after unilateral adrenalectomy for UPA. Design and Setting The NBPS was developed in an Asian cohort by incorporating predictors independently associated with remission of hypertension after unilateral adrenalectomy for UPA and validated in a Caucasian cohort. Participants Participants comprised patients with UPA achieving complete biochemical success after unilateral adrenalectomy. Main Outcome Measure Measurements included the predictive performance of the NBPS compared with 2 previously developed outcome prediction scores: aldosteronoma resolution score (ARS) and primary aldosteronism surgical outcome (PASO) score. Results Ninety-seven of 150 (64.7%) patients achieved complete clinical success after unilateral adrenalectomy in the training cohort and 57 out of 165 (34.5%) in the validation cohort. A nomogram was established incorporating sex, duration of hypertension, aldosterone-to-renin ratio, and target organ damage. The nomogram showed good C indices and calibration curves both in Asian and Caucasian cohorts. The area under the receiver operating characteristic curve (AUC) of the NBPS for predicting hypertension remission in the training cohort was 0.853 (0.786-0.905), which was superior to the ARS (0.745 [0.667-0.812], P = .019) and PASO score (0.747 [0.670-0.815], P = .012). The AUC of the NBPS in the validation cohort was 0.830 (0.764-0.884), which was higher than the ARS (0.745 [95% CI, 0.672-0.810], P = .045), but not significantly different from the PASO score (0.825 [95% CI, 0.758-0.880], P = .911). Conclusion The NBPS is useful in predicting clinical outcome for UPA patients, especially in the Asian population.

Primary aldosteronism (PA) is notably an independent risk factor for cerebral vascular disease but currently with limited knowledge among young adults. The objectives of the study were to investigate the prevalence of PA in patients under 45 years old with history of acute stroke and the clinical characteristics during stroke attack. We retrieved the medical records of 116 patients once admitted due to acute stroke and cross-sectionally conducted screening test as well as confirmatory test among those patients. An estimated prevalence of PA was 12.7% among all patients and 21.2% among patients combined with hypertension. During stroke attack, PA patients had experienced higher blood pressure as well as decreased potassium level. The average SBP and DBP of PA patients were 180.0 ± 30.9 and 125.9 ± 24.5 mmHg respectively, both remarkably higher than those without PA(mean SBP 148.9 ± 29.6 mmHg, mean DBP94.1 ± 20.5 mmHg). The mean potassium level was 3.13 ± 0.50 vs. 4.01 ± 0.40 mmol/l. The proportion of hypertension and hypokalemia were also increased for PA patients compared with patients without (hypertension 93.3% vs. 51.5%; hypokalemia 80% vs. 8.9%). Patients were equal in National Institutes of Health Stroke Scale (NIHSS) score as well as Glasgow Coma Score (GCS) and stroke subtypes. Considering the fact that excessive aldosterone had detrimental role on cerebral vascular system, we recommend a more rigorous screening for PA with stroke onset under 45 years old, especially those combined with severe hypertension as well as overt hypokalemia.

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2 A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression., Arctigenin (ATG) is the major active component of a Chinese herbal remedy known to reduce proteinuria in patients with diabetic kidney disease (DKD). Here, Zhong et al. identify PP2A as a pharmacological target of ATG in podocytes, and find that PP2A is responsible for some of the beneficial effects of ATG in mouse models of DKD.

