Background:Chronic kidney disease-associated pruritus (CKD-aP) is a common and debilitating condition in patients receiving in-centre haemodialysis. This study evaluated the efficacy and safety of difelikefalin (a new, intravenous treatment for moderate-to-severe CKD-aP approved in >40 countries) in a Chinese population receiving haemodialysis. Methods:This Phase 3, multicentre, randomized placebo-controlled study included a 12-week double-blind treatment period, during which patients received either difelikefalin or placebo, followed by an optional 14-week open-label extension, in which all patients received difelikefalin. Endpoints included change from baseline in the Worst Itching Intensity Numerical Rating Scale (WI-NRS) at Week 4 (primary endpoint), the percentage of patients achieving a clinically relevant ≥3-point change in WI-NRS, patient-reported health-related quality-of-life measures, and incidence of adverse events. Results:Difelikefalin-treated patients showed significantly greater improvements in least squares mean change from baseline in WI-NRS at Week 4 of the double-blind period compared with placebo [difelikefalin minus placebo: -0.81 (95% confidence interval: -1.25, -0.37); P = .0003], and patients with ≥3-point improvement in WI-NRS at Week 12 (48.7% versus 33.8%, nominal P = .0235). Difelikefalin also improved health-related quality of life, with clinically relevant changes observed in 5-D itch and Skindex-10 in most patients at Week 4 of the open-label extension (estimated ≥62% and ≥56%, respectively). Adverse events were mostly mild or moderate in severity and generally consistent with the known safety profile of difelikefalin. Conclusion:Difelikefalin effectively reduced pruritus intensity and improved quality of life in Chinese patients with CKD-aP receiving haemodialysis, supporting its use in this population.

Introduction: Enarodustat is an oral HIF-PHI for the treatment of chronic kidney disease anemia. Methods: This phase 3, multicenter, randomized 24-week study assessed enarodustat's noninferiority to rHuEPO for treating hemodialysis-dependent CKD (HD-CKD) anemia. Overall, 100 ESAs-treated patients were randomized 1:1 to enarodustat or rHuEPO for a 24-week treatment with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within target range 100-120 g/L. The primary efficacy endpoint was the between-group difference in mean Hb over weeks 20-24 (evaluation period [noninferiority margin: -10 g/L]). Safety was assessed by treatment-emergent adverse events (TEAEs). Results: Of the 100 patients treated (enarodustat: 50; rHuEPO: 50), 93 completed the study. Demographic and baseline characteristics were comparable. During the evaluation period, the mean Hb level was 106.81 g/L in the enarodustat group and 99.68 g/L in the rHuEPO group. Enarodustat was noninferior to rHuEPO (least squares mean difference: 7.47 g/L [95% confidence interval: 4.17, 10.78]; p < 0.001). The mean Hb level in the enarodustat group remained within the target range throughout the treatment period, with a maintenance rate of 79.6% during weeks 20-24 versus 51.0% for rHuEPO. After switching from ESAs, the enarodustat group showed increased total iron-binding capacity, transferrin, and serum iron, decreased hepcidin by week 4, and increased RET% by week 2. TEAEs incidences were comparable (enarodustat: 90.0%, rHuEPO: 90.0%), with no additional safety concerns for enarodustat. Conclusions: Enarodustat was noninferior to rHuEPO for the treatment of anemia in HD-CKD patients, with good safety and tolerability over 24 weeks.

