Inflammatory indexes and anemia in chronic kidney disease: correlation and survival analysis of the National Health and Nutrition Examination Survey 2005-2018.

BACKGROUND: There is currently no research on the correlation between novel inflammatory indexes systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the risk of anemia in chronic kidney disease (CKD) population, as well as survival analysis in CKD with anemia. METHODS: This investigation encompassed 4444 adult subjects out of the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018. The study utilized multi-variable logistic regression to assess the relationship between SII, NLR, PLR, and anemia risk occurrence in CKD population. Survival differences in CKD patients with anemia, based on varying levels of SII, NLR, and PLR were evaluated employing Kaplan-Meier and Cox proportional hazards models. RESULTS: The adjusted logistic regression model demonstrates that SII, NLR, and PLR are associated with the risk of anemia occurrence in CKD population. Kaplan-Meier's analysis reveals significant differences in survival rates among CKD patients with anemia stratified by NLR levels. The adjusted Cox proportional hazards model shows that the higher NLR group has a 30% elevated risk of all-cause mortality contrasted with lower group (hazard ratio, HR: 1.30, confidence interval (CI) [1.01, 1.66], p value <.04). Restricted cubic spline (RCS) demonstrates no nonlinear relationship between NLR and all-cause mortality. Lastly, sub-cohort analysis indicates that in populations with diabetes, hypertension, and hyperuricemia, NLR levels have a greater impact on all-cause mortality. CONCLUSIONS: Controlling inflammation may reduce the occurrence of anemia in CKD populations, with NLR serving to be a potential prognostic indicator for survival results within CKD patients suffering from co-morbid anemia.

Association between serum potassium, risk and prognosis of peritonitis in peritoneal dialysis patients - results from the Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study.

BACKGROUND: Hypokalemia has been associated with an increased risk of peritoneal dialysis (PD)-associated peritonitis. However, hypokalemia is commonly associated with malnutrition, inflammation, and severe coexisting comorbidities, which thus are suspected of being potential confounders. This study was aimed at testing whether hypokalemia was independently associated with the occurrence and prognosis of PD-associated peritonitis. METHODS: A national-level dataset from the Peritoneal Dialysis Telemedicine-assisted Platform Cohort (PDTAP) Study was used to explore the independent association of serum potassium with PD-associated peritonitis. Unmatched and propensity score-adjusted multivariate competing risk models, as well as univariate competing risk models following 1:1 propensity score matching, were conducted to balance potential biases between patients with and without hypokalemia. The association between potassium levels prior to peritonitis and treatment failure due to peritonitis was also investigated. RESULTS: During a median follow-up of 25.7 months in 7220 PD patients, there was a higher incidence of peritonitis in patients with serum potassium below 4.0 mmol/L compared to those with higher serum levels (677 [0.114/patient-year] vs. 914 [0.096/patient-year], P = 0.001). After adjusting for demographics, laboratory tests, residual renal function, and medication use, baseline potassium levels below 4.0 mmol/L were not linked to an increased risk of peritonitis, with a hazard ratio of 0.983 (95% CI 0.855-1.130, P = 0.810). This result remained consistent in both the propensity score adjusted multivariate competing risk regression (HR = 0.974, 95% CI 0.829-1.145, P = 0.750) and the univariate competing risk regression after 1:1 propensity score matching (Fine-Gray test, P = 0.218). The results were similar when analyzing patients with serum potassium level above or below 3.5 mmol/L. Lastly, hypokalemia before the occurrence of peritonitis was not independently associated with treatment failure. CONCLUSION: Hypokalemia was not found to be an independent risk factor for PD-associated peritonitis or treatment failure of peritonitis in China.

The pivotal role of glucose transporter 1 in diabetic kidney disease.