Plasma aldosterone/renin ratio (ARR) is a useful method for primary aldosteronism (PA) screening. However some confounders, such as medications and dietary, affect plasma renin and aldosterone levels, resulting in false-negative or -positive plasma ARR. This study investigated the association between postmenopausal osteoporosis (PMO) and plasma ARR. Bone mineral density (BMD) was measured by dual-energy X-ray-absorptiometry (DXA) in 324 normotensive postmenopausal women. Based on clinical characteristics and BMD, 186 and 96 subjects were diagnosed as PMO and osteopenia respectively, and the remaining 42 subjects were grouped as normal BMD. Plasma aldosterone concentration (PAC), plasma renin concentration (PRC), parathyroid hormone (PTH), bone alkaline phosphatase (BALP) and 25-Hydroxyvitamin D(25-(OH)D) were determined. Subjects with PMO showed significantly higher levels of PAC (121.0 ± 78.8 vs. 81.8 ± 71.5 pg/ml, p

Background/Aims: Whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) could benefit patients with diabetes and albuminuria remains controversial. A systematic review and meta-analysis were conducted to answer this question by comparing ACE inhibitors or ARB with placebo among these patients. Methods: In this meta-analysis, electronic data sources (Medline, the Cochrane Collaboration, and EMBASE) were searched. Randomized controlled trials (RCTs) comparing ACE inhibitors or ARB with placebo in subjects with diabetes and albuminuria (defined as urinary albumin-to-creatinine ratio, UACR≥30mg/g Cr) were included. Outcomes parameters were all-cause mortality, end stage renal disease (ESRD), doubling of serum creatinine levels, and cardiovascular events (CV). Results: Twenty-six RCTs (including 20 for ACE inhibitors and 6 for ARB) were included, comprising 10378 participants with diabetes and albuminuria. Compared to placebo, treatment with ACE inhibitors or ARBs did not reduce all-cause mortality or CV. For renal outcomes, ARBs significantly reduced the risk of ESRD by 23% (odds ratio 0.77, 95%CI 0.65-0.92), while ACE inhibitors were not associated with a decreased risk of ESRD (0.69, 0.43-1.10). Both ACE inhibitors and ARBs reduced the risk of doubling of the serum creatinine level (0.60, 0.39-0.91 for ACE inhibitors; 0.75, 0.64-0.88 for ARBs), and subgroup analyses for patients with macroalbuminuria or microalbuminuria showed similar results. Conclusion: In patients with diabetes and albuminuria, ARBs reduced risks of ESRD and doubling of the serum creatinine level. ACE inhibitors and ARBs failed to reduce all-cause mortality and CV. Based on the renoprotective effects, ARBs may be preferred for diabetic patients with albuminuria.

The diagnosis of primary aldosteronism typically requires at least one confirmatory test. The fludrocortisone suppression test is generally accepted as a reliable confirmatory test, but it is cumbersome. Evidence from accuracy studies of the saline infusion test (SIT) and the captopril challenge test (CCT) has provided conflicting results. This prospective study aimed to evaluate the diagnostic accuracy of the SIT and CCT using fludrocortisone suppression test as the reference standard. One hundred thirty-five patients diagnosed with primary aldosteronism and 101 patients diagnosed with essential hypertension who completed the 3 confirmatory tests were included for the diagnostic accuracy analysis. The areas under the receiver–operator characteristics curves of the CCT and SIT were 0.96 (95% confidence interval [CI], 0.92–0.98) and 0.96 (95% CI, 0.92–0.98), respectively, using post-test plasma aldosterone concentration (PAC) for diagnosis. However, the areas under the receiver–operator characteristics curves of the CCT decreased to 0.71 (95% CI, 0.65–0.77) when the PAC suppression percentage was used to diagnose primary aldosteronism. The optimal cutoff of PAC post-CCT was set at 11 ng/dL, resulting in a sensitivity of 0.90 (95% CI, 0.84–0.95) and a specificity of 0.90 (95% CI, 0.83–0.95), which were not significantly different from those of SIT (with PAC post-SIT set at 8 ng/dL, sensitivity: 0.85 [95% CI, 0.78–0.91], P =0.192; specificity: 0.92 [95% CI, 0.85–0.97], P =0.551). In conclusion, both CCT and SIT are accurate alternatives to the more complex fludrocortisone suppression test. Because CCT is safe and much easier to perform, it may serve as a more feasible alternative. When interpreting the results of CCT, PAC post-CCT is highly recommended.

