Interaction between anemia and hyperuricemia in the risk of all-cause mortality in patients with chronic kidney disease.

Aim: Both hyperuricemia and anemia are not only the manifestation of chronic kidney disease (CKD) but also related to its occurrence and development. A recent study has found that there was a synergetic effect between hyperuricemia and anemia on new-onset CKD. Herein we aimed to explore the roles of hyperuricemia and anemia in the all-cause mortality in patients with CKD. Methods: Data of adult patients with CKD were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2009-2018 in this retrospective cohort study. Weighted univariate and multivariate COX regression analyses were used to investigate the associations of hyperuricemia and anemia with all-cause mortality, and the evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs). The interaction effect between hyperuricemia and anemia on the risk of all-cause mortality was assessed via relative excess risk due to interaction (RERI) and attributable proportion of interaction (AP). Subgroup analyses of age, gender, CVD, hypertension, DM, and cancer were also performed to assess this interaction effect. Results: Among 3,678 eligible patients, 819 died from all causes. After adjusting for covariables, we found that CKD patients with anemia (HR = 1.72, 95%CI: 1.42-2.09) or hyperuricemia (HR = 1.21, 95%CI: 1.01-11.45) had a higher risk of all-cause mortality. There was a potential synergetic effect between anemia and hyperuricemia on all-cause mortality, with RERI of 0.630 and AP of 0.291. Moreover, this synergetic effect was also observed in ≥65 years old (AP = 0.330), male (AP = 0.355), hypertension (AP = 0.736), non-hypertension (AP = 0.281), DM (AP = 0.371), and cancer (AP = 0.391) subgroups. Conclusion: A potential synergetic effect between anemia and hyperuricemia on all-cause mortality was found in patients with CKD. However, further studies are needed to clarify the causal relationship between them.

Cognitive Domain Impairment and All-Cause Mortality in Older Patients Undergoing Hemodialysis.

The highly prevalent cognitive impairment in hemodialysis patients is associated with all-cause mortality; however, the role of different cognitive domain impairments in this association is still not clarified. Our objective was to determine the association between cognitive domain impairment and all-cause mortality in elderly adult patients undergoing hemodialysis. We conducted a prospective cohort study including patients from 11 hemodialysis centers in Beijing. Baseline data were collected, and a series of neuropsychological batteries covering 5 domains of cognitive function were included for the assessment of cognitive function. According to the fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria (DSM-V), the patients were classified as normal, mild, and major cognitive impairment for global and domain cognitive function, then followed up for 1 year. Kaplan-Meier survival analysis was used to compare the difference in the cumulative survival rate in different cognitive domains. A multivariate Cox proportional hazards regression analysis was used to determine the association between global or domain cognitive impairment and all-cause mortality. A total of 613 patients were enrolled, the mean age was 63.82 ± 7.14 years old, and 42.1% were women. After 49.53 ± 8.42 weeks of follow-up, 69 deaths occurred. Kaplan-Meier plots demonstrated a significant association of cognitive impairment in memory, executive function, attention, and language domains with all-cause death. Multivariate Cox regression analysis showed that mild and major impairment of global cognition (HR = 2.89 (95% CI, 1.01-8.34), p = 0.049 and HR = 4.35 (95% CI, 1.55-12.16), p = 0.005, respectively), executive cognitive domain (HR = 2.51 (95% CI, 1.20-5.24), p = 0.014; HR = 3.91 (95% CI, 1.70-9.03), p = 0.001, respectively), and memory cognitive domain (HR = 2.13 (95% CI, 1.07-4.24), p = 0.031; HR = 3.67 (95% CI, 1.71-7.92), p = 0.001, respectively) were associated with all-cause mortality. Combined impairment of 3, 4, and 5 cognitive domains was associated with all-cause mortality [HR = 5.75 (95% CI, 1.88-17.57), p = 0.002; HR = 12.42 (95% CI, 3.69-41.80), p < 0.001; HR = 13.48 (95% CI, 3.38-53.73), p < 0.001, respectively]. We demonstrate an association between the executive and memory cognitive domain impairment and all-cause mortality in hemodialysis patients. Our data suggest that the impairments in these cognitive domains might help in the early identification of hemodialysis patients at risk of death.

Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H2 S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 µmol·kg-1 ) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plasmids for the overexpression of wild-type Hrd1 and Hrd1 mutated at Cys115 were constructed. The interaction between Hrd1 and DGAT1 and DGAT2, the ubiquitylation level of DGAT1 and 2, the S-sulfhydration of Hrd1 were measured. Exogenous H2 S ameliorated the cardiac functions, decreased ER stress and reduced the number of LDs in db/db mice. Exogenous H2 S could elevate the ubiquitination level of DGAT 1 and 2 and increased the expression of Hrd1 in cardiac tissues of db/db mice. The S-sulfhydration of Hrd1 by NaHS enhanced the interaction between Hrd1 and DGAT1 and 2 to inhibit the formation of LD. Our findings suggested that H2 S modified Hrd1 S-sulfhydration at Cys115 to reduce the accumulation of LDs in cardiac tissues of db/db mice.

Cognitive impairment and associated risk factors in older adult hemodialysis patients: a cross-sectional survey.

The clinical epidemiological features of cognitive impairment in Chinese older adult patients undergoing hemodialysis are not clear, we aimed to identify the extent and patterns of cognitive impairment among those patients. We conducted a cross-sectional study of 613 hemodialysis patients aged 50 to 80 from 11 centers in Beijing. A neuropsychological battery of 11 tests covering domains of attention/processing speed, executive function, memory, language, and visuospatial function was applied, patients were classified as none, mild, or major cognitive impairment according to the fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria for cognitive impairment. Compared with Chinese population norms, 37.2% of the participants had mild cognitive impairment, 43.7% had major cognitive impairment. Memory and language were the most severe impaired domains in the mild cognitive impairment group, attention and visuospatial function domains were the most serious impaired domains in the major cognitive impairment group. Concomitant impairment across multiple cognitive domains was common. Factors associated with major cognitive impairment included age, education level, history of stroke and hypertension, dialysis vintage, and single-pool Kt/V. There is a high frequency of cognitive impairment in Chinese older adult hemodialysis patients, with varying severity and concomitant impairment across multiple domains.

Hydrogen sulphide ameliorating skeletal muscle atrophy in db/db mice via Muscle RING finger 1 S-sulfhydration.

Muscle atrophy occurs in many pathological states, including cancer, diabetes and sepsis, whose results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. Expression of Muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, was increased to induce the loss of muscle mass in diabetic condition. However, hydrogen sulphide (H2 S) plays a crucial role in the variety of physiological functions, including antihypertension, antiproliferation and antioxidant. In this study, db/db mice and C2C12 myoblasts treated by high glucose and palmitate and oleate were chose as animal and cellular models. We explored how exogenous H2 S attenuated the degradation of skeletal muscle via the modification of MuRF1 S-sulfhydration in db/db mice. Our results show cystathionine-r-lyase expression, and H2 S level in skeletal muscle of db/db mice was reduced. Simultaneously, exogenous H2 S could alleviate ROS production and reverse expression of ER stress protein markers. Exogenous H2 S could decrease the ubiquitination level of MYOM1 and MYH4 in db/db mice. In addition, exogenous H2 S reduced the interaction between MuRF1 with MYOM1 and MYH4 via MuRF1 S-sulfhydration. Based on these results, we establish that H2 S prevented the degradation of skeletal muscle via MuRF1 S-sulfhydration at the site of Cys44 in db/db mice.

Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice.

Hydrogen sulfide (H2S), an important gasotransmitter, regulates cardiovascular functions. Mitochondrial damage induced by the overproduction of reactive oxygen species (ROS) results in myocardial injury with a diabetic state. The purpose of this study was to investigate the effects of exogenous H2S on mitophagy formation in diabetic cardiomyopathy. In this study, we found that exogenous H2S could improve cardiac functions, reduce mitochondrial fragments and ROS levels, enhance mitochondrial respiration chain activities and inhibit mitochondrial apoptosis in the hearts of db/db mice. Our results showed that exogenous H2S facilitated parkin translocation into mitochondria and promoted mitophagy formation in the hearts of db/db mice. Our studies further revealed that the ubiquitination level of cytosolic parkin was increased and the expression of USP8, a deubiquitinating enzyme, was decreased in db/db cardiac tissues. S-sulfhydration is a novel posttranslational modification of specific cysteine residues on target proteins by H2S. Our results showed that the S-sulfhydration level of USP8 was obviously decreased in vivo and in vitro under hyperglycemia and hyperlipidemia, however, exogenous H2S could reverse this effect and promote USP8/parkin interaction. Dithiothreitol, a reducing agent that reverses sulfhydration-mediated covalent modification, increased the ubiquitylation level of parkin, abolished the effects of exogenous H2S on USP8 deubiquitylation and suppressed the interaction of USP8 with parkin in neonatal rat cardiomyocytes treated with high glucose, oleate and palmitate. Our findings suggested that H2S promoted mitophagy formation by increasing S-sulfhydration of USP8, which enhanced deubiquitination of parkin through the recruitment of parkin in mitochondria.