Diabetes mellitus (DM) is a significant public health problem. Diabetic kidney disease (DKD) is the most common complication of DM, and its incidence has been increasing with the increasing prevalence of DM. Given the association between DKD and mortality in patients with DM, DKD is a significant burden on public health resources. Despite its significance in DM progression, the pathogenesis of DKD remains unclear. Aberrant glucose uptake by cells is an important pathophysiological mechanism underlying DKD renal injury. Glucose is transported across the bilayer cell membrane by a glucose transporter (GLUT) located on the cell membrane. Multiple GLUT proteins have been identified in the kidney, and GLUT1 is one of the most abundantly expressed isoforms. GLUT1 is a crucial regulator of intracellular glucose metabolism and plays a key pathological role in the phenotypic changes in DKD mesangial cells. In an attempt to understand the pathogenesis of DKD better, we here present a review of studies on the role of GLUT1 in the development and progression of DKD.

Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target.

Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.

IgM kappa proliferative glomerulonephritis with monoclonal immunoglobulin deposition complicated with nocardiosis dermatitis: a case report and review of literature.

Rationale: Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders caused by monoclonal immunoglobulin (M protein) secreted by B cells or plasma cells. Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID) is a glomerular disease and a form of MGRS. Here, we presented a rare case of a patient with IgM kappa PGNMID complicated with nocardiosis dermatitis. Patient concerns and diagnoses: A 56-year-old man was admitted to the hospital because of cutaneous purpura and proteinuria. His initial pathological diagnosis indicated membranous proliferative glomerulonephritis, IgM(++), and subacute interstitial nephritis. Based on further examination, he was finally diagnosed to have IgM kappa PGNMID and subacute interstitial nephritis. After the initial diagnosis, the patient received hormonal therapy. During the treatment, nocardiosis dermatitis emerged as a complication, and the hormonal therapy was gradually reduced. The patient refused further treatment with rituximab, and his health is currently stable. Outcomes: IgM kappa PGNMID complicated with nocardiosis dermatitis is an extremely rare occurrence. Laboratory examination and pathological analysis are required to confirm the diagnosis of this disorder. Timely and accurate diagnosis is essential for the appropriate treatment of PGNMID.

Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

Renal interferon-inducible protein 16 expression is associated with disease activity and prognosis in lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE). However, the current management of LN remains unsatisfactory due to sneaky symptoms during early stages and lack of reliable predictors of disease progression. METHODS: Bioinformatics and machine learning algorithms were initially used to explore the potential biomarkers for LN development. Identified biomarker expression was evaluated by immunohistochemistry (IHC) and multiplex immunofluorescence (IF) in 104 LN patients, 12 diabetic kidney disease (DKD) patients, 12 minimal change disease (MCD) patients, 12 IgA nephropathy (IgAN) patients and 14 normal controls (NC). The association of biomarker expression with clinicopathologic indices and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to explore potential mechanisms. RESULTS: Interferon-inducible protein 16 (IFI16) was identified as a potential biomarker for LN. IFI16 was highly expressed in the kidneys of LN patients compared to those with MCD, DKD, IgAN or NC. IFI16 co-localized with certain renal and inflammatory cells. Glomerular IFI16 expression was correlated with pathological activity indices of LN, while tubulointerstitial IFI16 expression was correlated with pathological chronicity indices. Renal IFI16 expression was positively associated with systemic lupus erythematosus disease activity index (SLEDAI) and serum creatinine while negatively related to baseline eGFR and serum complement C3. Additionally, higher IFI16 expression was closely related to poorer prognosis of LN patients. GSEA and GSVA suggested that IFI16 expression was involved in adaptive immune-related processes of LN. CONCLUSION: Renal IFI16 expression is a potential biomarker for disease activity and clinical prognosis in LN patients. Renal IFI16 levels may be used to shed light on predicting the renal response and develop precise therapy for LN.

Renal C4d is a potential biomarker of disease activity and severity in pediatric lupus nephritis patients.