The aim of this study was to investigate the association of sarcopenia and diabetic foot disease (DFD) in a cross-sectional study. Body composition was assessed using dual-energy X-ray-absorptiometry (DXA) among 1105 patients with type 2 diabetes (120 patients with newly diagnosed DFD [DFD duration less than 3 months]). Severity of DFD was assessed, referring to foot ulcers, Wagner grade and the percentage of amputation. Skeletal muscle index (SMI) was calculated, and sarcopenia was defined as SMI less than 7.0 kg/m2 (in men) or 5.4 kg/m2 (in women). SMI was significantly decreased in patients with DFD compared to patients without (6.79 ± 1.20 vs. 7.21 ± 1.05 kg/m2, P P P = 0.027) after controlling confounders including age, diabetic duration and diabetic chronic complications. In DFD group, patients with sarcopenia exhibited more foot ulcers, higher Wagner grade and greater percentage of amputation compared to patients without sarcopenia. We conclude that sarcopenia is independently associated with DFD. Worse prognosis is seen in patients with DFD accompanied by sarcopenia.

The association between primary aldosteronism (PA) and obstructive sleep apnea (OSA) has been a matter of debate. 2016 Endocrine Society guideline recommends screening for PA all hypertensive patients with OSA. We designed a multicenter, multiethnic, cross-sectional study to evaluate the prevalence of PA in patients with OSA and the prevalence of OSA in unselected patients with PA. Two hundred and three patients with OSA (102 whites and 101 Chinese) were screened for PA, and 207 patients with PA (104 whites, 100 Chinese, and 3 of African descent) were screened for OSA by cardiorespiratory polygraphy. Eighteen patients with OSA (8.9%) had PA (11.8% of white and 5.9% of Chinese ethnicity). In patients without other indications for PA screening, the prevalence of PA dropped to 1.5%. The prevalence of OSA in patients with PA was 67.6%, consistent in both white and Chinese patients. A correlation between aldosterone levels and apnea/hypopnea index was observed in white patients with PA ( R 2 =0.225, P =0.016) but not in Chinese patients. Multinomial logistic regression confirmed a significant and independent association between plasma aldosterone levels and moderate to severe OSA diagnosis in white patients (odds ratio, 1.002; P =0.002). In conclusion, aldosterone levels may contribute to the severity of OSA in white patients with hyperaldosteronism, but patients with OSA are not at high risk of PA. Results of the present study challenge the current recommendation of the Endocrine Society guideline that all patients with OSA should be screened for PA, irrespective of the grade of hypertension.

Background We conducted a meta-analysis to investigate the association of circulating tumor necrosis factor-1 (TNFR-1) and TNFR-2 with diabetic kidney disease (DKD) progression, which is the first-ever quantitative analysis of these associations thus far. Whether TNFRs were better than albumin-creatinine ratio (ACR) in predicting DKD progression was also explored. Methods A systematic search of the PubMed, EMBASE, and Cochrane Library databases up to 1 February 2018, was conducted. The main outcome was DKD progression, which was defined as eGFR decline, macroalbuminuria, or incidence of DKD-related events. Eligible studies were included for pooled analysis using either fixed-effects or random-effects models to incorporate between-study variation by different measurement standards. Publication bias was evaluated using Egger's test. Results The meta-analysis included 6526 participants from 11 cohorts with circulating TNFR-1 measurements and 5385 participants from 10 prospective studies with circulating TNFR-2 measurements. Compared with the lowest level category, diabetic patients with the highest TNFR-1 or TNFR-2 level category exhibited a higher risk of DKD progression (RR 2.51, 95% CI [1.92-3.27] for TNFR-1; 3.23 [1.99-5.26] for TNFR-2). The risk of DKD progression was also increased with the per unit increment of TNFR-1 or TNFR-2 (1.68 [1.43-1.97] for TNFR-1; 1.69 [1.31-2.17] for TNFR-2). Although existing studies did not support a direct comparison between ACR and TNFRs, it was undeniable that TNFRs could improve the predictive value in DKD progression. Conclusions Circulating TNFR-1 and TNFR-2 are reliable predictors of DKD progression. Whether TNFRs are better than ACR at predicting DKD progression needs to be further investigated.

