Yi-Shen-Hua-Shi regulates intestinal microbiota dysbiosis and protects against proteinuria in patients with chronic kidney disease: a randomized controlled study.

CONTEXT: Yi-Shen-Hua-Shi (YSHS) is a traditional Chinese medicine that treats chronic kidney disease (CKD). However, its efficacy in reducing proteinuria and underlying mechanisms is unknown. OBJECTIVE: This single-center randomized controlled trial explored whether YSHS could improve proteinuria and modulate the gut microbiota. MATERIALS AND METHODS: 120 CKD patients were enrolled and randomized to receive the renin-angiotensin-aldosterone system (RAAS) inhibitor plus YSHS (n = 56) or RAAS inhibitor (n = 47) alone for 4 months, and 103 patients completed the study. We collected baseline and follow-up fecal samples and clinical outcomes from participants. Total bacterial DNA was extracted, and the fecal microbiome was analyzed using bioinformatics. RESULTS: Patients in the intervention group had a significantly higher decrease in 24-h proteinuria. After 4 months of the YSHS intervention, the relative abundance of bacteria that have beneficial effects on the body, such as Faecalibacterium, Lachnospiraceae, Lachnoclostridium, and Sutterella increased significantly, while pathogenic bacteria such as the Eggerthella and Clostridium innocuum group decreased. However, we could not find these changes in the control group. Redundancy analysis showed that the decline in 24-h proteinuria during follow-up was significantly correlated with various taxa of gut bacteria, such as Lachnospiraceae and the Lachnoclostridium genus in the YSHS group. KEGG analysis also showed the potential role of YSHS in regulating glycan, lipid, and vitamin metabolism. DISCUSSION AND CONCLUSION: The YSHS granule reduced proteinuria associated with mitigating intestinal microbiota dysbiosis in CKD patients. The definite mechanisms of YSHS to improve proteinuria need to be further explored. TRIAL REGISTRATION: ChiCTR2300076136, retrospectively registered.

Guillain-Barré syndrome: immunopathogenesis and therapeutic targets.

INTRODUCTION: Guillain-Barré syndrome (GBS) is a group of acute immune-mediated disorders in the peripheral nervous system. Both infectious and noninfectious factors are associated with GBS, which may act as triggers of autoimmune responses leading to neural damage and dysfunction. AREAS COVERED: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its vaccines as well as flaviviruses have been associated with GBS, although a robust conclusion has yet to be reached. Immunomodulatory treatments, including intravenous immunoglobulins (IVIg) and plasma exchange (PE), have long been the first-line therapies for GBS. Depending on GBS subtype and severity at initial presentation, the efficacy of IVIg and PE can be variable. Several new therapies showing benefits to experimental animals merit further investigation before translation into clinical practice. We review the state-of-the-art knowledge on the immunopathogenesis of GBS in the context of coronavirus disease 2019 (COVID-19). Immunomodulatory therapies in GBS, including IVIg, PE, corticosteroids, and potential therapies, are summarized. EXPERT OPINION: The association with SARS-CoV-2 remains uncertain, with geographical differences that are difficult to explain. Evidence and guidelines are lacking for the decision-making of initiating immunomodulatory therapies in mildly affected patients or patients with regional subtypes of GBS.

Hypoxic Conditioning: A Potential Perioperative Strategy to Reduce Abdominal Aortic Occlusion-Related Injury in Mouse Proximal and Distal Organs.

This study aimed to investigate the impact of abdominal aortic occlusion (AAO)- induced injury on the kidney, lower limb muscles, heart, and brain in mice, and the potential protective effects of hypoxic postconditioning (HyC). The experimental design employed an abdominal aortic occlusion (AAO) model, and involved three groups of mice: sham, AAO, and AAO+HyC. Ten minutes after the AAO model, mice were subjected to hypoxic treatment lowering oxygen concentration to 5% within 45 minutes, and then returned to a normal oxygen environment. Hematoxylin- eosin (HE) stain was used for Histopathological examinations, and Quantibody Mouse Array was used for detecting apoptosis and inflammation-related protein expression. Histopathological examinations showed that HyC mitigated pathological damage to proximal organs (kidneys and lower limb muscles), distal organs (heart and brain), and reduced inflammatory cell infiltration. Expression of apoptosis- and inflammation-related proteins in brain and heart tissues were also evaluated. HyC significantly increased cellular inhibitor of apoptosis 2 (cIAP2) in the brain and Bcl-2 and insulin-like growth factor 2 (IGF-2) in the heart. Additionally, HyC regulated the expression of several inflammation-related factors in both brain and heart tissues. Although further investigation is needed, particularly in human subjects, this study highlights the potential of HyC as a promising therapeutic strategy for reducing AAO-associated organ damage.