Exogenous H2S Induces Hrd1 S-sulfhydration and Prevents CD36 Translocation via VAMP3 Ubiquitylation in Diabetic Hearts.

Hydrogen sulfide (H2S) plays physiological roles in vascular tone regulation, cytoprotection, and ATP synthesis. HMG-CoA reductase degradation protein (Hrd1), an E3 ubiquitin ligase, is involved in protein trafficking. H2S may play a role in controlling fatty acid uptake in diabetic cardiomyopathy (DCM) in a manner correlated with modulation of Hrd1 S-sulfhydration; however, this role remains to be elucidated. The aim of the present study was to examine whether H2S can attenuate lipid accumulation and to explain the possible mechanisms involved in the regulation of the H2S-Hrd1/VAMP3 pathway. Db/db mice and neonatal rat cardiomyocytes treated with high glucose, palmitate and oleate were used as animal and cellular models of type 2 diabetes, respectively. The expression of cystathionine-γ-lyase (CSE), Hrd1, CD36 and VAMP3 was detected by Western blot analysis. In addition, Hrd1 was mutated at Cys115, and Hrd1 S-sulfhydration was examined using an S-sulfhydration assay. VAMP3 ubiquitylation was investigated by immunoprecipitation. Lipid droplet formation was tested by TEM, BODIPY 493/503 staining and oil red O staining. The expression of CSE and Hrd1 was decreased in db/db mice compared to control mice, whereas CD36 and VAMP3 expression was increased. NaHS administration reduced droplet formation, and exogenous H2S restored Hrd1 expression, modified S-sulfhydration, and decreased VAMP3 expression in the plasma membrane. Using LC-MS/MS analysis, we identified 85 proteins with decreased ubiquitylation, including 3 vesicle-associated membrane proteins, in the cardiac tissues of model db/db mice compared with NaHS-treated db/db mice. Overexpression of Hrd1 mutated at Cys115 diminished VAMP3 ubiquitylation, whereas it increased CD36 and VAMP3 expression and droplet formation. siRNA-mediated Hrd1 deletion increased the expression of CD36 in the cell membrane. These findings suggested that H2S regulates VAMP3 ubiquitylation via Hrd1 S-sulfhydration at Cys115 to prevent CD36 translocation in diabetes.

Hydrogen sulfide regulates muscle RING finger-1 protein S-sulfhydration at Cys44 to prevent cardiac structural damage in diabetic cardiomyopathy.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S) plays important roles as a gasotransmitter in pathologies. Increased expression of the E3 ubiquitin ligase, muscle RING finger-1 (MuRF1), may be involved in diabetic cardiomyopathy. Here we have investigated whether and how exogenous H2 S alleviates cardiac muscle degradation through modifications of MuRF1 S-sulfhydration in db/db mice. EXPERIMENTAL APPROACH: Neonatal rat cardiomyocytes were treated with high glucose (40 mM), oleate (100 µM), palmitate (400 µM), and NaHS (100 µM) for 72 hr. MuRF1 was silenced with siRNA technology and mutation at Cys44 . Endoplasmic reticulum stress markers, MuRF1 expression, and ubiquitination level were measured. db/db mice were injected with NaHS (39 µmol·kg-1 ) for 20 weeks. Echocardiography, cardiac ultrastructure, cystathionine-γ-lyase, cardiac structure proteins expression, and S-sulfhydration production were measured. KEY RESULTS: H2 S levels and cystathionine-γ-lyase protein expression in myocardium were decreased in db/db mice. Exogenous H2 S reversed endoplasmic reticulum stress, including impairment of the function of cardiomyocytes and structural damage in db/db mice. Exogenous H2 S could suppress the levels of myosin heavy chain 6 and myosin light chain 2 ubiquitination in cardiac tissues of db/db mice, and MuRF1 was modified by S-sulfhydration, following treatment with exogenous H2 S, to reduce the interaction between MuRF1 and myosin heavy chain 6 and myosin light chain 2. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that H2 S regulates MuRF1 S-sulfhydration at Cys44 to prevent myocardial degradation in the cardiac tissues of db/db mice. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Preparation of Lotus Root-Type Monolithic-Activated Carbons with an Hierarchical Pore Structure from Rice Husks and Their Adsorption of Vitamin B12.