Background: Systemic lupus erythematosus (SLE), a multisystemic autoimmune disease, is very aggressive in pediatric-onset patients as they are prone to develop lupus nephritis (LN). Although renal C4d positivity is correlated with the activity of renal disease and SLE in adult-onset LN patients, available information for pediatric-onset patients is limited. Methods: To evaluate the potential diagnostic significance of renal C4d staining in pediatric LN patients, we retrospectively detected C4d staining by immunohistochemistry on renal biopsy specimens from 58 pediatric LN patients. The clinical and laboratory data at the time of the kidney biopsy and the renal disease activity of histological injury were analyzed according to the C4d staining status. Results: Glomerular C4d (G-C4d)-positive staining was detected in all 58 cases of LN. Patients with a G-C4d score of 2 displayed more severe proteinuria than those with a G-C4d score of 1 (24-h urinary protein: 3.40 ± 3.55 g vs. 1.36 ± 1.24 g, P < 0.05). Peritubular capillary C4d (PTC-C4d) positivity was found in 34 of 58 LN patients (58.62%). The PTC-C4d-positive patient groups (patients with a PTC-C4d score of 1 or 2) had higher serum creatinine and blood urea nitrogen levels as well as renal pathological activity index (AI) and SLE disease activity index (SLEDAI) scores; however, they had lower serum complement C3 and C4 levels compared to PTC-C4d-negative patients (P < 0.05). In addition, there was positive tubular basement membrane C4d (TBM-C4d) staining in 11 of 58 LN patients (18.96%), and a higher proportion of TBM-C4d-positive patients than TBM-C4d-negative patients (63.63% vs. 21.27%) had hypertension. Conclusion: Our study revealed that G-C4d, PTC-C4d, and TMB-C4d were positively correlated with proteinuria, disease activity and severity, and hypertension, respectively, in pediatric LN patients. These data suggest that renal C4d is a potential biomarker for disease activity and severity in pediatric LN patients, providing insights into the development of novel identification and therapeutic approaches for pediatric-onset SLE with LN.

The Intestinal Microbiota Composition in Early and Late Stages of Diabetic Kidney Disease.

Many studies have suggested that gut microbiota dysbiosis may be one of the pathogenesis factors of diabetes mellitus (DM), while it is not clear whether it is involved in the development of diabetic kidney diseases (DKD). The objective of this study was to determine bacterial taxa biomarkers during the progression of DKD by investigating bacterial compositional changes in early and late DKD. 16S rRNA gene sequencing was performed on fecal samples, including the diabetes mellitus (DM), DNa (early DKD), and DNb (late DKD) groups. Taxonomic annotation of microbial composition was performed. Samples were sequenced on the Illumina NovaSeq platform. At the genus level, we found counts of Fusobacterium, Parabacteroides, and Ruminococcus_gnavus were significantly elevated both in the DNa group (P = 0.0001, 0.0007, and 0.0174, respectively) and the DNb group (P < 0.0001, 0.0012, and 0.0003, respectively) compared with those in the DM group. Only the level of Agathobacter was significantly decreased in the DNa group than the DM group and in the DNb group than the DNa group. Counts of Prevotella_9, Roseburia were significantly decreased in the DNa group compared with those in the DM group (P = 0.001 and 0.006, respectively) and in the DNb group compared with those in the DM group (P < 0.0001 and 0.003, respectively). Levels of Agathobacter, Prevotella_9, Lachnospira, and Roseburia were positively correlated with an estimated glomerular filtration rate (eGFR), but negatively correlated with microalbuminuria (MAU), 24 h urinary protein quantity (24hUP), and serum creatinine (Scr). Moreover, the areas under the curve (AUCs) of Agathobacter and Fusobacteria were 83.33% and 80.77%, respectively, for the DM and DNa cohorts, respectively. Notably, the largest AUC for DNa and DNb cohorts was also that of Agathobacter at 83.60%. Gut microbiota dysbiosis was found in the early and late stages of DKD, especially in the early stage. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD. IMPORTANCE It is not clear as to whether gut microbiota dysbiosis is involved in the progression of DKD. This study may be the first to explore gut microbiota compositional changes in diabetes, early-DKD, and late DKD. We identify different gut microbial characteristics during different stages of DKD. Gut microbiota dysbiosis is found in the early and late stages of DKD. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD, although further studies are warranted to illustrate these mechanisms.

