U-shaped association of serum magnesium with mild cognitive impairment among hemodialysis patients: a multicenter study.

BACKGROUND: The optimal serum magnesium level of patients undergoing hemodialysis (HD) with cognitive impairment is still unclear. This study aimed to evaluate the association between serum magnesium levels and mild cognitive impairment among HD patients. METHODS: This was a multicenter observational study. Patients undergoing hemodialysis from 22 dialysis centers in Guizhou Province, China were recruited into the study. HD patients were divided into five groups according to serum magnesium quintile. Cognitive function was measured with Mini Mental State Examination. The outcome was an incident mild cognitive impairment (MCI). Multivariate logistic regression analysis, restricted cubic spline and subgroup analysis were applied to explore the association of serum magnesium level with MCI. RESULTS: Among 3562 HD patients (mean age 54.3 years, 60.1% male), the prevalence of MCI was 27.2%. After adjusting for confounders, serum magnesium 0.41-0.83 mmol/L [odds ratios (OR) 1.55, 95% confidence interval (CI): 1.10-2.18] had a higher risk of MCI compared with serum magnesium of 1.19-1.45 mmol/L. A U-shaped association was identified between the serum magnesium and incident MCI (P for non-linearity = 0.004). The optimal range of magnesium level with the lowest risk of MCI was 1.12-1.24 mmol/L. As the serum magnesium level was lower than 1.12 mmol/L, the risk of MCI decreased by 24% per standard deviation (SD) increase in serum magnesium (OR 0.76, 95%CI: 0.62-0.93); when the serum magnesium level exceeds 1.24 mmol/L, a rise per SD increased the risk of MCI by 21% (OR = 1.20, 95%CI: 1.02-1.43). Subgroup analyses demonstrated that the associations were robust among individuals with low educational level, smoking, living alone, no working, and without hypertension or diabetes. CONCLUSIONS: Serum magnesium has a U-shaped association with MCI among HD patients. Both lower and higher serum magnesium can increase the risk of MCI for this population specifically. The optimal serum magnesium range with the lowest risk of MCI was 1.12-1.24 mmol/L.

The Impact of Malnutrition, Inflammation on Cognitive Impairment in Hemodialysis Patients: A Multicenter Study.

INTRODUCTION: Cognitive impairment is prevalent in patients undergoing hemodialysis (HD), which is related to the nutritional and inflammatory status of this population. Malnutrition-inflammation score (MIS) has been identified as a useful tool to evaluate nutrition and inflammation status. The aim of this study is to investigate the association between MIS and cognitive impairment in HD patients. METHODS: This was a multicenter observational cohort study with 1,591 patients undergoing HD. Nutritional and inflammatory status was evaluated with MIS, anthropometric measurements, and body composition assessments. Cognitive function was evaluated with the Mini Mental State Examination (MMSE). The associations between MIS and cognitive impairment were analyzed by multivariable logistic regression models. RESULTS: Among 1,591 HD patients, the mean MIS was 6.0 ± 2.6. Patients with higher MIS had significantly lower MMSE scores. 311 patients had cognitive impairment. After adjusting clinical confounders, higher MIS was independently associated with increased rate of cognitive impairment both as a categorized variable (OR, 1.358; 95% CI, 1.010-1.825; p = 0.045) and as a continuous variable (OR, 1.113; 95% CI, 1.053-1.178; p < 0.001). Subgroup analysis showed a stronger association between MIS and cognitive impairment in males, the population with age 41-60 years, and 61-80 years, no smoker, living by oneself, HD combined with or without hemoperfusion as dialysis modality. ROC curve analysis of MIS showed 60.1% sensitivity and 52.0% specificity in predicting cognitive impairment (AUC 0.604; 95% CI 0.567-0.640, p < 0.001). CONCLUSIONS: MIS was independently associated with cognitive impairment in HD patients.

Roxadustat (FG-4592) protects against ischaemia/reperfusion-induced acute kidney injury through inhibiting the mitochondrial damage pathway in mice.