OBJECTIVE:To evaluate the efficacy and safety of anrikefon (formerly known as HSK21542), a novel selective peripherally restricted kappa opioid receptor agonist, in patients with chronic kidney disease associated pruritus. DESIGN:Multicentre, double blind, randomised placebo controlled phase 3 trial. SETTING:50 centres in China, June 2022 to June 2024. PARTICIPANTS:652 patients with moderate to severe CKD associated pruritus undergoing haemodialysis were screened: 545 were randomly assigned (1:1 ratio) to receive either anrikefon (n=275) or placebo (n=270). INTERVENTIONS:Intravenous anrikefon (0.3 μg/kg body weight) or placebo three times weekly for 12 weeks, followed by an optional open label extension phase with anrikefon treatment for 40 weeks. MAIN OUTCOME MEASURES:The primary endpoint was the percentage of patients achieving at least a 4 point reduction in weekly mean 24 hour worst itching intensity numerical rating scale (WI-NRS) score from baseline to week 12. Secondary outcomes were the percentage of patients achieving at least a 3 point reduction in weekly mean WI-NRS score from baseline to week 12, as well as changes in itch related quality of life from baseline using the Skindex-10 and 5-D itch scales. The change in itch related quality of life from baseline to week 40 of open label treatment was also reported using the 5-D itch scale. The safety of anrikefon was evaluated throughout the trial. RESULTS:243/275 (88%) patients in the anrikefon group and 254/270 (94%) in the placebo group completed the 12 week double blind treatment. 443 subsequently entered the 40 week open label extension phase. 37% of patients in the anrikefon group showed at least a 4 point reduction in WI-NRS score at week 12 compared with 15% in the placebo group (P<0.001). The percentage of patients with at least a 3 point reduction in WI-NRS score from baseline to week 12 was 51% in the anrikefon group compared with 24% in the placebo group (P<0.001). The anrikefon group showed significant improvements in itch related quality of life (mean change from baseline in 5-D itch scale -5.3 v -3.1, P<0.001 and in Skindex-10 scale -15.2 v -9.3, P<0.001). Anrikefon also showed sustained long term efficacy during the open label extension phase at week 40, with persistent improvement in quality of life scores on the 5-D itch scale. Mild to moderate dizziness was more common in the anrikefon group than placebo group but without evident clinical consequences. CONCLUSIONS:In patients with moderate to severe pruritus undergoing haemodialysis, anrikefon was found to be safe and resulted in a noticeable reduction in itch intensity and an improvement in itch related quality of life. TRIAL REGISTRATION:ClinicalTrials.gov NCT05135390.

Lupus nephritis is typically treated with intravenous cyclophosphamide, which is associated with serious adverse effects. Oral mizoribine may be an alternative for induction therapy of lupus nephritis. However, large-scale, long-term, randomized clinical studies of mizoribine are lacking. To assess the efficacy and safety of oral mizoribine vs intravenous cyclophosphamide as induction therapy for Chinese patients with lupus nephritis. This prospective, multicenter, parallel-group, open-label, phase 3 randomized clinical trial recruited patients with class III, III+V, IV, IV+V, or V lupus nephritis aged 18 to 70 years from 40 centers in China. Inclusion criteria included 24-hour urinary protein level of 1.0 g or higher and systemic lupus erythematosus disease activity index of 8 or higher. The first patient was enrolled on November 29, 2014, and the study finished March 14, 2019. The follow-up period was 52 weeks. Data were analyzed from September 4, 2019, to January 21, 2020. Oral mizoribine (50 mg, 3 times a day) or cyclophosphamide (6 intravenous doses at 0.5-1.0 g/m2 body surface area, with a maximum dose of 1.0 g/d) for 52 weeks plus oral glucocorticoid. Total remission rate (complete remission rate plus partial remission rate) after 52 weeks (prespecified). A total of 250 patients were randomized, and 243 patients (mean [SD] age, 34.6 [10.7] years, 213 women [87.7%]) were treated (123 patients [50.6%] in the mizoribine group and 120 patients [49.4%] in the cyclophosphamide group). The total remission rate at 52 weeks was 66.1% (76 of 115 patients) in the mizoribine group and 76.8% (86 of 112 patients) in the cyclophosphamide group, and the relative risk ratio (mizoribine vs cyclophosphamide) was 0.861 (95% CI, 0.729-1.016). The lower limit of this 2-sided 95% CI was greater than the noninferiority margin of 0.726, indicating that mizoribine was noninferior to cyclophosphamide. Changes in other immune parameters and kidney function were generally similar between the groups. The incidence of any treatment-related treatment-emergent adverse events was 80.5% (99 of 123 patients) in the mizoribine group and 78.7% (96 of 122 patients) in the cyclophosphamide group, and the most frequent adverse event in both groups was upper respiratory tract infection (41 patients [33.3%] and 37 patients [30.3%], respectively). This randomized clinical trial shows that compared with intravenous cyclophosphamide, oral mizoribine was noninferior and well tolerated when used with glucocorticoid for induction therapy of active lupus nephritis. Mizoribine can be used as an alternative to intravenous cyclophosphamide as induction therapy for lupus nephritis. ClinicalTrials.gov Identifier: NCT02256150

