Increased serum methylmalonic acid levels were associated with the presence of cognitive dysfunction in older chronic kidney disease patients with albuminuria.

BACKGROUND: This study aimed to evaluate the correlation between serum methylmalonic acid (MMA) levels and cognition function in patients with chronic kidney disease (CKD). METHODS: In this cross-sectional study, we included 537 CKD individuals aged ≥ 60-year-old with albuminuria from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Four cognitive tests including the Digit Symbol Substitution Test (DSST), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Delayed Recall and Word Learning tests, and the Animal Fluency test (AF) were performed. Associations between MMA and cognition scores were assessed with linear regression models. RESULTS: MMA level was negatively associated with residual renal function and nutrition status. After multivariate adjustment, elevated serum MMA levels were independently correlated with decline of cognition in CKD patients with albuminuria. CONCLUSION: Our study showed that higher serum MMA levels were independently associated with the presence of cognition dysfunction in CKD patients. The exact pathogenesis of MMA and cognition needs further research.

Urotensin II can Induce Skeletal Muscle Atrophy Associated with Upregulating Ubiquitin-Proteasome System and Inhibiting the Differentiation of Satellite Cells in CRF Mice.

Skeletal muscle wasting and atrophy is highly prevalent in chronic renal failure (CRF) and increases the risk of mortality. According to our previous study, we speculate that urotensin II (UII) can induce skeletal muscle atrophy by upregulating ubiquitin-proteasome system(UPS) in CRF. C2C12 mouse myoblast cells were differentiated into myotubes, and myotubes were exposed to different concentrations of UII. Myotube diameters, myosin heavy chain(MHC), p-Fxo03A, skeletal muscle-specific E3 ubiquitin ligases such as muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin1) were detected. Three animal models (the sham operation mice as normal control (NC) group, wild-type C57BL/6 mice with 5/6 nephrectomy (WT CRF) group, UII receptor gene knock out (UT KO) mice with 5/6 nephrectomy (UT KO CRF) group) were designed. Cross-sectional area (CSA) of skeletal muscle tissues in three animal models were measured, and western blot detected protein of UII, p-Fxo03A, MAFbx and MuRF1, and immunofluorescence assays explored the satellite cell marker of Myod1 and Pax7, and PCR arrays detected the muscle protein degradation genes, protein synthesis genes and the genes which were involved in muscle components. UII could decrease mouse myotube diameters, and upregulate dephosphorylated Fxo03A protein. MAFbx and MuRF1 were higher in WT CRF group than that in NC group, but after UII receptor gene was knocked out (UT KO CRF), their expressions were downregulated. UII could inhibit the expression of Myod1 but not Pax7 in animal study. We first demonstrate that skeletal muscle atrophy induced by UII associated with upregulating ubiquitin-proteasome system and inhibiting the differentiation of satellite cells in CRF mice.

Irisin Ameliorated Skeletal Muscle Atrophy by Inhibiting Fatty Acid Oxidation and Pyroptosis Induced by Palmitic Acid in Chronic Kidney Disease.

INTRODUCTION: Protein-energy waste (PEW) is a common complication in patients with chronic kidney disease (CKD), among which skeletal muscle atrophy is one of the most important clinical features of PEW. Pyroptosis is a type of proinflammatory, programmed cell death associated with skeletal muscle disease. Irisin, as a novel myokine, has attracted extensive attention for its protective role in the complications associated with CKD, but its role in muscle atrophy in CKD is unclear. METHODS: Palmitic acid (PA)-induced muscular atrophy was evaluated by a reduction in C2C12 myotube diameter. Muscle atrophy model was established in male C57BL/6J mice treated with 0.2% adenine for 4 weeks and then fed a 45% high-fat diet. Blood urea nitrogen and creatinine levels, body and muscle weight, and muscle histology were assessed. The expression of carnitine palmitoyltransferase 1A (CPT1A) and pyroptosis-related protein was analysed by Western blots or immunohistochemistry. The release of IL-1ß was detected by enzyme-linked immunosorbent assay. RESULTS: In this study, we showed that PA-induced muscular atrophy manifested as a reduction in C2C12 myotube diameter. During this process, PA can also induce pyroptosis, as shown by the upregulation of NLRP3, cleaved caspase-1 and GSDMD-N expression and the increased IL-1ß release and PI-positive cell rate. Inhibition of caspase-1 or NLRP3 attenuated PA-induced pyroptosis and myotube atrophy in C2C12 cells. Importantly, irisin treatment significantly ameliorated PA-induced skeletal muscle pyroptosis and atrophy. In terms of mechanism, PA upregulated CPT1A, a key enzyme of fatty acid oxidation (FAO), and irisin attenuated this effect, which was consistent with etomoxir (CPT1A inhibitor) treatment. Moreover, irisin improved skeletal muscle atrophy and pyroptosis in adenine-induced mice by regulating FAO. CONCLUSION: Our study firstly verifies that pyroptosis is a novel mechanism of skeletal muscle atrophy in CKD. Irisin ameliorates skeletal muscle atrophy by inhibiting FAO and pyroptosis in CKD, and irisin may be developed as a potential therapeutic agent for the treatment of muscle wasting in CKD patients.

