Targeted therapy of kidney disease with nanoparticle drug delivery materials.

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications.

24-h Urinary Calcium Excretion and Renal Outcomes in Hospitalized Patients with and without Chronic Kidney Disease.

This study investigated the impact of 24-h urinary calcium excretion (UCaE) on renal function decline in hospitalized patients with and without chronic kidney disease (CKD). This study enrolled 3815 CKD patients in stages 1-4 and 1133 non-CKD patients admitted to the First Center of the Chinese PLA General Hospital between January 2014 and July 2022. The primary outcome for CKD patients was a composite of CKD progression, defined as a 40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease. Annual eGFR change was the secondary outcome. For non-CKD patients, the primary outcome was an eGFR decline of ≥20% or CKD incidence, while annual eGFR change was the secondary outcome. The association between UCaE and kidney function decline was assessed using Cox proportional hazards and generalized linear models. Primary outcomes were observed in 813 CKD patients and 109 non-CKD patients over a median follow-up of 3.0 and 4.1 years, respectively. For CKD patients, every 1-mmol/d increase in UCaE was associated with a 15% decreased risk of CKD progression. The hazard ratio (HR) was 0.85, with a 95% confidence interval (CI) of 0.77-0.93. For non-CKD patients, the risk of renal function decline decreased by 11%. The multivariate models indicated that there was an annual decrease in eGFR in both CKD and non-CKD patients, with a reduction of 0.122 mL/min/1.73 m2/year (p < 0.001) and 0.046 mL/min/1.73 m2/year (p = 0.004), respectively, for every 1-mmol/d increase in UCaE. CKD experiences a decrease in 24-h UCaE as early as stage 1, with a significant decline in stage 4. CKD and non-CKD patients with lower UCaE levels are at an increased risk of renal decline, regardless of other variables.

Network pharmacology and molecular docking technology-based predictive study of the active ingredients and potential targets of rhubarb for the treatment of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the main cause of end-stage renal failure. Rhubarb is a widely used traditional Chinese herb, and it has exhibited efficacy in reducing proteinuria, lowering blood sugar levels and improving kidney function in patients with DN. However, the exact pharmacological mechanism by rhubarb improves DN remain unclear due to the complexity of its ingredients. Hence, we systematically explored the underlying mechanisms of rhubarb in the treatment of DN. We adopted a network pharmacology approach, focusing on the identification of active ingredients, drug target prediction, gene collection, Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes enrichment. Molecular docking technology was used to verify the binding ability between the main active compounds and central therapeutic targets, and screen out the core active ingredients in rhubarb for the treatment of DN. Finally, molecular dynamics simulation was performed for the optimal core protein-ligand obtained by molecular docking using GROMACS software. The network analysis identified 16 active compounds in rhubarb that were linked to 37 possible therapeutic targets related to DN. Through protein-protein interaction analysis, TP53, CASP8, CASP3, MYC, JUN and PTGS2 were identified as the key therapeutic targets. By validation of molecular docking, finding that the central therapeutic targets have good affinities with the main active compounds of rhubarb, and rhein, beta-sitosterol and aloe-emodin were identified as the core active ingredients in rhubarb for the treatment of DN. Results from molecular dynamics simulations showed that TP53 and aloe-emodin bound very stably with a binding free energy of - 26.98 kcal/mol between the two. The results of the gene enrichment analysis revealed that the PI3K-Akt signalling pathway, p53 signalling pathway, AGE-RAGE signalling pathway and MAPK signalling pathway might be the key pathways for the treatment of DN, and these pathways were involved in podocyte apoptosis, glomerular mesangial cell proliferation, inflammation and renal fibrosis. Based on the network pharmacology approach and molecular docking technology, we successfully predicted the active compounds and their respective targets. In addition, we illustrated the molecular mechanisms that mediate the therapeutic effects of rhubarb against DN. These findings provided an important scientific basis for further research of the mechanism of rhubarb in the treatment of DN.

Osteocalcin association with vascular function in chronic kidney disease.