Background Chronic kidney disease-associated pruritus (CKD-aP) is a common and distressing symptom in hemodialysis patients. This Phase II trial evaluated the efficacy and safety of HSK21542, a selective kappa-opioid receptor agonist, in managing CKD-aP.Methods Adult patients on hemodialysis with moderate to severe pruritus, were randomized 1:1:1 to placebo, or HSK21542 (0.3 mu g/kg or 0.6 mu g/kg) administered thrice weekly post-dialysis for 12 weeks. The primary endpoint was the change from baseline in the weekly mean of the worst itching intensity Numerical Rating Scale (WI-NRS) score at week 12. Secondary endpoints included quality-of-life assessments, safety evaluations, and pharmacokinetic properties.Results A total of 90 patients were enrolled. At week 12, mean changes in WI-NRS scores from baseline were -2.94 for the placebo group, -3.40 for the 0.3 mu g/kg HSK21542 group, and -2.21 for the 0.6 mu g/kg HSK21542 group. The percentages of patients who had a reduction of 3 points or above in their WI - NRS scores were 44.4% in the placebo group, 62.1% in the 0.3 mu g/kg HSK21542 group, and 37.0% in the 0.6 mu g/kg HSK21542 group. The 0.30 mu g/kg HSK21542 group demonstrated more significant improvements in Skindex - 16 scores compared to the placebo. The 5-D Itch Scale scores also presented similar trends. Both the 0.3 mu g/kg and 0.6 mu g/kg doses of HSK21542 were well - tolerated, with no dose-dependent adverse effects.Conclusion The 0.3 mu g/kg dose of HSK21542 demonstrated superior efficacy and safety in reducing pruritus and improving quality of life in hemodialysis patients.

Introduction: Renal anemia is a common complication among patients with non-dialysis chronic kidney disease (ND-CKD), and there remains an unmet need for more efficient and convenient daily oral medications to improve patient outcomes. This study aimed to evaluate the efficacy and safety of enarodustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, in treating anemia for ND-CKD patients. Methods: This phase 3 study was conducted at 48 centers across China, enrolling 156 ND-CKD patients. Participants were randomly randomized in a 2:1 ratio to receive either enarodustat or placebo for an initial 8-week double-blind period, followed by a 16-week open-label period during which all patients received enarodustat. Results: The primary endpoint was the mean change in hemoglobin (Hb) levels from baseline to the average level during weeks 7-9. Secondary endpoints focused on Hb concentration or treatment pattern, while exploratory endpoints assessed iron metabolism-related parameters. The mean (+/- SD) change in Hb levels from baseline to weeks 7-9 was 15.99 (+/- 9.46) g/L in the enarodustat group, compared to -0.14 (+/- 8.08) g/L in the placebo group, resulting in a mean difference of 16.00 (+/- 1.54) g/L (p < 0.001). During weeks 7-9, 85.3% of patients in the enarodustat group achieved Hb levels >= 100 g/L with 86.0% maintaining this level during weeks 21-25. In the first 4 weeks, the Hb increased by 11.82 (+/- 9.56) g/L in the enarodustat group. By week 9, the mean change in hepcidin level was -42.94 (+/- 37.56) ng/mL in the enarodustat group, compared to +4.58 (+/- 33.34) ng/mL in the placebo group. Enarodustat also improved other iron-related parameters and reduced the need for iron supplements. The safety profile of enarodustat was well tolerable with adverse events comparable to those of the placebo. Conclusion: Enarodustat effectively corrected renal anemia with a manageable safety profile. Its once-daily oral administration offers convenience that may enhance the adherence. Enarodustat shows the potential as a promising therapy for anemic patients with ND-CKD. Anemia happens when the body does not have enough hemoglobin (Hb), which is a protein in red blood cells and responsible for carrying oxygen. Renal anemia is common in patients with non-dialysis chronic kidney disease (ND-CKD). This study looked at whether enarodustat, a new oral drug, could help treat anemia in these patients. The study involved 156 patients with ND-CKD. Some patients received enarodustat, while the others received a placebo (a tablet with no active ingredient but having the same appearance with enarodustat) for 8 weeks. During this period, no patients knew if they were taking the active drug, followed by another 16-week period during which all patients were certain to took enarodustat. The results showed that enarodustat significantly increased the levels of Hb compared to the placebo. Most patients receiving enarodustat reached target Hb levels, and this improvement continued over the following 16 weeks. The drug also helps with the way the body handles iron, which is important for producing red blood cells, reducing the need for additional iron treatments. The drug was generally well tolerated, with side effects similar to those of the placebo. Because enarodustat is a once-daily tablet, it looks easier for patients to use than drugs administered in other ways or with irregular frequency. The usage also potentially helps patients to stick to treatment. This study suggests that enarodustat could be a promising option for treating anemia in people with ND-CKD. (c) 2024 The Author(s). Published by S. Karger AG, Basel

Finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, has shown promising efficacy and safety profiles in the management of chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM). However, evidence for its role in non-diabetic CKD patients require further investigation. This retrospective, real-world study involved non-diabetic CKD patients from April 2023 to June 2024. Participants received finerenone alongside standard CKD treatment. Primary clinical results included changes in the urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and serum potassium (sK+) levels. The data were collected initially and during follow-ups at 1, 3, 6, and 12 months. In total, 37 non-diabetic CKD patients were included in the population; 21 individuals (56.8

Importance:Kidney biopsy pathology via transmission electron microscopy (TEM) is essential for diagnosing glomerular diseases, offering critical information on glomerular basement membrane (GBM) thickness, foot process (FP) number, and electron-dense deposits (EDDs). These tasks are laborious and time-consuming. Objective:To develop and validate an artificial intelligence (AI) diagnostic system, TEM image-based AI-assisted device (TEM-AID), that accurately segments and measures glomerular ultrastructures (including the GBM, FPs, and EDDs) and determines glomerular disease subtypes using TEM images. Design, Setting, and Participants:This diagnostic study used a large, multicenter cohort including 160 727 TEM images from 31 670 patients with chronic kidney disease across 6 medical centers from January 2021 to December 2023. TEM-AID was trained and validated on 26 650 patients from 1 center and tested externally on 5020 patients (5 test sets) plus a human-AI test set (454 patients representing 7 glomerular disease subtypes). Data were analyzed from January to December 2024. Exposures:TEM-AID integrates 4 modules. Segmentation combined YOLO-v8 detection, segment anything model, and human-in-the-loop refinement to segment GBMs, podocyte FPs, and EDDs. Measurement quantified GBM thickness, FP fusion degree, and EDD deposition sites. Classification used least absolute shrinkage and selection operator-selected deep learning and statistical features with a stacking classifier to diagnose 7 glomerular disease subtypes: immunoglobin A nephropathy, membranous nephropathy, lupus nephritis, diabetic nephropathy, minimal change disease, mesangial proliferative glomerulonephritis, and thin basement membrane nephropathy. Main Outcomes and Measures:Outcomes of interest were segmentation performance (mean intersection-over-union [IOU], Dice coefficient), subtype classification accuracy, area under the receiver operating characteristic curve (AUC), and human-AI diagnostic concordance. Results:A total of 31 670 patients (mean [SD] age, 43.2 [16.5] years; 17 372 [54.9%] male) contributed 160 727 TEM images for analysis. Segmentation achieved a mean (SD) IOU of 0.835 (0.062) and Dice of 0.874 (0.023). Subtype classification accuracy was 0.911 (95% CI, 0.904-0.918) in internal validation and 0.895 to 0.914 in external tests. Macro-AUC ranged from 0.972 to 0.989 across cohorts. In human-AI testing (454 patients), TEM-AID accuracy (0.886 (95% CI, 0.859-0.912]; AUC, 0.963 [95% CI, 0.937-0.989]) exceeded clinicians' unaided performance. Clinicians' accuracy improved by a mean (SD) of 11.7% (5.2%) when they used TEM-AID. Conclusions and Relevance:In this multicenter diagnostic study, TEM-AID precisely quantified glomerular ultrastructures and determined glomerular disease subtypes from TEM images, significantly enhancing diagnostic efficiency and accuracy. This system provides quantitative evaluation tools to support clinical pathologists in diagnostic workflows, demonstrating robust multicenter performance.