Ischaemia-reperfusion (I/R) is one of the main factors of acute kidney injury (AKI). mitochondrial damage pathway are important features of I/R induced-acute kidney injury (IRI-AKI). Hypoxia-inducible factor (HIF) expression in renal tubule segments is up-regulated during AKI. Herein, we investigated the role of FG-4592 in a mouse model of IRI-AKI to confirm whether FG-4592 is beneficial in AKI. We found that pretreatment with FG-4592 significantly ameliorated renal function and renal histological damage in mice after IRI. Furthermore, these results suggest that pretreatment with FG-4592 significantly reduced the tubular cells apoptosis (decreased TUNEL-positive cells, Bax, caspase12 levels), attenuated mitochondrial damage (increased ATPß, PPARγ, mitochondrial DNA copy number, and decreased cytoplasmic cytochrome C), and alleviated DNA damage after IRI. In conclusion, pretreatment with FG-4592 may effectively prevent kidney from IRI possibly by via diminishing tubular cells injuries and protection of mitochondrial damage pathway. These results further validate that FG-4592 may be an effective drug in the clinical treatment of IRI-AKI.

The treatment and follow-up of 'recurrence' with discharged COVID-19 patients: data from Guizhou, China.

We reported 20 cases of discharged COVID-19 patients whose RT-PCR test results showed 're-positive'. After finding 're-positive', these patients were admitted to hospital for the second time and were followed up until the end of May 2020. We recorded detailed treatment and follow-up process, and collected relevant data. The possible causes and potential clinical significance of this phenomenon are discussed.

Clinical characteristics of 134 convalescent patients with COVID-19 in Guizhou, China.

BACKGROUND: Previous studies have focused on the clinical characteristics of hospitalized patients with the novel 2019 coronavirus disease (COVID-19). Limited data are available for convalescent patients. This study aimed to evaluate the clinical characteristics of discharged COVID-19 patients. METHODS: In this retrospective study, we extracted data for 134 convalescent patients with COVID-19 in Guizhou Provincial Staff Hospital from February 15 to March 31, 2020. Cases were analyzed on the basis of demographic, clinical, and laboratory data as well as radiological features. RESULTS: Of 134 convalescent patients with COVID-19, 19 (14.2%) were severe cases, while 115 (85.8%) were non-severe cases. The median patient age was 33 years (IQR, 21.8 to 46.3), and the cohort included 69 men and 65 women. Compared with non-severe cases, severe patients were older and had more chronic comorbidities, especially hypertension, diabetes, and thyroid disease (P < 0.05). Leukopenia was present in 32.1% of the convalescent patients and lymphocytopenia was present in 6.7%, both of which were more common in severe patients. 48 (35.8%) of discharged patients had elevated levels of alanine aminotransferase, which was more common in adults than in children (40.2% vs 13.6%, P = 0.018). A normal chest CT was found in 61 (45.5%) patients during rehabilitation. Severe patients had more ground-glass opacity, bilateral patchy shadowing, and fibrosis. No significant differences were observed in the positive rate of IgG and/or IgM antibodies between severe and non-severe patients. CONCLUSION: Leukopenia, lymphopenia, ground-glass opacity, and fibrosis are common in discharged severe COVID-19 patients, and liver injury is common in discharged adult patients. We suggest physicians develop follow-up treatment plans based on the different clinical characteristics of convalescent patients.

Silencing of long noncoding RNA XIST protects against renal interstitial fibrosis in diabetic nephropathy via microRNA-93-5p-mediated inhibition of CDKN1A.