Activated carbon is widely used in many fields because of its well-developed pore structure. Especially in hemoperfusion, activated carbon beads derived from macroporous resin spheres are the predominant adsorbents in hemoditoxifiers. In comparison, biomass-activated carbon attracts more extensive attention on account of its renewability and environmental protection. In this study, a lotus root-type monolithic-activated carbon with a hierarchical pore structure was made from rice husks by the injection molding process followed by carbonization and activation. The straight square channels with the side length of about 1.3 mm were designable, and these channels with adjustable lengths were favorable for the fluid flow during blood purification compared with the tightly packed carbon beads in commercialized hemoditoxifiers. Complementally, the hierarchical nano-sized pores in the walls of the big channels would contribute much to the adsorption capacity for the monolith. Specifically, the adsorption of vitamin B12, a representative of middle molecular toxins in human blood, was about 3.7 mg g-1, which was acquired by simulated in vitro hemoperfusion tests and this demonstrated the promising application of the lotus root-type biomass-activated carbon in hemoperfusion.

Exogenous H2S reduces the acetylation levels of mitochondrial respiratory enzymes via regulating the NAD+-SIRT3 pathway in cardiac tissues of db/db mice.

Hydrogen sulfide (H2S), a gaseous molecule, is involved in modulating multiple physiological functions, such as antioxidant, antihypertension, and the production of polysulfide cysteine. H2S may inhibit reactive oxygen species generation and ATP production through modulating respiratory chain enzyme activities; however, the mechanism of this effect remains unclear. In this study, db/db mice, neonatal rat cardiomyocytes, and H9c2 cells treated with high glucose, oleate, and palmitate were used as animal and cellular models of type 2 diabetes. The mitochondrial respiratory rate, respiratory chain complex activities, and ATP production were decreased in db/db mice compared with those in db/db mice treated with exogenous H2S. Liquid chromatography with tandem mass spectrometry analysis showed that the acetylation level of proteins involved in the mitochondrial respiratory chain were increased in the db/db mice hearts compared with those with sodium hydrosulfide (NaHS) treatment. Exogenous H2S restored the ratio of NAD+/NADH, enhanced the expression and activity of sirtuin 3 (SIRT3) and decreased mitochondrial acetylation level in cardiomyocytes under hyperglycemia and hyperlipidemia. As a result of SIRT3 activation, acetylation of the respiratory complexe enzymes NADH dehydrogenase 1 (ND1), ubiquinol cytochrome c reductase core protein 1, and ATP synthase mitochondrial F1 complex assembly factor 1 was reduced, which enhanced the activities of the mitochondrial respiratory chain activity and ATP production. We conclude that exogenous H2S plays a critical role in improving cardiac mitochondrial function in diabetes by upregulating SIRT3.

One-year patency rate of native arteriovenous fistulas reconstructed by vascular stripping in hemodialysis patients with venous neointimal hyperplasia.

OBJECTIVE: There are limited therapeutic measures for stenosis of arteriovenous fistulas (AVFs) due to venous neointimal hyperplasia (VNH). In the current retrospective study, we reviewed the clinical data of hemodialysis patients who underwent AVF reconstruction by VNH stripping. The primary measure of interest was the secondary patency rate of the restored AVF. METHODS: The study included hemodialysis patients who underwent AVF reconstruction by VNH stripping (group A), AVF reconstruction proximal to the original fistula (group B), or creation of a new AVF (group C). Patency was evaluated immediately after the surgery and at follow-up visits. RESULTS: Of 353 patients who underwent AVF reconstructions, 327 (91.9%) were for late AVF failure. The final analysis included 305 patients: 76, 128, and 101 patients in groups A, B, and C, respectively. The three groups were comparable in age, sex, causes for AVF, AVF sites, and the artery for the AVF (P > .05). At 3-month follow-up, the secondary AVF patency rate was comparable across the three groups at 93.4%, 92.2%, and 92.1% in groups A, B, and C, respectively. The patency rate at 6 and 12 months was also comparable across groups A, B, and C at 89.5%, 89.8%, and 88.1% at 6 months and 84.2%, 85.9%, and 81.2% at 12 months, respectively. CONCLUSIONS: Reconstructing the AVF by surgically removing VNH is an effective technique for late hemodialysis access failure, with maximal preservation of blood vessels.

Restoration of autologous arteriovenous fistula by vascular stripping in a hemodialysis patient with venous neointimal hyperplasia.

A significant number of arteriovenous fistulae fail because of venous neointimal hyperplasia-associated vascular blockage. We developed a surgical technique for repairing arteriovenous fistulae by surgically removing neointimal hyperplasia and vessel re-anastomosis. Here, we report the successful treatment of a case that developed arteriovenous fistula stenosis because of venous neointimal hyperplasia.