Importance:Lupus nephritis is typically treated with intravenous cyclophosphamide, which is associated with serious adverse effects. Oral mizoribine may be an alternative for induction therapy of lupus nephritis. However, large-scale, long-term, randomized clinical studies of mizoribine are lacking. Objective:To assess the efficacy and safety of oral mizoribine vs intravenous cyclophosphamide as induction therapy for Chinese patients with lupus nephritis. Design, Setting, and Participants:This prospective, multicenter, parallel-group, open-label, phase 3 randomized clinical trial recruited patients with class III, III+V, IV, IV+V, or V lupus nephritis aged 18 to 70 years from 40 centers in China. Inclusion criteria included 24-hour urinary protein level of 1.0 g or higher and systemic lupus erythematosus disease activity index of 8 or higher. The first patient was enrolled on November 29, 2014, and the study finished March 14, 2019. The follow-up period was 52 weeks. Data were analyzed from September 4, 2019, to January 21, 2020. Interventions:Oral mizoribine (50 mg, 3 times a day) or cyclophosphamide (6 intravenous doses at 0.5-1.0 g/m2 body surface area, with a maximum dose of 1.0 g/d) for 52 weeks plus oral glucocorticoid. Main Outcomes and Measures:Total remission rate (complete remission rate plus partial remission rate) after 52 weeks (prespecified). Results:A total of 250 patients were randomized, and 243 patients (mean [SD] age, 34.6 [10.7] years, 213 women [87.7%]) were treated (123 patients [50.6%] in the mizoribine group and 120 patients [49.4%] in the cyclophosphamide group). The total remission rate at 52 weeks was 66.1% (76 of 115 patients) in the mizoribine group and 76.8% (86 of 112 patients) in the cyclophosphamide group, and the relative risk ratio (mizoribine vs cyclophosphamide) was 0.861 (95% CI, 0.729-1.016). The lower limit of this 2-sided 95% CI was greater than the noninferiority margin of 0.726, indicating that mizoribine was noninferior to cyclophosphamide. Changes in other immune parameters and kidney function were generally similar between the groups. The incidence of any treatment-related treatment-emergent adverse events was 80.5% (99 of 123 patients) in the mizoribine group and 78.7% (96 of 122 patients) in the cyclophosphamide group, and the most frequent adverse event in both groups was upper respiratory tract infection (41 patients [33.3%] and 37 patients [30.3%], respectively). Conclusions and Relevance:This randomized clinical trial shows that compared with intravenous cyclophosphamide, oral mizoribine was noninferior and well tolerated when used with glucocorticoid for induction therapy of active lupus nephritis. Mizoribine can be used as an alternative to intravenous cyclophosphamide as induction therapy for lupus nephritis. Trial Registration:ClinicalTrials.gov Identifier: NCT02256150.

The genetic etiology of diabetic nephropathy (DN) is masked by inaccurate phenotyping and ethnic disparities. Here, we conduct a stepwise genome-wide association study (GWAS) in the Chinese Han population, using a precise phenotype of biopsy-proven DN as cases, patients with type 2 diabetes without microvascular complications as controls, and healthy individuals for comparison. Our analysis reveals that the genetic etiology of DN is primarily attributed to an inherent susceptibility to kidney injury. We identify 10 suggestive loci, 5 of which have a high probability of being causal, with a missense variant in TCN2 (p.K77M) as the top candidate. Subsequent multidimensional analyses reveal that genetic variants associated with tubulointerstitial injury are key contributors to the DN predisposition. Furthermore, in vitro and in vivo experiments confirm that TCN2 p.K77M induces mitochondrial dysfunction, exacerbating renal tubular cell damage under high-glucose conditions. Our study elucidates the genetic architecture of biopsy-proven DN and provides a mechanistic rationale for its pathogenesis.

Recent studies have suggested that ferroptosis participates in various renal diseases. However, its effect on focal segmental glomerulosclerosis remains unclear. This study analyzed the GSE125779 and GSE121211 datasets to identify the differentially expressed genes (DEGs) in renal tubular samples with and without FSGS. The Cytoscape was used to construct the protein-protein interaction network. Moreover, the ferroptosis-related genes (FRGs) were obtained from the ferroptosis database, while ferroptosis-related DEGs were obtained by intersection with DEGs. The target genes were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The GSE108112 dataset was used to verify the expression of target FRGs. Besides, we built the mRNA-miRNA network regarding FRGs using the NetworkAnalyst database, and circRNAs corresponding to key miRNAs were predicted in the ENCORI database. In this study, 16 ferroptosis-related DEGs were identified between FSGS and healthy subjects, while five co-expressed genes were obtained by three topological algorithms in Cytoscape. These included the most concerned Hub genes JUN, HIF1A, ALB, DUSP1 and ATF3. The KEGG enrichment analysis indicated that FRGs were associated with mitophagy, renal cell carcinoma, and metabolic pathways. Simultaneously, the co-expressed hub genes were analyzed to construct the mRNA-miRNA interaction network and important miRNAs such as hsa-mir-155-5p, hsa-mir-1-3p, and hsa-mir-124-3p were obtained. Finally, 75 drugs targeting 54 important circRNAs and FRGs were predicted. This study identified the Hub FRGs and transcriptomic molecules from FSGS in renal tubules, thus providing novel diagnostic and therapeutic targets for FSGS.