Associations between renal function, hippocampal volume, and cognitive impairment in 544 outpatients.

Background: Cognitive impairment and brain atrophy are common in chronic kidney disease patients. It remains unclear whether differences in renal function, even within normal levels, influence hippocampal volume (HCV) and cognition. We aimed to investigate the association between estimated glomerular filtration rate (eGFR), HCV and cognition in outpatients. Methods: This single-center retrospective study enrolled 544 nonrenal outpatients from our hospital. All participants underwent renal function assessment and 3.0 T magnetic resonance imaging (MRI) in the same year. HCV was also measured, and cognitive assessments were obtained. The correlations between eGFR, HCV, and cognitive function were analyzed. Logistic regression analysis was performed to identify the risk factors for hippocampal atrophy and cognitive impairment. Receiver-operator curves (ROCs) were performed to find the cut-off value of HCV that predicts cognitive impairment. Results: The mean age of all participants was 66.5 ± 10.9 years. The mean eGFR of all participants was 88.5 ± 15.1 mL/min/1.73 m2. eGFR was positively correlated with HCV and with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. Univariate and multivariate logistic regression analysis showed Age ≥ 65 years, eGFR < 75 mL/min/1.73 m2, Glucose ≥6.1 mmol/L and combined cerebral microvascular diseases were independent risk factors for hippocampal atrophy and Age ≥ 65 years, left hippocampal volume (LHCV) <2,654 mm3 were independent risk factors for cognitive impairment in outpatients. Although initial unadjusted logistic regression analysis indicated that a lower eGFR (eGFR < 75 mL/min/1.73 m2) was associated with poorer cognitive function, this association was lost after adjusting for confounding variables. ROC curve analysis demonstrated that LHCV <2,654 mm3 had the highest AUROC [(0.842, 95% CI: 0.808-0.871)], indicating that LHCV had a credible prognostic value with a high sensitivity and specificity for predicting cognitive impairment compared with age in outpatients. Conclusion: Higher eGFR was associated with higher HCV and better cognitive function. eGFR < 75 mL/min/1.73 m2 was an independent risk factor for hippocampal atrophy after adjusting for age. It is suggested that even eGFR < 75 mL/min/1.73 m2, lower eGFR may still be associated with hippocampal atrophy, which is further associated with cognitive impairment. LHCV was a favorable prognostic marker for predicting cognitive impairment rather than age.

Prevalence of cognitive impairment and its predictors among chronic kidney disease patients: A systematic review and meta-analysis.

BACKGROUND: Cognitive impairment (CI) is common among patients with chronic kidney disease (CKD), and is associated with a poor prognosis. We assessed the prevalence and associated factors of CI in patients with CKD. METHODS: A systematic review and meta-analysis were conducted by searching PubMed, Embase, and the Web of Science through December 1, 2023. Random effects models were performed with subgroup analyses to further explore the heterogeneity. RESULTS: 50 studies involving 25,289 CKD patients were included. The overall prevalence of CI was 40% (95% confidence interval 33-46). The pooled prevalence of CI was relatively higher in CKD patients from Africa (58%), Asia (44%) and America (37%). Attention and executive dysfunction appeared to be the most common manifestations. The prevalence of CI was higher among patients with hemodialysis (53%) and peritoneal dialysis (39%) than those without dialysis (32%) and post-kidney transplanted (26%). In addition, advanced age, the presence of diabetes and hypertension might increase the risk of CI in CKD patients. CONCLUSIONS: People with CKD have a high prevalence of CI, especially in patients with hemodialysis. An early and comprehensive screening for CI in CKD patients is needed to improve clinical outcomes. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42023412864).

Cross-over study of influence of oral vitamin C supplementation on inflammatory status in maintenance hemodialysis patients.