Long noncoding RNAs (lncRNAs) have been reported to play an important role in diabetic nephropathy (DN). However, the molecular mechanism involved in this process remains poorly understood. Thus, the present study aimed to explore the function and molecular mechanism of dysregulated lncRNA X-inactive specific transcript (XIST) in DN. DN mouse models were established by streptozotocin treatment, and human renal tubular epithelial HK-2 cells were exposed to high glucose to produce an in vitro model. XIST was highly expressed in renal tissues of patients with DN, mice with DN, and high glucose-exposed HK-2 cells. To identify the interaction among XIST, miR-93-5p, and cyclin-dependent kinase inhibitor 1A (CDKN1A) and to analyze the functional significance of their interaction in renal interstitial fibrosis, we altered endogenous expression of XIST and miR-93-5p and CDKN1A. Dual-luciferase reporter assay results suggested that XIST was highly expressed in the kidney tissue of DN mice and high glucose-exposed HK-2 cells. XIST was identified to be a lncRNA that could bind to miR-93-5p, and CDKN1A was a target of miR-93-5p. Downregulated expression of XIST led to an increase in miR-93-5p expression, thereby decreasing CDKN1A and suppressing renal interstitial fibrosis in DN. Consistently, XIST knockdown reduced the expression of fibrosis markers (fibronectin, collagen type IV, and transforming growth factor-ß1). Restoration of CDKN1A or decreasing miR-93-5p yielded a reversed effect on renal interstitial fibrosis. In conclusion, our study demonstrated that silenced XIST inducing miR-93-5p-dependent CDKN1A inhibition was beneficial for preventing renal interstitial fibrosis in DN, which may provide a future strategy to prevent the progression of DN.

Associations of metabolic syndrome, its severity with cognitive impairment among hemodialysis patients.

BACKGROUND: In the general population, metabolic syndrome (MetS) is associated with increased risk of cognitive impairment, including global and specific cognitive domains. These associations are not well studied in patients undergoing hemodialysis and were the focus of the current investigation. METHODS: In this multicenter cross-sectional study, 5492 adult hemodialysis patients (3351 men; mean age: 54.4 ± 15.2 years) treated in twenty-two dialysis centers of Guizhou, China were included. The Mini-Mental State Examination (MMSE) was utilized to assess mild cognitive impairment (MCI). MetS was diagnosed with abdominal obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariate logistic and linear regression models were used to examine the associations of MetS, its components, and metabolic scores with the risk of MCI. Restricted cubic spline analyses were performed to explore the dose-response associations. RESULTS: Hemodialysis patients had a high prevalence of MetS (62.3%) and MCI (34.3%). MetS was positively associated with MCI risk with adjusted ORs of 1.22 [95% confidence interval (CI) 1.08-1.37, P = 0.001]. Compared to no MetS, adjusted ORs for MCI were 2.03 (95% CI 1.04-3.98) for 22.51 (95% CI 1.28-4.90) for 3, 2.35 (95% CI 1.20-4.62) for 4, and 2.94 (95% CI 1.48-5.84) for 5 components. Metabolic syndrome score, cardiometabolic index, and metabolic syndrome severity score were associated with increased risk of MCI. Further analysis showed that MetS was negatively associated with MMSE score, orientation, registration, recall and language (P < 0.05). Significant interaction effect of sex (P for interaction = 0.012) on the MetS-MCI was observed. CONCLUSION: Metabolic syndrome was associated with MCI in hemodialysis patients in a positive dose-response effect.

Decreased Intracellular to Total Body Water Ratio and Depressive Symptoms in Patients with Maintenance Hemodialysis.

Objective: Depression is a common psychiatric disorder and related to poor outcomes in patients undergoing maintenance hemodialysis (MHD). Previous studies have reported some associations between sarcopenia and depressive symptoms. Recently, intracellular water (ICW) and total body water (TBW) have been found to reflect muscle function and muscle mass. ICW/TBW ratio is a marker of sarcopenia that is simple to assess. However, the relationship between ICW/TBW ratio and depression has not been explored in MHD patients. Methods: In our cross-sectional and multi-center study, 3300 adult MHD patients were included from June 1, 2021, to August 30, 2021. Depressive symptoms were evaluated using the Beck Depression Inventory-II (BDI-II). TBW and ICW were measured by Body Composition Monitor (BCM). Multivariable logistic regression, stratified analyses, and interactive analyses were conducted to assess the relationship between ICW/TBW ratio and depression. Results: About 16.5% of the 3300 MHD patients were found to have depressive symptoms. The prevalence of depression increased with decreasing quartiles of ICW/TBW ratios, and decreased ICW/TBW ratio was independently associated with depression after adjusting for potential confounders. Patients in Quartile 1 of ICW/TBW ratios were more likely to have depressive symptoms (odds ratio 1.55, 95% confidence interval 1.07-2.22; p=0.002) than those in Quartile 4. History of diabetes and education status had interactive roles in the relationship between depression and ICW/TBW ratios (p < 0.05). The association of ICW/TBW ratios and depression existed in patients of both genders and different education levels, but only in non-diabetic patients. Conclusion: In MHD patients, the decreased ratio of ICW/TBW was independently related to high depression rates.