A 5-year follow-up study found declining disease development rates from latent tuberculosis infection. In the latter 3 years, the incidence, per 100 person-years, was 0.26 for interferon-γ release assay positives and 0.19 for tuberculin skin test positives (P = .28). In addition, all round have been checked.

Objectives: To compare the effect of surgical or medical treatment on the risk of cardiovascular diseases (CVD) and all-cause mortality in patients with established primary aldosteronism (PA). Methods: We searched PUBMED, MEDLINE and Cochrane Library for the meta-analysis. We included patients who were diagnosed with PA following guideline-supported protocols and received surgery or mineralocorticoid receptor antagonist (MRA)-based medical treatment, and age-sex matched patients with treated essential hypertension (EH). Primary endpoints were CVD incidence and all-cause mortality. Results: Compared with EH, patients with treated PA had a higher risk of CVD [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.39–2.31]. This elevated risk was only observed in patients with medically treated PA [OR 2.11; 95%CI 1.88–2.38] but not in those with surgically treated PA. The risk of all-cause mortality was significantly lower in patients with treated PA [OR 0.86; 95% CI 0.77–0.95] compared to EH. The reduced risk was only observed in patients with surgically treated PA [OR 0.47; 95% CI 0.34–0.66], but not in those with medically treated PA. Conclusions: Patients with medically treated PA have a higher risk of CVD compared to patients with EH. Surgical treatment of PA reduces the risk of CVD and all-cause mortality in patients with PA.

The aim of this study is to evaluate the pharmacokinetic and pharmacodynamic (PK-PD) profiles of lispro administered by the QS-M needle-free jet injector in Chinese subjects.A randomized, double-blind, double-dummy, cross-over study was performed. Eighteen healthy volunteers were recruited. Lispro (0.2 units/kg) was administered by the QS-M needle-free jet injector or by conventional pen. Seven-hour euglycemic clamp tests were performed.A larger area under the curve (AUCs) of insulin concentration and glucose infusion rate (GIR) during the first 20 minutes after lispro injection by the jet injector compared to the insulin pen was observed (24.91 ± 15.25 vs. 12.52 ± 7.60 mg. kg(-1), P 0.001 for AUCGIR,0-20 min; 0.36 ± 0.24 vs. 0.10 ± 0.04 U min L(-1), P 0.001 for AUCINS, 0-20 min). Needle-free injection showed a shorter time to reach maximum insulin concentration (37.78 ± 11.14 vs. 80.56 ± 37.18 min, P 0.001) and GIR (73.24 ± 29.89 vs. 116.18 ± 51.89 min, P = 0.006). There were no differences in total insulin exposure and hypoglycemic effects between the two devices.Lispro administered by QS-M needle-free injector results in earlier and higher insulin exposure than conventional pen, and a greater early glucose-lowering effect with similar overall potency.