An updated meta-analysis on the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor treatment of anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS: A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS: Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS: HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

High glucose dialysate-induced peritoneal fibrosis: Pathophysiology, underlying mechanisms and potential therapeutic strategies.

Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to dialysate frequently leads to peritoneal fibrosis, which alters the function of the peritoneal membrane and results in withdrawal from peritoneal dialysis in patients. Among others, high glucose dialysate is considered as a predisposing factor for peritoneal fibrosis in patients on peritoneal dialysis. Glucose-induced inflammation, metabolism disturbance, activation of the renin-angiotensin-aldosterone system, angiogenesis and noninflammation-induced reactive oxygen species are implicated in the pathogenesis of high glucose dialysate-induced peritoneal fibrosis. Specifically, high glucose causes chronic inflammation and recurrent peritonitis, which could cause migration and polarization of inflammatory cells, as well as release of cytokines and fibrosis. High glucose also interferes with lipid metabolism and glycolysis by activating the sterol-regulatory element-binding protein-2/cleavage-activating protein pathway and increasing hypoxia inducible factor-1α expression, leading to angiogenesis and peritoneal fibrosis. Activation of the renin-angiotensin-aldosterone system and Ras-mitogen activated protein kinase signaling pathway is another contributing factor in high glucose dialysate-induced fibrosis. Ultimately, activation of the transforming growth factor-ß1/Smad pathway is involved in mesothelial-mesenchymal transition or epithelial-mesenchymal transition, which leads to the development of fibrosis. Although possible intervention strategies for peritoneal dialysate-induced fibrosis by targeting the transforming growth factor-ß1/Smad pathway have occasionally been proposed, lack of laboratory evidence renders clinical decision-making difficult. We therefore aim to revisit the upstream pathways of transforming growth factor-beta1/Smad and propose potential therapeutic targets for high glucose-induced peritoneal fibrosis.

Caffeine intake improves the cognitive performance of patients with chronic kidney disease.

Objective: Cognitive impairment is a common complication of chronic kidney disease (CKD). Caffeine intake has been reported to improve cognitive performance in several studies. However, whether the benefits of caffeine intake on cognitive function apply to patients with CKD remains unknown. Methods: We performed a retrospective cross-sectional study based on the National Health and Nutrition Examination Survey (NHANES). The data of CKD subjects and non-CKD subjects from NHANES 2011-2014 were analyzed. Propensity score matching (PSM) was performed based on age, sex, diabetes, cancer, educational level, energy intake and protein intake to select subjects. The Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD-WL), the CERAD Word List Recall Test (CERAD-DR), the Animal Fluency Test (AF) and the Digit Symbol Substitution Test (DSST) were used, whereby the occurrence of cognitive impairment was identified. Logistic regression models were performed to evaluate the association between caffeine intake and cognitive performance in CKD and non-CKD participants. Stratified analyses according to the stage of CKD and the urinary albumin/creatinine ratio levels were performed. Plot curves were then generalized to present a non-linear relationship, and the inflection point for each non-linear model was obtained by using a recursive algorithm. Results: Cognitive impairment was more prevalent in CKD patients than in non-CKD subjects. For CKD patients, caffeine intake was associated with higher CERAD-WL, CERAD-DR, AF and DSST scores. For non-CKD subjects, caffeine intake was associated with higher DSST scores only. Subgroup analysis revealed that caffeine only benefited the cognitive function of patients with CKD stages 2 and 3. The analysis showed non-linear relationships of caffeine intake and cognitive function for both CKD and non-CKD subjects. The inflection point of caffeine intake for CKD patients was 279 mg/day. Conclusion: The recommended dose of caffeine intake to improve the cognitive function of CKD patients is ≤279 mg/day.

Irisin alleviates vascular calcification by inhibiting VSMC osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling pathway in chronic kidney disease.