[Clinical observation of different doses of continuous renal replacement therapy for severe pneumonia with acute kidney injury].

OBJECTIVE: To explore the efficacy of different doses of continuous renal replacement therapy (CRRT) in the treatment of severe pneumonia with acute kidney injury. METHODS: Twenty-eight patients with severe pneumonia and acute kidney injury were recruited from our hospital between February 2009 and March 2012. They divided into 3 groups: group A receiving a large dose of continuous veno-venous hemodiafiltration (CVVHDF) (70 ml×kg(-1)×h(-1), n = 9), group B a moderate dose of CVVHDF (45 ml×kg(-1)×h(-1), n = 8) and group C a low dose of CVVHDF (25 ml×kg(-1)×h(-1), n = 11). Before and after treatment, the changes of patient conditions, renal function and blood gas analysis were recorded. Such biomarkers as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), white blood cell (WBC) and neutrophil granulocyte (N) were determined. RESULTS: Compared with group C, the levels of leucocyte ((11.0 ± 3.2)×10(9)/L, (11.1 ± 5.3)×10(9)/L vs (8.5 ± 2.7)×10(9)/L), CRP ((89 ± 10), (90 ± 14) vs (107 ± 13) mg/L), TNF-α ((99 ± 39), (103 ± 28) vs (123 ± 35) pg/L), IL-6 ((54 ± 22), (69 ± 20) vs (81 ± 24) pg/L) and IL-8 ((104 ± 50), (138 ± 63) vs (167 ± 71) pg/L) decreased significantly in groups A and B after treatment (all P < 0.05). There were no differences in the levels of CRP, IL-6, IL-8 or TNF-α levels between groups B and C (all P > 0.05). The recovery of kidney function was much more rapid in group A than in groups B and C. CONCLUSION: The large dose of CRRT may be more effective in the clearance of inflammatory mediators and improved survival of severe pneumonia with acute kidney injury than moderate and low doses.

Hyperhomocysteinemia exacerbates acute kidney injury via increased mitochondrial damage.

Acute kidney injury (AKI) is a complex and common set of multifactorial clinical syndromes, and associated with increased in-hospital mortality. There is increasing evidence that Hyperhomocysteinemia (HHcy) is highly associated with the development of a variety of kidney diseases, including AKI. However, the pathogenesis of HHcy in AKI remains unclear. In this study, we investigated the effect and mechanism of HHcy on cisplatin-induced AKI in mice and NRK-52E cells cultured with HHcy. We confirmed that mice with HHcy had higher serum levels of creatinine and more severe renal tubule injury after cisplatin injection. We found that HHcy aggravated renal mitochondrial damage, mainly manifested as decreased ATP ß, significantly increased cytoplasmic Cyt C expression and the ADP/ATP ratio, and a significantly decreased mitochondrial DNA (mtDNA) copy number. In addition, we found that HHcy accelerated cisplatin-induced renal DNA damage; culturing NRK-52E cells with homocysteine (Hcy) could significantly increase apoptosis and mitochondrial damage. Interestingly, we found that Mdivi-1 reduced Hcy-induced mitochondrial damage, thereby reducing the level of apoptosis. In conclusion, these results suggest that HHcy might aggravate the development of AKI by increasing mitochondrial damage and that reducing Hcy levels or inhibiting mitochondrial damage may be a potential therapeutic strategy to delay the development of AKI.