Background Interstitial fibrosis is the primary determinant of the progression of chronic kidney disease (CKD), and noninvasive identification of interstitial fibrosis is a major challenge. We aimed to explore the diagnostic value of secreted protein acidic and rich in cysteine (SPARC) in serum and urine in kidney fibrosis. Methods Single-cell transcriptome analysis was used to measure SPARC expression in healthy reference kidneys and those of patients with CKD. A total of 674 patients with CKD who underwent renal biopsy served as the training cohort (n = 322) and the validation cohort (n = 352). Serum and urinary SPARC levels were measured at the time of kidney biopsy. In vivo and in vitro models of kidney fibrosis were also used to confirm the role of SPARC. Results Increased SPARC expression was detected in kidney fibrosis tissues. Higher serum SPARC levels were associated with increased severity of kidney fibrosis. Moreover, the area under the receiver operating characteristic curve (AUC-ROC) (AUC 0.86) was greater for the serum SPARC level than for the urinary SPARC level and estimated glomerular filtration rate (eGFR). The combination of the serum and urinary SPARC levels and eGFR increased the AUC-ROC for predicting kidney fibrosis from 0.86 to 0.90. The diagnostic performance of serum or urinary SPARC levels was consistent in the validation cohort. In vivo and in vitro models of kidney fibrosis also confirmed the upregulation of SPARC expression. Conclusions Serum and urinary SPARC levels may be potential biomarkers for kidney fibrosis and may be useful for noninvasive diagnosis.

ABSTRACT Background The efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD). Methods This was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug. Results Between 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference −1.17 mg/dl (95% CI −1.694 to −0.654, P < .001). More patients receiving tenapanor achieved a serum phosphorous level <5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor. Conclusions Tenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.

IMPORTANCE Baseline findings from the China Dialysis Calcification Study (CDCS) revealed a high prevalence of vascular calcification (VC) among patients with end-stage kidney disease; however, data on VC progression were limited. OBJECTIVES To understand the progression of VC at different anatomical sites, identify risk factors for VC progression, and assess the association of VC progression with the risk of cardiovascular events and death among patients receiving maintenance dialysis. Design, Setting, and ParticipantsThis cohort study was a 4-year follow-up assessment of participants in the CDCS, a nationwide multicenter prospective cohort study involving patients aged 18 to 74 years who were undergoing hemodialysis or peritoneal dialysis. Participants were recruited from 24 centers across China between May 1, 2014, and April 30, 2015, and followed up for 4 years. A total of 1489 patients receiving maintenance dialysis were included in the current analysis. Data were analyzed from September 1 to December 31, 2021. ExposuresPatient demographic characteristics and medical history; high-sensitivity C-reactive protein laboratory values; serum calcium, phosphorus, and intact parathyroid hormone (iPTH) values; and previous or concomitant use of medications. MAIN OUTCOMES AND MEASURES The primary outcome was progression of VC at 3 different anatomical sites (coronary artery, abdominal aorta, and cardiac valves) and identification of risk factors for VC progression. Participants received assessments of coronary artery calcification (CAC), abdominal aortic calcification (AAC), and cardiac valve calcification (CVC) at baseline, 24 months, 36 months, and 48 months. Secondary outcomes included (1) the association between VC progression and the risk of all-cause death, cardiovascular (CV)-related death, and a composite of all-cause death and nonfatal CV events and (2) the association between achievement of serum calcium, phosphorus, and iPTH target levels and the risk of VC progression. RESULTS Among 1489 patients, the median (IQR) age was 51.0 (41.0-60.0) years; 59.5% of patients were male. By the end of 4-year follow-up, progression of total VC was observed in 86.5% of patients; 69.6% of patients had CAC progression, 72.4% had AAC progression, and 33.4% had CVC progression. Common risk factors for VC progression at the 3 different anatomical sites were older age and higher fibroblast growth factor 23 levels. Progression of CAC was associated with a higher risk of all-cause death (model 1 [adjusted for age, sex, and body mass index]: hazard ratio [HR], 1.97 [95% CI, 1.16-3.33]; model 2 [adjusted for all factors in model 1 plus smoking status, history of diabetes, and mean arterial pressure]: HR, 1.89 [95% CI, 1.11-3.21]; model 3 [adjusted for all factors in model 2 plus calcium, phosphorus, intact parathyroid hormone, and fibroblast growth factor 23 levels and calcium-based phosphate binder use]: HR, 1.92 [95% CI, 1.11-3.31]) and the composite of all-cause death and nonfatal CV events (model 1: HR, 1.98 [95% CI, 1.19-3.31]; model 2: HR, 1.91 [95% CI, 1.14-3.21]; model 3: HR, 1.95 [95% CI, 1.14-3.33]) after adjusting for all confounding factors except the presence of baseline calcification. Among the 3 targets of calcium, phosphorus, and iPTH, patients who achieved no target levels (model 1: odds ratio [OR], 4.75 [95% CI, 2.65-8.52]; model 2: OR, 4.81 [95% CI, 2.67-8.66]; model 3 [for this analysis, adjusted for all factors in model 2 plus fibroblast growth factor 23 level and calcium-based phosphate binder use]: OR, 2.76 [95% CI, 1.48-5.16]), 1 target level (model 1: OR, 3.71 [95% CI, 2.35-5.88]; model 2: OR, 3.62 [95% CI, 2.26-5.78]; model 3: OR, 2.19 [95% CI, 1.33-3.61]), or 2 target levels (model 1: OR, 2.73 [95% CI, 1.74-4.26]; model 2: OR, 2.69 [95% CI, 1.71-4.25]; model 3: OR, 1.72 [95% CI, 1.06-2.79]) had higher odds of CAC progression compared with patients who achieved all 3 target levels. CONCLUSIONS AND RELEVANCE In this study, VC progressed rapidly in patients undergoing dialysis, with different VC types associated with different rates of prevalence and progression. Consistent achievement of serum calcium, phosphorus, and iPTH target levels was associated with a lower risk of CAC progression. These results may be useful for increasing patient awareness and developing appropriate strategies to improve the management of chronic kidney disease-mineral and bone disorder among patients undergoing dialysis.