BACKGROUND AND AIMS: Vascular calcification (VC) is an intricate active process, significantly controlled by vascular smooth muscle cells (VSMCs). Mitochondrial dysfunction plays a pivotal role in VC and VSMCs osteoblastic transformation. We previously reported that decreased levels of Irisin were independently associated with VC in hemodialysis patients. The present study aimed to investigate the role of Irisin in VC, especially in VSMCs osteoblastic transformation and mitochondrial function. METHODS: In vitro, VSMCs calcification was induced by ß-glycerophosphate, while in vivo VC was triggered by adenine and high phosphorus diet. Alizarin red, Von Kossa staining, and calcium and Alp activity were performed to test VC. Western blot and immunohistochemical staining were employed to analyze the expression of proteins associated with VSMCs osteoblastic transformation and AMPK signaling. Mitochondrial membrane potential (MMP) and structures were observed by immunofluorescence staining. RESULTS: Irisin alleviated VSMCs calcification induced by ß-glycerophosphate. Mechanistically, Irisin activated AMPK and downregulated the expression of Drp1, further alleviating mitochondria fission and VSMCs osteoblastic transformation. In vivo, Irisin decreased serum creatinine, urea and phosphorous levels in chronic kidney disease (CKD) mice. Importantly, Irisin treatment postponed CKD-associated VC with the upregulation of α-Sma and p-AMPK expression, and the downregulation of Runx2 and Drp1 expression. CONCLUSIONS: Our results firstly reveal that Irisin inhibits CKD-associated VC. Irisin suppresses VSMCs osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling.

Severity of frailty as a significant predictor of mortality for hemodialysis patients: a prospective study in China.

Background: Frailty is known to be highly prevalent in older hemodialysis (HD) patients. We studied the prevalence of frailty and its associated factors in Chinese HD patients. We further studied if frailty could predict survival in HD patients. Methods: This is a prospective study involving patients receiving maintenance HD in the dialysis center of Xuanwu Hospital, Beijing. Study subjects were enrolled from October to December, 2017 and followed up for two years. Demographic data, comorbidities and biological parameters were collected. Frailty was assessed using the Fried frailty phenotype at baseline. Cox regression analysis was performed to identify the relationship between frailty and mortality in HD patients. Kaplan-Meier was plotted using the cutoff value obtained by ROC curve to evaluate survival rates in different frailty status. Results: Total of 208 HD patients were enrolled with a mean age of 60.5±12.7 years. According to the frailty criteria, at baseline the prevalence of robust, pre-frail and frail in HD patients was 28.7%, 45.9%, and 25.4%, respectively. The two-year all-cause mortality was 18.8% (39/207) and underlying causes of death included coronary artery disease (CAD), cerebrovascular disease (CVD), hyperkalemia, severe infection, malignant tumor and others. Survival curve showed the patients with frailty score ≥4 to have significantly shorter survival time as compared to patients with frailty score ≤ 3. Frailty predicted two-year mortality when frailty score ≥4 with a sensitivity of 70% and a specificity of 83.67% with an AUC of 0.819. Frailty score was positively associated with age and ratio of ultrafiltration volume to dry weight, while negatively associated with levels of serum albumin, uric acid and diastolic blood pressure after HD. Conclusions: Our results confirm frailty to be very common among HD patients and severity of frailty was a significant predictor of mortality for HD patients. Factors such as age, malnutrition and low blood pressure are the factors to be associated with frailty. Interdialytic weight gain inducing excessive ultrafiltration volume is an important risk factor.

Lower serum irisin levels are associated with the increasing mortality of cardiovascular and cerebrovascular diseases in hemodialysis patients.

BACKGROUND: Irisin is a recently discovered myokine/adipokine and lower levels of irisin were proved to be associated with adverse outcomes of cardiovascular and cerebrovascular diseases (CCVD) in general population. A significant decrease of irisin concentrations were also detected in patients with chronic kidney disease (CKD). In the present study, we investigated whether the serum irisin levels were associated with cardiovascular and cerebrovascular mortality in hemodialysis (HD) patients. METHODS: This retrospective cohort study enrolled 152 HD patients. Kaplan-Meier analysis was used to estimate the cumulative mortality of CCVD. The differences between the survival curves were compared by log-rank test. A multivariable Cox regression analysis was employed to identify the predictors of CCVD related deaths. RESULTS: Among 152 HD patients, 55 patients died and 18 of them died of CCVD, 97 HD patients survived. Compared with the survival group, patients died of CCVD had significantly lower serum irisin levels [23.6 (2.2, 319.4) vs. 45.7 (2.1, 367.8) ng/mL, P<0.05]. The Kaplan-Meier survival curves showed that patients with lower levels of irisin had higher CCVD mortality. The Cox regression analysis indicated lower irisin level as an independent risk factor for CCVD mortality in HD patients but not for all-cause mortality. CONCLUSIONS: Our results provided an association between lower irisin level and CCVD mortality in HD patients. Lower levels of irisin increased the mortality of CCVD in HD patients.