Resting metabolic rate and its adjustments as predictors of risk protein-energy wasting in hemodialysis patients.

BACKGROUND: The purpose of the present study was to explore the association between resting metabolic rate (RMR) and protein-energy wasting (PEW) risk in Chinese hemodialysis patients by age and gender subgroup. METHODS: RMR and body composition (body cell mass (BCM) and fat mass) of 774 patients undergoing hemodialysis were estimated by bio-electrical impedance analysis (BIA). Anthropometric data were collected by a standard measurement protocol, and the upper arm muscle circumference (AMC) was calculated. Biochemical nutritional and dialysis parameters were obtained. Linear regression analysis was used to analyze the relationship among RMR, body composition and nutritional factors. RESULTS: The mean age was 54.96 ± 15.78 years. RMR level in patients was 1463.0 (1240.5, 1669.0) kcal/d. In multiple linear regression models, BCM, left calf circumference (LCC), fat mass were the determinants association with RMR (P<0.001). Among the patients in the sample, 133 (17.2%) had been diagnosed with PEW per International Society of Renal Nutrition and Metabolism (ISRNM) criteria and 363 (46.9%) were being at risk PEW. The area under the receiver-operating characteristic curve (AUC) of RMR for predicting risk PEW was greater than RMR/BCM and RMR/body surface area (BSA). When the cutoff of RMR was 1481 kcal/d it had the higher sensitivity and specificity (82 and 42%), and the AUC was 0.68 in elderly maintenance hemodialysis (MHD) patients (P<0.001). After adjustment for potential confounders, lowest RMR quartile level (<1239) increased the risk of PEW (OR = 4.71, 95% CI: 1.33-16.64, P=0.016) in all patients. CONCLUSIONS: Older patients with PEW have a lower RMR reduction. RMR and RMR/BCM may play the role in objective screening to detect risk PEW in MHD patients, especially in males.

Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis.

BACKGROUND: Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. METHODS: Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. RESULTS: Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. CONCLUSION: Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

Hyperhomocysteinemia Exacerbates Cisplatin-induced Acute Kidney Injury.

Hyperhomocysteinemia (HHcy) has been linked to several clinical manifestations including chronic kidney disease. However, it is not known whether HHcy has a role in the development of acute kidney injury (AKI). In the present study, we reported that HHcy mice developed more severe renal injury after cisplatin injection and ischemia-reperfusion injury shown as more severe renal tubular damage and higher serum creatinine. In response to cisplatin, HHcy mice showed more prevalent tubular cell apoptosis and decreased tubular cell proliferation. Mechanistically, a heightened ER stress and a reduced Akt activity were observed in kidney tissues of HHcy mice after cisplatin injection. Stimulating cultured NRK-52E cells with Hcy significantly increased the fraction of cells in G2/M phase and cell apoptosis together with decreased Akt kinase activity. Akt agonist IGF-1 rescued HHcy-induced cell cycle arrest and cell apoptosis. In conclusion, the present study provides evidence that HHcy increases the sensitivity and severity of AKI.

Homocysteine in Renal Injury.

BACKGROUND: Homocysteine (Hcy) is an intermediate of methionine metabolism. Hyperhomocysteinemia (HHcy) can result from a deficiency in the enzymes or vitamin cofactors required for Hcy metabolism. Patients with renal disease tend to be hyperhomocysteinemic, particularly as renal function declines, although the underlying cause of HHcy in renal disease is not entirely understood. SUMMARY: HHcy is considered a risk or pathogenic factor in the progression of chronic kidney disease (CKD) as well as the cardiovascular complications. KEY MESSAGES: In this review, we summarize both clinical and experimental findings that reveal the contribution of Hcy as a pathogenic factor to the development of CKD. In addition, we discuss several important mechanisms mediating the pathogenic action of Hcy in the kidney, such as local oxidative stress, endoplasmic reticulum stress, inflammation and hypomethylation.

Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a.

Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.