Osteocalcin (OCN) is a bone-derived and vitamin K dependent hormone that affects energy metabolism and vascular calcification. The relationship between serum OCN and vascular function in patients with chronic kidney disease (CKD) is uncertain. This study investigated the association between serum OCN and vascular function as expressed with reactive hyperemia index (RHI) and augmentation index (AIx) measured by Endo-PAT 2000 device. This cross-sectional analysis was based on 256 pre-dialysis CKD patients who had completed the Endo-PAT 2000 test and serum OCN at the First Center of Chinese PLA Hospital from November 2017 to December 2019. Based on whether the RHI was less than 1.67, the patients were divided into endothelial dysfunction and normal endothelial function groups. Multiple logistic and linear regression were used to analyze the association between OCN and vascular function. Subgroup analyses were performed to examine the effects of OCN on vascular function in different CKD populations. After multivariate adjustment, CKD with low OCN were more likely to have endothelial dysfunction (OR: 0.794; 95%CI: 0.674-0.934; P = .006); on the contrary, patients with high OCN had a higher degree of arterial stiffness (standardized ß: 0.174; P = .003). Subgroup analyses showed that higher OCN was associated with severe arterial stiffness but a better endothelial function in young (age < 65 years, PRHI /PAIx@75  = .027/.011), male (PRHI /PAIx@75  = .040/.016), patients with a history of hypertension (PRHI /PAIx@75  = .004/.009) or diabetes (PRHI /PAIx@75  = .005/.005), and in early CKD (PRHI /PAIx@75  = .014/.015). In conclusion, serum OCN correlates with vascular function in CKD patients: beneficial for endothelial function but detrimental to arterial stiffness.

A Novel Gene CDC27 Causes SLE and Is Associated With the Disease Activity.

Background: As genetic genetic factors are important in SLE, so screening causative genes is of great significance for the prediction and early prevention in people who may develop SLE. At present, it is very difficult to screen causative genes through pedigrees. The analytical method described herein can be used to screen causative genes for SLE and other complex diseases through pedigrees. Methods: For the first time, 24 lupus pedigrees were analyzed by combining whole exon sequencing and a variety of biological information tools including common-specific analysis, pVAAST (pedigree variant annotation, analysis and search tool), Exomiser (Combining phenotype and PPI associated analysis), and FARVAT (family based gene burden), and the causative genes of these families with lupus identified. Selected causative genes in peripheral-blood mononuclear cells (PBMCs) were evaluated by quantitative polymerase chain reaction (qPCR). Results: Cell division cycle 27 (CDC27) was screened out by common-specific analysis and Exomiser causative gene screening. FARVAT analysis on these families detected only CDC27 at the extremely significant level (false discovery rate <0.05) by three family-based burden analyses (BURDEN, CALPHA, and SKATO). QPCR was performed to detect for CDC27 in the PBMCs of the SLE family patients, sporadic lupus patients, and healthy people. Compared with the healthy control group, CDC27 expression was low in lupus patients (familial and sporadic patients) (P<0.05) and correlated with lupus activity indicators: negatively with C-reactive protein (CRP) (P<0.05) and erythrocyte sedimentation rate (P<0.05) and positively with complement C3 and C4 (P<0.05). The CDC27 expression was upregulated in PBMCs from SLE patients with reduced lupus activity after immunotherapy (P<0.05). Based on Receiver operating characteristic (ROC) curve analysis, the sensitivity and specificity of CDC27 in diagnosing SLE were 82.30% and 94.40%. Conclusion: The CDC27 gene, as found through WES combined with multiple analytical method may be a causative gene of lupus. CDC27 may serve as a marker for the diagnosis of SLE and is closely related to the lupus activity. We hope that the analytical method in this study will be used to screen causative genes for other diseases through small pedigrees, especially among non-close relatives.

Increased cancer-specific mortality of very small size in carcinoembryonic antigen-elevated rectal cancer.

BACKGROUND: The present study aimed to investigate the cause-specific survival (CSS) of very small rectal cancer in the context of preoperative serum carcinoembryonic antigen (CEA) elevation. METHODS: Patients diagnosed with node-negative rectal cancer from the Surveillance, Epidemiology, and End Results (SEER) database from January 2004 to December 2010 meeting the inclusion criteria were identified for this study. The Cox proportional hazards regression analyses were conducted to identify independent factors associated with CSS. Pearson's chi-squared tests and Kaplan-Meier methods were performed. RESULTS: A total of 8,413 patients were included into our study. Kaplan-Meier analyses showed lower 7-year CSS rate of very small tumors (≤5 mm) compared to those larger than 40 mm (70.4% vs. 76.0%, log-rank P=0.469). Multivariate Cox analyses showed that patients with very small tumor size (≤5 mm) was also associated with a significantly increased risk of cancer-specific mortality compared with those with large tumor size (HR =2.567, 95% CI: 1.285 to 5.130, P=0.008, using ≥41 mm, C+ as a reference). CONCLUSIONS: Very small tumor size in the context of preoperative serum CEA elevation could be a surrogate for biological aggressiveness. Our finding would provide a better understanding of tumor biology for us and elicit more future biological researches.