Dapagliflozin inhibits the activity of lateral habenula to alleviate diabetes mellitus-induced depressive-like behavior.

The prevalence of depression in diabetes mellitus (DM) patients is very high, and it severely impacts the prognosis and quality of life of these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new type of oral hypoglycemic drugs, have been shown to alleviate depressive symptoms in DM patients; however, the mechanism underlying this effect is not well understood. The lateral habenula (LHb) plays an important role in the pathogenesis of depression expresses SGLT2, suggesting that the LHb may mediate antidepressant effects of SGLT2 inhibitors. The current study aimed to investigate the involvement of the LHb in the antidepressant effects of the SGLT2 inhibitor dapagliflozin. Chemogenetic methods were used to manipulate the activity of LHb neurons. Behavioral tests, Western blotting, immunohistochemistry, and neurotransmitter assays were used to determine the effects of dapagliflozin on the behavior of DM rats, AMP-activated protein kinase (AMPK) pathway and c-Fos expression in the LHb and 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the dorsal raphe nucleus (DRN). We found that DM rats demonstrated depressive-like behavior, increased c-Fos expression, and decreased AMPK pathway activity in the LHb. Inhibition of LHb neurons alleviated the depressive-like behavior of DM rats. Both systemic and local LHb administration of dapagliflozin alleviated the depressive-like behavior and reversed the changes of the AMPK pathway and c-Fos expression in the LHb of DM rats. Dapagliflozin, when microinjected into the LHb, also increased 5-HIAA /5-HT in the DRN. These results suggest that dapagliflozin directly acts on the LHb to alleviate DM-induced depressive-like behavior and that the underlying mechanism involves activating the AMPK signaling pathway, leading to the inhibition of LHb neuronal activity, which in turn increases serotonergic activity in the DRN. These results will help develop new strategies for the treatment of DM-induced depression.

Oxidative stress as a culprit in diabetic kidney disease.

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease (ESRD), and the prevalence of DKD has increased worldwide during recent years. DKD is associated with poor therapeutic outcomes in most patients, but there is limited understanding of its pathogenesis. This review suggests that oxidative stress interacts with many other factors in causing DKD. Highly active mitochondria and NAD(P)H oxidase are major sources of oxidants, and they significantly affect the risk for DKD. Oxidative stress and inflammation may be considered reciprocal causes of DKD, in that each is a cause and an effect of DKD. Reactive oxygen species (ROS) can act as second messengers in various signaling pathways and as regulators of metabolism, activation, proliferation, differentiation, and apoptosis of immune cells. Epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs can modulate oxidative stress. The development of new technologies and identification of new epigenetic mechanisms may provide novel opportunities for the diagnosis and treatment of DKD. Clinical trials demonstrated that novel therapies which reduce oxidative stress can slow the progression of DKD. These therapies include the NRF2 activator bardoxolone methyl, new blood glucose-lowering drugs such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists. Future studies should focus on improving early diagnosis and the development of more effective combination treatments for this multifactorial disease.

Efficacy and Safety of Mizoribine for the Treatment of Refractory Nephrotic Syndrome: Protocol for a Multicenter, Controlled, Open-label, Randomized Controlled Trial.