BACKGROUND: Both vitamin C deficiency and inflammation are prevalent in maintenance hemodialysis (MHD) patients. In this study, we aimed to elucidate the effect of oral vitamin C supplementation on inflammatory status in MHD patients with low vitamin C level and high hypersensitive C-reactive protein (hs-CRP) level. METHODS: A total of 128 patients were recruited in our present study. Patients were divided into two groups. In group 1 (n = 67), patients were orally administered with 200 mg/day vitamin C in the first 3 months, and then the vitamin C supplementation was withdrawn in the next 3 months. In group 2 (n = 61), patients were not given vitamin C in the first 3 months, and then they were orally administered with 200 mg/day in the next 3 months. Levels of hs-CRP, prealbumin, albumin and hemoglobin as well as the EPO resistance index (ERI) were determined at the baseline and every 3 months throughout the study. Plasma vitamin C level was determined by high-performance liquid chromatography with UV detection. RESULTS: Among the 128 patients, 28 of them dropped out of the study before completion. Consequently, a total of 100 patients (group 1: n = 48; group 2: n = 52) were included in the final analysis. At the baseline, the plasma vitamin C level of all patients was less than 4 µg/mL. However, this proportion was decreased to 20% after the vitamin C supplementation for 3 months. Compared with patients without the vitamin C supplementation, a decreased level of hs-CRP and an increased level of prealbumin were induced by the vitamin C supplementation for 3 months in both groups. However, levels of these biomarkers returned to their original state after the supplementation was withdrawn. Same beneficial effects on plasma albumin, hemoglobin and ERI response to vitamin C supplementation were observed in the two groups without statistical significance. CONCLUSIONS: The inflammatory status in MHD patients with plasma vitamin C deficiency and high levels of inflammatory markers could be partially improved by long-term oral administration of small doses of vitamin C. TRIAL REGISTRATION: The clinical trial number: NCT01356433.

Associated factors of cardiac valve calcification and its prognostic effects among patients with chronic kidney disease: a systematic review and meta-analysis.

Background: Cardiac valve calcification (CVC) is highly prevalent and a risk factor for adverse outcomes in patients with chronic kidney disease (CKD). This meta-analysis aimed to investigate the risk factors for CVC and association between CVC and mortality in CKD patients. Method: Three electronic databases including PubMed, Embase, and Web of Science were searched for relevant studies up to November 2022. Hazard ratios (HR), odds ratios (OR), and 95% confidence intervals (CI) were pooled using random-effect meta-analyses. Results: 22 studies were included in the meta-analysis. Pooled analyses showed that CKD patients with CVC were relatively older, had a higher body mass index, left atrial dimension, C-reaction protein level, and a declined ejection fraction. Calcium and phosphate metabolism dysfunction, diabetes, coronary heart disease, and duration of dialysis were all predictors for CVC in CKD patients. The presence of CVC (both aortic valve and mitral valve) increased the risk of all-cause and cardiovascular mortality in CKD patients. However, the prognostic value of CVC for mortality was not significant anymore in patients with peritoneal dialysis. Conclusion: CKD patients with CVC had a greater risk of all-cause and cardiovascular mortality. Multiple associated factors for development of CVC in CKD patients should be taken into consideration by healthcare professionals to improve prognosis. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42022364970].

Serum irisin levels are negatively associated with blood pressure in dialysis patients.

Elevated blood pressure is highly prevalent among dialysis patients and is associated with high mortality. Irisin is a newly found myokine that has been indicated to be related to blood pressure regulation in animal experiments. Data regarding the effect of serum irisin levels on blood pressure in dialysis patients are limited. To identify the association between serum irisin levels and blood pressure and examine determinant factors of systolic blood pressure in dialysis patients, we recruited 300 dialysis patients at Xuanwu Hospital Capital Medical University. Serum irisin levels were assessed by enzyme-linked immunosorbent assay kits. Blood pressure was self-measured on 7 consecutive days by an automated sphygmomanometer. The Pearson correlation test showed that the natural logarithm of irisin was negatively correlated with systolic blood pressure (r = -0.462, P < 0.001) and pulse pressure (r = -0.487, P < 0.001), but not correlated with diastolic blood pressure (r = -0.022, P = 0.709). Multivariate analysis revealed that the natural logarithm of irisin (ß = -0.336, P < 0.001), lean tissue mass (ß = 0.164, P = 0.005), diabetes mellitus (ß = 0.165, P = 0.003) and serum calcium (ß = -0.135, P = 0.019) were significant determinant factors for systolic blood pressure. This study is the first to demonstrate that serum irisin levels are significantly negatively associated with blood pressure in dialysis patients. Further studies are needed to provide possible mechanisms. We demonstrated that serum irisin levels were negatively associated with blood pressure in dialysis patients, which may provide a new target for antihypertensive treatment.

Association between vitamin C deficiency and dialysis modalities.