Preparation of sulfonated porous carbon nanotubes/activated carbon composite beads and their adsorption of low density lipoprotein.

The high level of low density lipoprotein (LDL) in plasma is the main cause of atherosclerosis. Hemoperfusion is an ideal therapy to lower the level of LDL in human blood system while therapeutic effect is determined by the adsorbent. The adsorbent must have suitable pore structure and specific functional groups. Carbon nanotubes (CNTs) could be a new adsorbent material because CNTs have high specific surface area and they can be modified by a variety of functional groups. Porous carbon composite beads with the CNTs and phenolic resin mixture were synthesized by suspension polymerization, following with carbonization and steam-activation. Then the porous composite beads were sulfonated with a sulfanilic acid anhydrous by diazotization and coupling reaction. The potential application of the sulfonated porous composite beads in adsorbing low density lipoprotein (LDL) from human serum was investigated. The results showed that the sulfonic acid groups on the composite beads could lower LDL levels greatly by electrostatic interaction with electropositive LDL. The higher 20-100 nm pore volume the composite beads had, the more LDL they could adsorb. The 20-100 nm pore volume was enhanced by adding more CNTs and improving CNTs dispersion (ultrasonic crushing). The sulfonated composite beads containing 45 wt% CNTs presented the highest adsorption capacity to LDL 10.46 mg/g, showing a good prospect as LDL adsorbent in hemoperfusion.

Clinical observations of mycophenolate mofetil therapy in refractory primary nephrotic syndrome.

Mycophenolate mofetil (MMF) is an effective immunosuppressive agent in renal transplantation, and preliminary studies suggest that it may also be effective in the treatment of lupus nephritis. This study investigated the efficacy and safety of MMF therapy in patients with refractory primary nephrotic syndrome in a prospective multicentre clinical observation. Nineteen refractory nephrotic patients with minimal change disease or mesangial proliferative glomerulonephritis were enrolled in this study. Combined MMF and prednisone therapy was used for 6 months with an initial MMF dose of 1.0-2.0 g/day and a prednisone dose of 20-60 mg/day; both drugs were tapered gradually. It was found that all patients achieved clinical remission and 11 of 19 responded within 4 weeks, and 12 of 19 patients entered complete clinical remission. The prednisone dose in those patients who were previously steroid dependent could be successfully tapered. During follow up, three patients experienced transient increasing of proteinuria associated with infections and recovered without an adjustment of therapy. One patient was withdrawn from the study because of a fall in haemoglobin levels; other adverse effects did not necessitate withdrawal. Follow-up renal biopsies in two patients found no alteration in renal pathology. Mycophenolate mofetil is an effective and well-tolerated immunosuppressive agent for patients with refractory nephrotic syndrome.

Serum insulin-like growth factor 1 level and nutritional assessment in nondialytic patients with chronic renal failure.

AIM: In order to understand the nutritional status of nondialytic patients with chronic renal failure (CRF), nutritional assessment was made in 20 nondialytic patients (15 males and 5 females; mean age 43.7 +/- 15.1 years). METHODS: Twenty CRF inpatients were selected for nutritional assessment, and 20 normal subjects served as controls. The serum insulin-like growth factor 1 (IGF-1) concentration was measured by ELISA. Serum albumin, prealbumin, and transferrin levels were also determined. RESULTS: The mean IGF-I and transferrin levels in the CRF patients were significantly lower than those in normal subjects (IGF-1: 176.2 +/- 92.5 microg/l vs. 266.7 +/- 101.7 microg/l, p < 0.01; transferrin: 2.57 +/- 0.58 g/l vs. 3.18 +/- 0.27 g/l, p < 0.05). The IGF-1 levels in 7 patients with a serum albumin concentration <40.0 g/l were significantly lower than those in 13 patients with a serum albumin concentration >40.0 g/l (95.6 +/- 42.4 microg/l vs. 219.6 +/- 82.7 microg/l, p < 0.01). The IGF-1 levels in cases treated with alpha-ketoacid were higher than in those without alpha-ketoacid treatment. The IGF-1 levels were positively correlated with creatinine clearance (r = 0.7066, p < 0.01) and serum transferrin concentration (r = 0.5347, p < 0.05). CONCLUSIONS: The fact that serum IGF-1 was correlated with serum transferrin and creatinine clearance suggests that IGF-1 may be a good indicator for assessing the nutritional status of CRF patients. The serum IGF-1 level in CRF patients is probably lower than that in normal subjects and could be improved by nutritional therapy.