Background Hepatitis B virus-associated glomerulonephritis is a common form of secondary glomerulonephritis in China. However, the clinicopathological features and long-term prognosis of Hepatitis B virus-associated Glomerulonephritis remain only partially known. Methods Biopsy-proven Hepatitis B virus-associated Glomerulonephritis patients were enrolled between November 1994 and December 2013 at our center. The composite endpoints were doubling serum creatinine, end-stage renal disease, or death from renal disease during follow-up. The clinicopathological features and predictors of the long-term prognosis of Hepatitis B virus-associated Glomerulonephritis patients were explored. Results The median age of the 259 Hepatitis B virus-associated Glomerulonephritis patients was 31.0 years (IQR 24.0–40.0), and 71.0% were males. Among the patients, 45.2% presented with nephrotic syndrome, and 45.9% presented with proteinuria combined with hematuria. The two most prevalent pathological patterns were IgA nephropathy (27.0%) and membranous nephropathy (27.0%). The mean follow-up period was 68.8 ± 46.9 months. The 3-, 5-, and 10-year clinical event-free survival rates were 93.4%, 85.2%, and 70.3%, respectively. Multivariable Cox regression analysis showed that hypertension (HR 2.580, 95% CI 1.351–4.927, P = 0.004), hyperuricemia (HR 2.101, 95% CI 1.116–3.954, P = 0.021), glomerulosclerosis ( P = 0.001), and intrarenal arterial lesions ( P = 0.041) were independent predictors of composite clinical event endpoint. Patients in the antiviral therapy group exhibited a significantly better prognosis compared to those who received no antiviral therapy (log-rank χ 2 = 5.772, P = 0.016). Conclusion Hepatitis B virus-associated Glomerulonephritis has specific clinicopathologic features and should not be considered a benign disease in adults. Hypertension, hyperuricemia, glomerulosclerosis, and intrarenal arterial lesions were independent predictors of the long-term prognosis in Hepatitis B virus-associated Glomerulonephritis patients. Antiviral therapy could be effective in improving the long-term prognosis of Hepatitis B virus-associated Glomerulonephritis patients. Graphic abstract

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial.Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05–0.80 μg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed.Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05–0.80 μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05–0.80 μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 μg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score.Conclusion: HSK21542 was well tolerated in the dose range 0.05–0.80 μg/kg in hemodialysis patients. HSK21542-0.3 μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT04470154.

AbstractRecent studies have demonstrated the close relationship between parathyroid adenoma (PA) and thyroid follicular adenoma (FTA). However, the underlying pathogenesis remains unknown. This study focused on exploring common pathogenic genes, as well as the pathogenesis of these two diseases, through bioinformatics methods. This work obtained PA and FTA datasets from the Integrated Gene Expression Database to identify the common differentially expressed genes (DEGs) of two diseases. The functions of the genes were investigated by GO and KEGG enrichment. The program CytoHubba was used to select the hub genes, while receiver operating characteristic curves were plotted to evaluate the predictive significance of the hub genes. The DGIbd database was used to identify gene-targeted drugs. This work detected a total of 77 DEGs. Enrichment analysis demonstrated that DEGs had activities of 3′,5′-cyclic AMP, and nucleotide phosphodiesterases and were associated with cell proliferation. NOS1, VWF, TGFBR2, CAV1, and MAPK1 were identified as hub genes after verification. The area under the curve of PA and FTA was>0.7, and the hub genes participated in the Relaxin Signaling Pathway, focal adhesion, and other pathways. The construction of the mRNA-miRNA interaction network yielded 11 important miRNAs, while gene-targeting drug prediction identified four targeted drugs with possible effects. This bioinformatics study demonstrated that cell proliferation and tumor suppression and the hub genes co-occurring in PA and FTA, have important effects on the occurrence and progression of two diseases, which make them potential diagnostic biomarkers and therapeutic targets.