BACKGROUND: Nephrotic syndrome that is resistant to steroid therapy is termed refractory nephrotic syndrome (RNS), a condition that is associated with an increased risk of end-stage renal disease. Immunosuppressants are used to treat RNS; however, prolonged use may lead to significant adverse effects. Mizoribine (MZR) is a novel agent used in long-term immunosuppressive therapy, which has few adverse effects, but data on its long-term use in patients with RNS are unavailable. OBJECTIVE: We propose a trial to examine the efficacy and safety of MZR compared with cyclophosphamide (CYC) in Chinese adult patients with RNS. METHODS: This is a multicenter, randomized, controlled interventional study with a screening phase (1 week) and a treatment phase (52 weeks). This study has been reviewed and approved by the Medical Ethics Committees of all 34 medical centers that are participating. Patients with RNS consent to participation, and are enrolled and randomized to an MZR group or a CYC group (1:1 ratio), with each group receiving tapering doses of oral corticosteroids. Participants are assessed for adverse effects, and laboratory results are collected at 8 visits during the treatment phase (weeks 4, 8, 12, 16, 20, 32, 44, and 52 [exit visit]). Participants are able to withdraw voluntarily, and investigators are required to remove patients when there are safety concerns or deviations from the protocol. RESULTS: The study started in November 2014 and was completed in March 2019. A total of 239 participants from 34 hospitals in China have been enrolled. Data analysis has been completed. The results are being finalized by the Center for Drug Evaluation. CONCLUSIONS: This study examines the safety and efficacy of MZR as a long-term treatment approach for Chinese adults with RNS. It is the longest lasting and largest randomized controlled trial to examine MZR in Chinese patients. The results can help determine whether RNS should be considered as an additional indication for MZR treatment in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT02257697; https://clinicaltrials.gov/ct2/show/NCT02257697. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/46101.

Effects of Selenium on Chronic Kidney Disease: A Mendelian Randomization Study.

BACKGROUND: Previous observational studies have shown that there is a controversial association between selenium levels and chronic kidney disease (CKD). Our aim was to assess the causal relationship between selenium levels and CKD using Mendelian randomization (MR) analysis. METHODS: We used the two-sample Mendelian randomization (MR) method to analyze the causal role of selenium levels on CKD risk. The variants associated with selenium levels were extracted from a large genome-wide association study (GWAS) meta-analysis of circulating selenium levels (n = 5477) and toenail selenium levels (n = 4162) in the European population. Outcome data were from the largest GWAS meta-analysis of European-ancestry participants for kidney function to date. Inverse variance weighted (IVW) method was used as the main analysis and a series of sensitivity analyses were carried out to detect potential violations of MR assumptions. RESULTS: The MR analysis results indicate that the genetically predicted selenium levels were associated with decreased estimated glomerular filtration (eGFR) (effect = -0.0042, 95% confidence interval [CI]: -0.0053-0.0031, p = 2.186 × 10-13) and increased blood urea nitrogen (BUN) (effect = 0.0029, 95% confidence interval [CI]: 0.0006-0.0052, p = 0.0136) with no pleiotropy detected. CONCLUSIONS: The MR study indicated that an increased level of selenium is a causative factor for kidney function impairment.

Idiopathic membranous nephropathy with renal amyloidosis: A case report.

Background: Immunoglobulin light chain amyloidosis is a clonal, non-proliferative plasma cell disorder, in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Membranous nephropathy (MN) is a group of diseases characterized by deposition of immune complexes under the epithelial cells of glomerular basement and diffuse thickening of the basement membrane. Most patients with idiopathic MN (IMN) have been exposed to phospholipase A2 receptor (PLA2R) antigen, and anti-PLA2R antibodies that attack podocytes can be detected in their blood. IMN combined with amyloidosis nephropathy without secondary factors is rare. The present study describes a patient with IMN combined with immunoglobulin light chain amyloidosis nephropathy. Case report: A 39-year-old man was admitted to our hospital because of weight loss and edema. His clinical manifestation was nephrotic syndrome. Renal pathology revealed MN. A positive Congo red staining and the pathognomonic apple-green birefringence under cross-polarized light were considered to be associated with amyloid nephropathy. Immunofluorescence showed that λ light chain was positive. Heavy chain deposition disease and amyloid-associated protein amyloidosis were excluded by immunofluorescence and immunohistochemistry, respectively. Subsequent examinations showed that his serum was negative for antibodies against the PLA2R, but PLA2R was present in renal tissue. The final diagnosis was IMN with light chain amyloid nephropathy. Conclusion: Renal amyloidosis accompanied by IMN is uncommon. Attention should be paid to the subtype of the disease and the exclusion of secondary factors. Perfect clinical and pathological examination are helpful for the classification and staging of the disease. Congo red staining, light microscopy, immunofluorescence, immunohistochemistry, electron microscopic examination, pathological tissue staining for PLA2R antigen and testing for anti-PLA2R antibody in serum are helpful.