It has been previously demonstrated that miR-1934 was specially regulated by adiponectin, an anti-inflammatory adipokine, in adipose tissue (AT) in vivo. Herein we investigated the role of miR1934 in the regulation of inflammatory response. Compared with chow-diet fed mice, miR1934 expression was down-regulated in epididymal AT of high-fat diet-induced obese mice. miR1934 expression was down-regulated as well in omental AT of obese subjects in comparison with lean subjects. The circulating miR-1934 was also lower in obese subjects and its levels were correlated negatively with body mass index (BMI), waist circumference (WC), low-density lipoprotein cholesterol (LDL-c), insulin resistance and high-sensitivity C-reactive protein (hs-CRP). The down-regulation of miR1934 in obesity was mimicked by TNF-α treatment of 3T3-L1 adipocytes. Moreover, overexpression of miR1934 suppressed the TNF-α-induced gene expression of interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) in 3T3-L1 adipocytes. De novo formed AT in nude mice transplanted with 3T3-L1 preadipocytes overexpressing miR1934 displayed a reduction in IL-6, TNF-α, IL-1β and an enhancement in IL-10 gene expression when compared with transplant with 3T3-L1 preadipocytes overexpressing miR1934 scrambled control sequence. These results suggest that miR1934 is an important anti-inflammatory factor and may represent a novel mechanism for controlling AT inflammation.

Hypertensive nephropathy is one of the major causes of chronic kidney disease (CKD). Bisphenol A (BPA) is associated with elevated blood pressure and urinary albuminuria. The aim of this study is to evaluate the association between serum BPA with the progression of CKD in patients with primary hypertension.In this prospective study, 302 patients with primary hypertension were followed up for 6 years (195 men and 107 women, 65.29 ± 9.78 years at baseline). The baseline values of serum BPA were measured. Renal function was measured as estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation (eGFRcr-cys). Regression models were used to calculate associations of serum BPA with the annual change in eGFR and the risk of CKD progression.Baseline serum BPA concentration was 0.61(0.26, 2.44) ng/ml and was significantly negatively correlated with the annual change in eGFR (R = -0.197, P 0.001). After adjusting for clinical factors, baseline serum BPA level had a significant negative association with the annual change in eGFR (β = -0.132, P = 0.007). Univariate logistic regression analysis showed that the baseline age, SBP, eGFR, and serum BPA levels were predictors of CKD stage 3 or greater. In multivariate logistic regression analysis, patients with high serum BPA levels exhibited a five-fold increased risk of developing CKD stage 3 or greater compared with patients with low serum BPA levels [odds ratio 4.79 (95% confidence interval 1.81, 14.25), P = 0.004].Serum BPA may be a predictor of CKD progression in patients with primary hypertension.

AimsCell-free DNA (cfDNA) is associated with diabetes and cardiovascular diseases. Our study was to evaluate whether serum cfDNA could predict the progression of diabetic kidney disease (DKD).MethodsIn this prospective study, a total of 160 patients with DKD were enrolled, and the kidney function was followed up by measurement of estimated glomerular filtration rate (eGFR) and urinary albumin–creatinine ratio (UACR) for three consecutive years. At baseline, concentrations of serum cfDNA were measured. DKD progression was defined as two-continuous decrease in eGFR and changes of UACR from less than 300 mg/g at baseline to higher than 300 mg/g at last follow-up. Regression models were used to analyze associations of serum cfDNA with the DKD progression.ResultsIn total, 131 patients finished all the follow-up visits. At the end of the study, 64 patients showed decreased eGFR and 29 patients had changes of UACR from less than 300 mg/g at baseline to higher than 300 mg/g at follow-up. At baseline, the progression group had higher serum cfDNA levels than the non-progression group (960.49 (816.53, 1073.65) ng/mL vs 824.51 (701.34, 987.06) ng/mL, p=0.014). Serum cfDNA levels were significantly negatively associated with the 1.5-year eGFR change (r=−0.219 p=0.009) and 3-year eGFR change (r=−0.181, p=0.043). Multivariate logistic analyses showed that after adjustment of age, gender, body mass index, fast plasma glucose, smoking, triglycerides, total cholesterol, duration of diabetes, systolic blood pressure, diabetic retinopathy, eGFR, high sensitivity C-reactive protein, angiotensin receptor blocker/ACE inhibitor usage, with the increase of one SD of serum cfDNA levels, the risk of DKD progression increased by 2.4 times (OR, 2.46; 95% CI 1.84 to 4.89).ConclusionSerum cfDNA is closely associated with DKD, and it might be a predictor of DKD progression in patients with type 2 diabetes.