Zhibaidihuang Decoction (ZBDHD) is a traditional Chinese medicine with immense potential to treat IgA nephropathy. However, its core ingredients and representative mechanism remain unclear. In this study, we uncovered the key component and underlying mechanisms of ZBDHD for IgA nephropathy by applying network pharmacology and molecular docking approaches. This was done by first identifying the active ingredients and, subsequently, their corresponding gene targets in ZBDHD with the help of the Traditional Chinese Medicine Systems Pharmacology and analysis platform (TCMSP) database, thereby constructing the drug-compound-target network. The IgA nephropathy-associated genes were then identified using GeneCards, Drugbank, and OMIM databases. The overlapped targets were later obtained to establish Protein-Protein Interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, we performed molecular docking among active compounds and hub genes, and thereby verified the key compound of ZBDHD. The drug-compound-gene network consisted of 289 nodes and 1,113 edges. The top four active ingredients were beta-sitosterol, kaempferol, quercetin and stigmasterol. The top five hub genes in the PPI network were AKT1, ILB1, IL-6, TNF, and TP53. Molecular docking results could demonstrate that there was high affinity among active compounds and the core targets, while quercetin may possibly be the key compound of ZBDHD. We first identified the positive compound and the candidate molecular mechanisms of ZBDHD in an IgA nephropathy treatment and discovered that quercetin might be the core compound of ZBDHD in the treatment of IgA nephropathy.

Background: The removal techniques for peritoneal dialysis (PD) catheters are open surgical dissection (OD) and the ‘pull technique’ (PT). The latter is limitedly used because of uncertainty about its feasibility and safety. This study aimed to compare the outcomes and complications between the two techniques. Methods: This retrospective study included patients who underwent PD catheter removal from January 2015 to January 2021 in four PD centres in China. The patients were grouped according to the different removal techniques and were followed up to observe the potential complications. Results: The demographic characteristics of patients in the PT ( n = 68) and OD ( n = 44) groups showed no significant difference. The indications for PD catheter removal were similar between the two groups, except for a higher frequency of peritonitis in the OD group ( p = 0.010). In the PT group, the main complications were broken catheter (7.4%), superficial cuff infection (4.8%) and subcutaneous bleeding (4.8%). In the OD group, the main complications were death (9.1%) and subcutaneous bleeding (4.6%). Conclusion: PT might be a safe and reliable technique for PD catheter removal compared to OD. Considering its simple and non-invasive nature, PT should be recommended as the alternative to OD in suitable PD patients.

The systemic review and meta-analysis aimed to identify the predictors for short-term successful weaning from CRRT in severe AKI patients. PubMed, Embase, the Cochrane Library, and grey literature were searched for relevant studies investigating variables for short-term successful weaning from CRRT to August 2022. Our criteria included patients with AKI who required CRRT but excluded patients with kidney failure. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using fixed-effect (I-2 <= 50% and P-value of the Q statistic > 0.1) or random-effect models (I-2>50% or p-value of the Q statistic <= 0.1) as appropriate. Our search yielded 11 studies and described 11 variables. The pooled analysis showed that chronic kidney disease (OR = 0.638, 95% CI: 0.491-0.829), CRRT duration (OR = 0.913, 95% CI: 0.882-0.946), and urine output at the cessation of CRRT (per 100 mL/day increase) (OR = 1.084, 95% CI: 1.061-1.108) were predictive factors for short-term successful weaning from CRRT. Male (OR = 0.827, 95% CI: 0.627-1.092), diabetes mellitus (OR = 0.970, 95% CI: 0.761-1.237), and sepsis (OR = 0.911, 95% CI: 0.717-1.158) were unrelated to the short-term weaning from CRRT. The relationship between hypertension, use of vasopressors or inotropes at the starting of CRRT, use of vasopressors or inotropes at the cessation of CRRT, use of diuretics at the cessation of CRRT, serum creatinine at the cessation of CRRT, and short-term weaning from CRRT remains unclear. Additional prospective studies are needed to evaluate this relationship further.