Identification of diagnostic gene biomarkers and immune infiltration in patients with diabetic kidney disease using machine learning strategies and bioinformatic analysis.

Objective: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early diagnosis is critical to prevent its progression. The aim of this study was to identify potential diagnostic biomarkers for DKD, illustrate the biological processes related to the biomarkers and investigate the relationship between them and immune cell infiltration. Materials and methods: Gene expression profiles (GSE30528, GSE96804, and GSE99339) for samples obtained from DKD and controls were downloaded from the Gene Expression Omnibus database as a training set, and the gene expression profiles (GSE47185 and GSE30122) were downloaded as a validation set. Differentially expressed genes (DEGs) were identified using the training set, and functional correlation analyses were performed. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forests (RF) were performed to identify potential diagnostic biomarkers. To evaluate the diagnostic efficacy of these potential biomarkers, receiver operating characteristic (ROC) curves were plotted separately for the training and validation sets, and immunohistochemical (IHC) staining for biomarkers was performed in the DKD and control kidney tissues. In addition, the CIBERSORT, XCELL and TIMER algorithms were employed to assess the infiltration of immune cells in DKD, and the relationships between the biomarkers and infiltrating immune cells were also investigated. Results: A total of 95 DEGs were identified. Using three machine learning algorithms, DUSP1 and PRKAR2B were identified as potential biomarker genes for the diagnosis of DKD. The diagnostic efficacy of DUSP1 and PRKAR2B was assessed using the areas under the curves in the ROC analysis of the training set (0.945 and 0.932, respectively) and validation set (0.789 and 0.709, respectively). IHC staining suggested that the expression levels of DUSP1 and PRKAR2B were significantly lower in DKD patients compared to normal. Immune cell infiltration analysis showed that B memory cells, gamma delta T cells, macrophages, and neutrophils may be involved in the development of DKD. Furthermore, both of the candidate genes are associated with these immune cell subtypes to varying extents. Conclusion: DUSP1 and PRKAR2B are potential diagnostic markers of DKD, and they are closely associated with immune cell infiltration.

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.

Associations between short-term exposure of ambient particulate matter and hemodialysis patients death: A nationwide, longitudinal case-control study in China.

BACKGROUND: Long-term exposure to particulate air pollutants can lead to an increase in mortality of hemodialysis patients, but evidence of mortality risk with short-term exposure to ambient particulate matter is lacking. This study aimed to estimate the association of short-term exposure to ambient particulate matter across a wide range of concentrations with hemodialysis patients mortality. METHODS: We performed a time-stratified case-crossover study to estimate the association between short-term exposures to PM2.5 and PM10 and mortality of hemodialysis patients. The study included 18,114 hemodialysis death case from 279 hospitals in 41 cities since 2013. Daily particulate matter exposures were calculated by the inverse distance-weighted model based on each case's dialysis center address. Conditional logistic regression were implemented to quantify exposure-response associations. The sensitivity analysis mainly explored the lag effect of particulate matter. RESULTS: During the study period, there were 18,114 case days and 61,726 control days. Of all case and control days, average PM2.5 and PM10 levels were 43.98 µg/m3 and 70.86 µg/m3, respectively. Each short-term increase of 10 µg/m3 in PM2.5 and PM10 were statistically significantly associated with a relative increase of 1.07 % (95 % confidence interval [CI]: 0.99 % - 1.15 %) and 0.89 % (95 % CI: 0.84 % - 0.94 %) in daily mortality rate of hemodialysis patients, respectively. There was no evidence of a threshold in the exposure-response relationship. The mean of daily exposure on the same day of death and one-day prior (Lag 01 Day) was the most plausible exposure time window. CONCLUSIONS: This study confirms that short-term exposure to particulate matter leads to increased mortality in hemodialysis patients. Policy makers and public health practices have a clear and urgent opportunity to pass air quality control policies that care for hemodialysis populations and incorporate air quality into the daily medical management of hemodialysis patients.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in maintenance dialysis: a meta-analysis.