Benefits of resistant starch type 2 for patients with end-stage renal disease under maintenance hemodialysis: a systematic review and meta-analysis.

Background: Resistant starch type 2 (RS2) has been documented to regulate gut microbiota and to improve the clinical outcomes of several diseases. However, whether RS2 may benefit patients with end-stage renal disease under maintenance hemodialysis (MHD) remains unknown. Methods: We conducted a systemic review and meta-analysis of randomized controlled trials (RCTs). Adult patients receiving MHD were treated with RS2 (CRD42020160332). The primary outcomes were changes of uremic toxins, and the secondary outcomes were changes of inflammatory indicators, albumin and phosphorus. Results: After screening 65 records, five RCTs (n = 179) were included. A significant decrease of blood urea nitrogen (weighted mean difference (WMD) = -6.91, 95% CI: -11.87 to -1.95, I2 = 0%, P = 0.006), serum creatinine (WMD = -1.11, 95% CI: -2.18 to -0.05, I2 = 44%, P = 0.04) and interleukin (IL)-6 in blood (standard mean difference (SMD) = -1.08, 95% CI: -1.64 to -0.53, I2 = 35%, P = 0.0001) was revealed in the RS2 group. Analyses of blood levels of uric acid, p-cresyl sulfate, indoxyl sulfate, high sensitive C-reaction protein, albumin and phosphorus yielded no significant difference. Conclusions: Our results suggest that RS2 may improve the residual renal function of patients under MHD and mitigate a proinflammatory response.

Comparing the predictive values of five scales for 4-year all-cause mortality in critically ill elderly patients with sepsis.

BACKGROUND: Several severity scales have been documented to predict the short-term mortality of septic patients. However, the predictive efficacies of different severity scales in the long-term mortality of the elderly have yet to be evaluated. METHODS: In the retrospective study, a cohort of 4,370 elderly (≥65 years) septic patients admitted to the intensive care unit (ICU) were divided into three different age groups, i.e., the younger-old group (65 years ≤ age <75 years), the older-old group (75 years ≤ age <85 years) and the oldest-old group (age ≥85 years). Five scales, including the Simplified Acute Physiology Score II (SAPS II), the Oxford Acute Severity of Illness Score (OASIS), the Modified Logistic Organ Dysfunction System (MLODS), the Systemic Inflammatory Response Syndrome (SIRS) and Sequential Organ Failure Assessment (SOFA), were used for disease severity evaluations. The Kaplan-Meier survival curve, and the area under the receiver operating characteristic curve (AUC) were used to assess prognostic values of the long-term mortality of each severity scale. RESULTS: Compared with patients in the oldest-old group, those in the younger-old and the older-old groups had higher scores of SAPS II and OASIS, indicating more serious illness and worse prognosis. The survival time of patients was inversely related to age; the mean survival time was the longest in the youngerold group, followed by the older-old group and the oldest-old group. SAPS II had the best prognostic value (AUC: 0.648 for SAPS II, 0.579 for MLODS, 0.577 for SOFA, 0.612 for OASIS and 0.515 for SIRS, P<0.01) for the 4-year all-cause mortality. Elderly patients with an SAPS II score >43 had a lower survival rate regardless of age. CONCLUSIONS: The long-term mortality of elderly patients with sepsis is increased with age. SAPS II can better predict the long-term prognosis of elderly septic patients in ICU.

Convulsive status epilepticus as the initial presentation of superwarfarin poisoning: a case report.