The relationship between monocyte count and mortality seemed to be varied in different diseases, and it remains unclear in type 2 diabetes (T2D). We conducted a prospective study to investigate whether monocyte count predict all-cause mortality in patients with T2D. In this prospective study, a total of 1073 patients with T2D were enrolled at baseline and 880 patients completed the follow up. The median follow-up time was 47 months. At baseline, clinical characteristics including height, weight, waist circumference, blood pressure were recorded. Biochemical parameters including counts of white blood cells (WBCC), neutrophil (NC) and monocyte (MC), lipid profiles, glycated hemoglobin (HbA1c), serum creatinine were measured. Charlson comorbidity index (CCI) was calculated based on age and comorbidities. Participants were stratified into low, median, and high tertiles according to the baseline MC. Regression models were used to analyze the associations of peripheral MC and the all-cause mortality. Compared to the survived subjects, the baseline MC was significantly higher in patients who deceased during the follow-up (0.45 ± 0.16 vs 0.37 ± 0.15 × 109/L, P = .003). In the multivariate Cox hazard models, subjects in higher MC tertile showed higher risks of all-cause mortality (low tertile as the reference, hazard ratio [HR] 95%CI 2.65 [0.84,8.31] and 3.73 [1.14,12.24] for middle and high MC tertile, respectively) after adjusted for gender, body mass index, CCI, duration of T2D, history of hypertension and metabolic syndrome, drugs, levels of high-sensitivity C-reactive protein, systolic blood pressure, HbA1c, WBCC, and NC. In T2D patients with macro-vascular complications at baseline, 1-SD increment of MC resulted in 1.92-fold higher risk of all-cause mortality. However, the relationship disappeared in subjects without macro-vascular complications at baseline (1.13 [0.72, 1.78], P = .591). Peripheral monocyte count is an independent predictor of all-cause mortality in T2D, especially for subjects with macro-vascular complications.

The HIV-1 protein Rev is an essential viral regulatory protein that facilitates the nuclear export of intron-containing viral mRNAs. Its sequence is organized into short, structured, functionally well-characterized motifs joined by less understood linker regions. We recently carried out a competitive deep mutational scanning study, which determined the relative fitness of every amino acid at every position of Rev in replicating viruses. This study confirmed many known constraints in Rev’s established interaction motifs, but also identified positions of mutational plasticity within these regions as well as in surrounding linker regions. Here, we probe the mutational limits of these linkers by designing and testing the activities of multiple truncation and mass substitution mutations. We find that these regions possess previously unknown structural, functional or regulatory roles, not apparent from systematic point mutational approaches. Specifically, the N- and C-termini of Rev contribute to protein stability; mutations in a turn that connects the two main helices of Rev have different effects in nuclear export assays and viral replication assays; and a linker region which connects the second helix of Rev to its nuclear export sequence has structural requirements for function. Thus, we find that Rev function extends beyond its characterized motifs, and is in fact further tuned by determinants within seemingly plastic portions of its sequence. At the same time, Rev’s ability to tolerate many of these massive truncations and substitutions illustrates the overall mutational and functional robustness inherent in this viral protein.Author Summary (non-technical summary)HIV-1 Rev is an essential viral protein that controls a critical step in the HIV life cycle. It is responsible for transporting viral mRNA messages from the nucleus to the cytoplasm where they can contribute to the formation new virus particles. In order to understand how different regions of the Rev protein sequence are involved in its function, we introduced truncations and mass substitution mutations in the protein sequence and tested their effect on protein function. Through this study, we not only confirmed previous work highlighting known functionally important regions in Rev, but also found that a large portion of Rev, with little known functional roles influence Rev function and stability. We also show that although protein sequence is critical to its function, Rev can tolerate large variations to its sequence without disrupting its function significantly.