BACKGROUND: Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients. METHODS: A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021. RESULTS: Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model. CONCLUSION: HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

Telemedicine and Clinical Outcomes in Peritoneal Dialysis: A Propensity-Matched Study.

INTRODUCTION: Telemedicine (TM) has shown to provide potential benefits on clinical outcomes in patients with chronic kidney disease but limited evidences published in the peritoneal dialysis (PD) population. This study aimed to explore the long-term effects of TM on the mortality and technique failure. METHODS: The Peritoneal Dialysis Telemedicine-assisted Platform Cohort Study (PDTAP Study) was conducted prospectively in 27 hospitals in China since 2016. Patient and practice data were collected through the doctor-end of the TM app (Manburs) for all participants. TM including self-monitoring records, on-line education materials, and real-time physician-patient contact was only performed for the patient-end users of the Manburs. The primary outcome was all-cause mortality. The secondary outcomes were cause-specific mortality and all-cause and cause-specific permanent transfer to hemodialysis. RESULTS: A total of 7,539 PD patients were enrolled between June 2016 and April 2019, with follow-up till December 2020. Patients were divided into two cohorts: TM group (39.1%) and non-TM group (60.9%). A propensity score was used to create 2,160 matched pairs in which the baseline covariates were well-balanced. There were significantly lower risks of all-cause mortality (HR 0.59 [0.51, 0.67], p < 0.001), CVD mortality (HR 0.59 [0.49, 0.70], p < 0.001), all-cause transfer to hemodialysis (0.57 [0.48, 0.67], p < 0.001), transfer to hemodialysis from PD-related infection (0.67 [0.51, 0.88], p = 0.003), severe fluid overload (0.40 [0.30, 0.55], p < 0.001), inadequate solute clearance (0.49 [0.26, 0.92], p = 0.026), and catheter-related noninfectious complications (0.41 [0.17, 0.97], p = 0.041) in the TM group compared with the non-TM group. CONCLUSION: This study indicated real-world associations between TM usage and reduction in patient survival and technique survival through a multicenter prospective cohort.

A noninvasive artificial neural network model to predict IgA nephropathy risk in Chinese population.

Renal biopsy is the gold standard for Immunoglobulin A nephropathy (IgAN) but poses several problems. Thus, we aimed to establish a noninvasive model for predicting the risk probability of IgAN by analyzing routine and serological parameters. A total of 519 biopsy-diagnosed IgAN and 211 non-IgAN patients were recruited retrospectively. Artificial neural networks and logistic modeling were used. The receiver operating characteristic (ROC) curve and performance characteristics were determined to compare the diagnostic value between the two models. The training and validation sets did not differ significantly in terms of any variables. There were 19 significantly different parameters between the IgAN and non-IgAN groups. After multivariable logistic regression analysis, age, serum albumin, serum IgA, serum immunoglobulin G, estimated glomerular filtration rate, serum IgA/C3 ratio, and hematuria were found to be independently associated with the presence of IgAN. A backpropagation network model based on the above parameters was constructed and applied to the validation cohorts, revealing a sensitivity of 82.68% and a specificity of 84.78%. The area under the ROC curve for this model was higher than that for logistic regression model (0.881 vs. 0.839). The artificial neural network model based on routine markers can be a valuable noninvasive tool for predicting IgAN in screening practice.