Bromadiolone, a widely-used rodent control drug, could act as a long-acting anticoagulant. Patients of bromadiolone poisoning often present with multiorgan hemorrhage. However, neurological symptoms of bromadiolone poisoning are seldom reported. We report a rare case with convulsive status epilepticus as the initial presentation of bromadiolone poisoning. A previously healthy 18-year-old man presented with persistent unconsciousness and repeated convulsive seizures. Magnetic resonance imaging revealed lesions in the corpus callosum. Laboratory test revealed the microscopic hematuria, prolonged prothrombin time, prolonged activated partial thromboplastin time and the presence of bromadiolone. The patient was diagnosed as the bromadiolone poisoning and treated with hemofiltration, vitamin K and prothrombin complex. Consciousness of the patient was regained and all neurological symptoms diminished after 7 days. Coagulopathy was totally corrected after 3 weeks, and a 2-month regimen of vitamin K supplementation was prescribed after discharge. Our case suggests that bromadiolone poisoning may involve the central nervous system. The atypical and initial symptoms of neurological disorders might lead to misdiagnosis of bromadiolone poisoning. Poisoning should be considered when acute neurological symptoms are combined with bleeding tendency. The vitamin K treatment is effective for both coagulopathy and central nervous system disorders in bromadiolone poisoning.

Factors Associated with Brachial-Ankle Pulse Wave Velocity in an Apparently Healthy Chinese Population.

PURPOSE: To investigate the factors influencing brachial-ankle pulse wave velocity (baPWV) in an apparently healthy Chinese population, especially the associations between baPWV and indices of blood pressure (BP). METHODS: A total of 1123 participants with no history of hypertension were enrolled in this study, and the baPWV and BP of all four limbs were measured along with other covariates. Correlation analyses and multivariate linear regression models were used to identify factors associated with baPWV. RESULTS: A total of 1123 participants (male 43.3%, mean age: 58.4 ± 13.9 years) were included. The average baPWV was 14.87 ± 3.21 m/s, and no difference was found between the sexes. Age was positively correlated with baPWV (r = 0.65, p < 0.01), especially in females (r = 0.71 versus 0.56 in males). The correlation coefficient between age and baPWV increased markedly after the age of 65 years. In addition, the resting heart rate (RHR), waist-hip ratio, glomerular filtration rate, and plasma glucose level were significantly correlated with baPWV (r = 0.25, 0.22, -0.43, and 0.25, respectively; p < 0.01). BP parameters were highly positively correlated with baPWV, especially systolic BP (SBP) and pulse pressure (PP). Multivariate regression revealed that age, BP parameters, and RHR were independently correlated with baPWV (p < 0.01) after adjusting for confounding factors. The standardized coefficients of SBP were greater than those of PP, followed by diastolic BP (DBP). CONCLUSION: BaPWV increased with age, especially after 65 years. Age, BP, and RHR were independent factors associated with baPWV. The effect of SBP on baPWV was more prominent than that of PP.

Better pulmonary function is associated with greater handgrip strength in a healthy Chinese Han population.

BACKGROUND: Handgrip strength (HGS) has been widely studied in clinical and epidemiological settings, but the relationship between HGS and pulmonary function is still controversial. This study analysed pulmonary function and HGS stratified by sex and age in a healthy Chinese Han population, as well as the associations between HGS and pulmonary function parameters. METHODS: HGS was measured by a Jamar dynamometer and pulmonary function was tested using a portable spirometer. Frequencies and variables are presented as percentages and means ± standard deviations, respectively. Chi-square tests were used for comparisons of categorical variables, and Student's t-tests or Mann-Whitney U-tests were used for continuous variables. Pearson's correlation coefficients were used to analyse the normally distributed variables, and Spearman correlation coefficients were used to analyse the non-normally distributed variables. Multivariate linear regression models were employed to explore the relationships between HGS and parameters of pulmonary function. The statistical significance was set at p < 0.01. RESULTS: Cross-sectional data were available for 1519 subjects (59.0% females, 57.9 ± 13.3 years old). Males had higher average HGS than females (40.2 vs. 25.0 kg, p < 0.01), as well as better pulmonary function. Both HGS and pulmonary function parameters were significantly inversely correlated with age (r ≤ - 0.30, p < 0.01). The maximum value of vital capacity (VC max), forced expiratory volume in 3 s (FEV 3) and forced vital capacity (FVC) were strongly correlated with HGS among the pulmonary function indices (r = 0.72, 0.70 and 0.69, respectively, p < 0.001). In the multivariate linear regression analysis, HGS and height were positively correlated, while age and pulse pressure were negatively correlated with HGS. In males, the FVC, VC max and FEV3 increased by 0.02 L, 0.023 L and 0.03 L in per 1 kg increase in HGS, respectively. The HGS coefficients for females were smaller than those for males. CONCLUSIONS: Both pulmonary function and HGS were inversely correlated with age, and better pulmonary function was associated with greater handgrip strength.