Objective This study aims to evaluate whether serum Bisphenol A (BPA) is a risk factor for hyperuricemia. Methods In this prospective study, a total of 482 participants without hyperuricemia were enrolled at baseline and followed up for 6 years. Clinical characteristics were recorded, and serum levels of uric acid and BPA were measured. Participants were stratified into tertiles according to low, median, and high baseline serum BPA levels. Regression models were used to analyze associations of serum BPA with the change in uric acid and the risk of developing hyperuricemia. Results At baseline, serum concentrations of BPA was 0.51 (0.24–2.37) ng/mL. After 6 years of follow-up, the change in serum uric acid concentration from baseline to the 6-year mark was significantly higher in subjects with higher baseline BPA concentration (0.03 ± 0.19, 0.07 ± 0.21, and 0.11 ± 0.25 mg/dL for low, median, and high tertiles, respectively, P = 0.006). When adjusted for potential confounders, such as age, renal function, and history of diabetes and hypertension, multivariable logistic analyses showed that subjects in the median or high baseline BPA tertiles exhibited a twofold higher risk of 6-year hyperuricemia incidence compared to subjects in the low baseline BPA tertile [odds ratio (OR) = 2.28 (95% CI: 1.05–4.95) for the median tertile; 2.42 (1.07–5.48) for the high tertile, Pfor Trend = 0.043]. Conclusion In conclusion, serum BPA is an independent risk factor for hyperuricemia.

The relationship between bisphenol A (BPA) and diabetes remains controversial. This study aims to investigate whether serum BPA level could predict the 5-year incidence of type 2 diabetes (T2D).A nested case-control study was performed among Chinese who participated in the environment, inflammation and metabolic diseases study (2008-2013). Of the 3510 subjects who were free of diabetes, 232 subjects developed diabetes during the 5-year follow-up. Cases and controls were matched for age and gender by a ratio of 1:1. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β) and insulin resistance (HOMA-IR). Participants were stratified into tertiles based on low, median and high baseline serum BPA levels. Regression models were used to analyze the relationship between serum BPA concentration and the incidence of T2D.At baseline, no significant difference in serum BPA concentration was observed between patients with T2D and controls [1.3 (0.3, 3.7) vs. 1.6 (0.4, 3.9) μmol/L, P = 0.199]; serum BPA concentration was positively associated with fasting plasma glucose (r = 0.27, P 0.001); however, neither HOMA-β nor HOMA-IR correlated with serum BPA concentration. During the follow-up, baseline BPA levels could not predict the 5-year T2D incidence, whether or not adjusted for the potential confounders such as body mass index and blood pressure. [Low BPA tertile was the reference, OR 0.66 (95% CI 0.30, 1.44) for median, OR 0.93 (95% CI 0.41, 2.13) for high.] CONCLUSION: BPA is not associated with a 5-year T2D incidence. These data do not support previous cross-sectional study that BPA exerted a detrimental effect on glucose metabolism.

Aim It is well known that lipid accumulation and inflammation are two important steps in pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD). However, fewer studies have explored the direct relationship between lipid accumulation and inflammation in early NAFLD. Tumor necrosis factor alpha (TNF-α) is one of the classical inflammatory cytokines. AMP-activated protein kinase (AMPK) is known as a critical regulator of energy homeostasis in metabolic processes. This study aims to investigate the role of TNF-α on lipid deposition of HepG2 cells and examine the modification of AMPK pathway. Main methods TNF-α was added in HepG2 cells and lipid accumulation was analyzed by Oil Red O staining and quantitative test of triglyceride (TG). The expressions of phosphorylated AMPK and its pathway (including mTOR and SREBP-1) were determined. Furthermore, an AMPK agonist (metformin or AICAR) or antagonist (compound C) was co-administrated with TNF-α in HepG2 cells to investigate its effect on TNF-α induced lipid deposition. Key findings A significant increment of TG content in HepG2 cells was observed after TNF-α treatment. Meanwhile, substantially suppressed AMPK and ACC phosphorylation, enhanced mTOR and p70S6K phosphorylation, and increased protein expression of FAS and SREBP-1 were found. Co-treatment with metformin or AICAR decreased the TNF-α-induced intracellular TG, accompanied by significantly enhanced AMPK and ACC phosphorylation, suppressed mTOR and p70S6K phosphorylation, and reduced SREBP-1 and FAS expressions. On the contrary, while co-incubated with compound C, AMPK and ACC phosphorylation were suppressed and the inhibitory effect of metformin on HepG2 cell lipid deposition was also attenuated. Significance Our results suggest that TNF-α directly induces lipid accumulation in HepG2 cells, at least in part, through the inhibition of AMPK/mTOR/SREBP-1 pathway.