AIM: We designed a cross-sectional study to investigate plasma vitamin C level in patients who underwent maintenance haemodialysis (MHD) and continuous ambulatory peritoneal dialysis (CAPD) to explore whether there is a difference in vitamin C deficiency between MHD patients and CAPD patients. METHODS: This investigation included 382 dialysis patients without vitamin C supplement before the study. Demographic characteristics, laboratory tests, ascorbic acid and total plasma vitamin C level were measured. A linear regression model was built to explore the association between vitamin C deficiency and dialysis modalities after adjusting for age, dialysis vintage, gender, Charlson index, modality of dialysis and hsCRP. RESULTS: The range of plasma vitamin C level was from 0.48 µg/mL to 31.16 µg/mL. 35.9% (n = 137) patients had severe vitamin C deficiency (<2 µg/mL). Plasma vitamin C level was inversely associated with age and dialysis vintage. After age and dialysis vintage were adjusted, vitamin C deficiency was associated with MHD. R square for model fitting was relatively low, which implied that there were other vitamin C influencing factors not included in the model. CONCLUSIONS: Vitamin C deficiency is common in dialysis patients, especially in patients treated with MHD.

Development and validation of a new dry weight estimation method using single frequency bioimpedance in hemodialysis patients.

BACKGROUND: We proposed a new method to estimate dry weight (DW) using single frequency bioimpedance. METHODS: We hypothesized that the change in whole body resistance at 50 kHz (R(50)) was proportional to the ultrafiltration volume (UFV) during a hemodialysis (HD) session. When the targeted resistance estimated in healthy subjects was reached, the patient achieved his/her DW. UFV and R(50) were monitored in 40 HD patients. Another 43 HD patients were stratified into 2 groups to validate this method. RESULTS: The change in whole body resistance was proportional to UFV in each of the 40 HD patients. In the DW(decrease) group, pre-dialysis systolic blood pressure (n = 29, 154.5 ± 22.8 vs. 146.9 ± 22.3, p < 0.05) and antihypertensive medicine (4.7 ± 3.6 vs. 3.3 ± 2.2, p < 0.05) decreased without adverse symptoms change. In the DW(increase) group, the number of adverse symptoms in 1 week (n = 14, 26 vs. 6, p < 0.05) decreased without a change in systolic blood pressure. CONCLUSION: This method may become a convenient and cheaper way to estimate DW in HD patients.

Identification of potential key protein interaction networks of BK virus nephropathy in patients receiving kidney transplantation.

We aim to identify the key protein interaction networks and implicated pathways of BK virus nephropathy (BKVN) via bioinformatic methods. The microarray data GSE75693 of 30 patients with stable kidney transplantation and 15 with BKVN were downloaded and analyzed by using the limma package to identify differentially expressed genes (DEGs). Then the gene ontology (GO) functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were done to investigate the molecular function (MF), biological process (BP), cellular components (CC) and pathways of DEGs. Finally, protein-protein interactions (PPIs) were constructed, and the hub proteins were  identified. As a result, 249 up-regulated genes and 253 down-regulated genes of BKVN patients were selected based on criteria of P > 0.01 and fold change >2.0. GO and KEGG showed that DEGs were mainly located in nucleus and cytosol, and were implicated in the immune responses. In the PPI analysis, 26 up-regulated and 8 down-regulated proteins composed the pivotal interaction network. CXCL10, EGF and STAT1 were identified as hub proteins in BKVN. In conclusion, CXCL10, EGF and STAT1 may induce kidney injuries by promoting inflammation and prohibiting reparation of tissue damage in BKVN.

Expression of LOX-1 in human mesangial cells is increased by Ox-LDL and IL-1ß treatment.

The present study aimed to determine whether the expression of lectin-like oxidized LDL receptor 1 (LOX-1) could be induced by oxidized low-density lipoprotein (Ox-LDL) and interleukin 1ß (IL-1ß) in human mesangial cells (HMCs). Oil Red O staining was used to observe the uptake of Ox-LDL by HMCs stimulated with IL-1ß, and reverse transcription-quantitative polymerase chain reaction analysis and western blotting were used to examine the expression of LOX-1 in HMC following Ox-LDL and IL-1ß treatment. Uptake of Ox-LDL by HMCs was upregulated upon stimulation with IL-1ß. Furthermore, Ox-LDL (10-40 µg/ml) treatment induced LOX-1 mRNA and protein expression in a dose-dependent manner. In addition, when HMCs were treated with IL-1ß and Ox-LDL, the expression of LOX-1 was enhanced further. These results indicated that inhibiting LOX-1 expression or inhibiting the Ox-LDL/LOX-1 signaling axis may be a potential novel method for treating renal disease.