Transcription complexes that assemble at the HIV-1 promoter efficiently initiate transcription but generate paused RNA polymerase II downstream from the start site. The virally encoded Tat protein hijacks positive transcription elongation factor b (P-TEFb) to phosphorylate and activate this paused polymerase. In addition, Tat undergoes a series of reversible post-translational modifications that regulate distinct steps of the transcription cycle. To identify additional functionally important Tat cofactors, we performed RNAi knockdowns of sixteen previously identified Tat interactors and found that a novel E3 ligase, PJA2, ubiquitinates Tat in a non-degradative manner and specifically regulates the step of HIV transcription elongation. Interestingly, several different lysine residues in Tat can function as ubiquitin acceptor sites, and variable combinations of these lysines support both full transcriptional activity and viral replication. Further, the polyubiquitin chain conjugated to Tat by PJA2 can itself be assembled through variable ubiquitin lysine linkages. Importantly, proper ubiquitin chain assembly by PJA2 requires that Tat first binds its P-TEFb cofactor. These results highlight that both the Tat substrate and ubiquitin modification have plastic site usage, and this plasticity is likely another way in which the virus exploits the host molecular machinery to expand its limited genetic repertoire.

Pigment epithelium-derived factor (PEDF) plays an important role in insulin resistance (IR). The study aims to investigate the effect of rosiglitazone, an insulin sensitizer, on PEDF production and release both in vivo and in vitro. Male SD rats were divided into normal control group, high-fat group, and rosiglitazone group. Hyperinsulinemic euglycemic clamp was performed to evaluate insulin sensitivity. IR models of 3T3-L1 adipocytes and HepG2 cells were established by the hyperinsulinemic method. Glucose uptake was examined to validate IR of adipocytes, and phosphorylation of protein kinase B and glycogen synthesis kinase 3β were examined to validate IR of HepG2 cells. Rosiglitazone, 2-chloro-5-nitro-N-phenylbenzamide (GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ), and compound C (inhibitor of AMP-activated protein kinase [AMPK]) were used for the in vitro intervention. In vivo, the high-fat group showed increased serum PEDF levels, which negatively correlated with insulin sensitivity, whereas the rosiglitazone treatment decreased the serum PEDF and down-regulated PEDF expression in fat and liver of the obese rats, concomitant with significantly enhanced insulin sensitivity. In vitro, the IR cells showed increased PEDF secretion and expression, whereas rosiglitazone lowered PEDF secretion and expression, accompanied with increased insulin sensitivity. Interestingly, combination with 2-chloro-5-nitro-N-phenylbenzamide did not influence the effect of rosiglitazone on PEDF. However, rosiglitazone stimulated AMPK phosphorylation in fat and liver of the obese rats, whereas in vitro, when combined with compound C, the effect of rosiglitazone on PEDF was abrogated. In summary, rosiglitazone inhibits the expression and secretion of PEDF in fat and liver via promoting AMPK phosphorylation rather than peroxisome proliferator-activated receptor-γ, and changes of PEDF induced by rosiglitazone are closely associated with IR improvement.