Rationale & Objective Chronic kidney disease (CKD) is associated with substantial economic burden. Early identification of high-risk patients with CKD can facilitate timely intervention and reduce CKD-related medical costs. This study assessed the association between CKD progression risk and healthcare burden. Study Design Retrospective observational analysis. Setting and Participants 1,050,552 United-States adult patients in Optum’s electronic health records database between 1/1/2007 and 9/30/2022. Exposures Risk of CKD progression as determined a laboratory-based machine learning model. Outcomes All-cause healthcare resource utilization (HRU) and medical costs. Analytical Approach A previously published and validated machine learning model, Klinrisk, was applied to classify patients into 3 groups based on their risk of CKD progression (low, medium, and high). All-cause inpatient admissions, emergency room (ER) visits, outpatient visits were evaluated in each risk group during the 1 year after CKD diagnosis. Average medical costs (2023 USD) were calculated as the average length of stay for inpatient admissions, average number of ER and outpatient visits multiplied by the corresponding unit costs as estimated from a prior study. Results Patients with higher predicted CKD progression risk had higher healthcare burden. High-risk patients averaged 1.49 inpatient admissions, 0.83 ER visits, and 35.75 outpatient visits per year compared with 0.31 inpatient admissions, 0.63 ER visits, and 24.45 outpatient visits among low-risk patients. The total annual medical costs for low-, medium-, and high-risk patients were $16,018, $22,090, and $50,218, respectively. Limitations Our analysis only considered direct medical costs to the payer and omitted indirect costs (e.g. transportation, capital, health records). The Klinrisk model only predicts CKD progression, not cardiovascular disease outcomes. Conclusions Patients at high risk of CKD progression as predicted by the Klinrisk model had higher HRU and medical costs and may benefit from medical intervention and care management to reduce economic burden.

Aims Iron deficiency occurs commonly in chronic kidney disease (CKD), but its association with heart failure and other cardiovascular (CV) outcomes, independent of anaemia, is not well defined. Methods We conducted a post-hoc analysis of the Anaemia Studies in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial. We assessed the independent associations of transferrin saturation (TSAT) and ferritin levels with CV and mortality outcomes using time-updated multivariable Cox regression models. The primary outcome was heart failure hospitalization (HFH) or CV death. Results Among 3872 participants (median age 67 years, 56% women, median estimated glomerular filtration rate 18 mL/min/1.73 m(2)), those with lower TSAT were more likely to be women, have diabetes, atrial fibrillation, and a history of CV disease. In fully adjusted models (including haemoglobin), compared to TSAT >30-<= 40%, time-updated TSAT <= 20% was associated with a two-fold higher risk of the primary outcome (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.62-2.80), with similar associations observed for HFH (HR 1.97, 95% CI 1.40-2.79) and for CV death (HR 2.19, 95% CI 1.45-3.29), as well as all-cause mortality (HR 1.60, 95% CI 1.25-2.03). Ferritin levels <= 100 ng/mL (vs >100 to <= 300 ng/mL) were not associated with a higher risk of any CV or mortality outcomes. Conclusions Iron deficiency defined by low TSAT, but not low ferritin levels, is associated with increased risk of heart failure and CV death in CKD, independent of haemoglobin.

INTRODUCTION:Finerenone reduced the risk of heart and kidney events in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in FIDELITY, a prespecified pooled analysis combining data from the phase III FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) trials. This FIDELITY analysis aimed to identify and assess key predictors of finerenone discontinuation and evaluate the impact of discontinuation on its efficacy in people with CKD and T2D. METHODS:Adults with CKD (urine albumin-to-creatinine ratio 30-≤5,000 mg/g, estimated glomerular filtration rate [eGFR] ≥25 mL/min/1.73 m2) and T2D on optimized renin-angiotensin system inhibition were randomized 1:1 to finerenone or placebo. Baseline characteristics were identified and assessed as predictors of treatment discontinuation using a multivariate Cox proportional hazards model. Stratified Cox models with treatment discontinuation as a time-varying covariate were used to assess the effect of treatment discontinuation on composite kidney and cardiovascular (CV) outcomes (kidney: kidney failure, sustained ≥57% eGFR decrease from baseline over at least 4 weeks, or kidney-related death; CV: CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). RESULTS:Among 12,990 participants included in the analysis, 22.8% and 21.6% prematurely discontinued treatment in the finerenone and placebo arms, respectively. Advanced age, White/Black race, lower eGFR, higher urine albumin-to-creatinine ratio, and higher serum potassium at baseline were identified as predictors of finerenone discontinuation. Crude event rates per 100 patient-years for the composite kidney and CV outcomes were lower with finerenone versus placebo under treatment (kidney: 1.09 vs. 1.71; CV: 2.98 vs. 3.78) as well as after discontinuation (kidney: 11.95 vs. 13.67; CV: 14.07 vs. 14.73). The effect of finerenone on composite kidney and CV outcomes appeared to be reduced after discontinuation (hazard ratio [HR] = 0.82; 95% confidence interval [CI] 0.66-1.02; HR = 0.93; 95% CI: 0.79-1.09, respectively) versus the time on-treatment (HR = 0.65; 95% CI: 0.54-0.78; pinteraction = 0.0959; HR = 0.79; 95% CI: 0.70-0.88; pinteraction = 0.0960, respectively). CONCLUSION:In FIDELITY, treatment discontinuation rates were similar in the finerenone and placebo arms. Finerenone demonstrated numerically higher kidney and CV benefits during treatment versus after discontinuation.

Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) have a high risk of cardiovascular (CV) and kidney complications, largely driven by inflammation, fibrosis, and albuminuria. Despite advancements in standard therapies, many patients remain at high risk, necessitating new treatments that target these underlying mechanisms. Finerenone exerts antiinflammatory and antifibrotic effects, demonstrating a more favorable hyperkalemia profile than steroidal mineralocorticoid receptor antagonists (MRAs). Studies have demonstrated that finerenone significantly reduces the urinary albumin-to-creatinine ratio (UACR), with many patients achieving a ≥ 30% reduction in UACR, which mediates the treatment effect on kidney and CV outcomes. The FIDELIO-DKD and FIGARO-DKD trials, supported by the FIDELITY pooled analysis, highlight finerenone's ability to improve kidney and CV outcomes across diverse populations with CKD and T2D. Current guidelines, including those from the American Diabetes Association and Kidney Disease: Improving Global Outcomes, endorse finerenone for patients with CKD and T2D who have albuminuria and an estimated glomerular filtration rate (eGFR) ≥ 25 ml/min per 1.73 m2. These recommendations emphasize its role in reducing the residual risk of CKD progression and CV complications. Finerenone represents an important advancement in the management of CKD and T2D, offering substantial benefits in UACR modulation and cardiorenal protection. By examining its clinical efficacy and safety profile, this review aims to provide a comprehensive understanding of how finerenone contributes to improved outcomes for patients with CKD and T2D, emphasizing its position as a pivotal component of contemporary treatment strategies.

While intention-to-treat analyses in randomized controlled trials provide unbiased comparisons of randomized treatment policies, many investigators also execute "On-Treatment" analyses that count events occurring while participants are still receiving randomized treatment. "On-Treatment" analyses, which are not supported by randomization, lead to non-comparable treatment groups and hence potential inferential errors. This article concerns another problem related to "On-Treatment" analysis when the study interventions have different dosing frequencies, for example, when one treatment is dosed daily and the other monthly. Failing to account properly for such differential dosing in the analysis can introduce serious additional bias. We discuss potential pitfalls associated with such analyses and provide a simple remedy to attenuate the problem introduced when comparing treatments with differential dosing frequency: to wit, extend the "On-Treatment" period by an amount equal to the dosing frequency. We illustrate the approach with the ASCEND trial program. The ASCEND Trials, which compared daprodustat to standard of care in patients with anemia of chronic kidney disease, administered the treatments under different dosing frequencies.

Background and hypothesis Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is approved for treatment of anemia in dialysis patients with CKD in some parts of the world. This subgroup analysis examined the efficacy and safety of daprodustat versus darbepoetin alfa in patients with anemia of CKD undergoing peritoneal dialysis (PD).Methods ASCEND-D (NCT02879305) was an open-label, Phase 3 trial; patients with CKD were randomized to daprodustat daily and epoetin alfa (HD patients) or darbepoetin alfa (PD patients). In PD patients, prespecified analyses of the co-primary endpoints of mean change in hemoglobin from baseline to Weeks 28-52 using an ANOVA model and first occurrence of a major cardiovascular event (MACE) using a Cox proportional hazards model were conducted. The secondary endpoints were average monthly intravenous iron dose to Week 52 and treatment-emergent adverse events. Additional post hoc analyses were conducted.Results Overall, 340 PD patients (daprodustat n = 171, darbepoetin alfa n = 169) were randomized. Mean age was 53.6 years (+/- 14 SD), 55% male, 56% White. For daprodustat and darbepoetin alfa groups respectively, mean change in hemoglobin was 0.38 and 0.23 g/dL [adjusted mean difference 0.15, 95% confidence interval (CI), -0.04, 0.34], and first occurrence of adjudicated MACE occurred in 40 (23.4%) and 46 (27.2%) patients (HR 0.84; 95% CI, 0.55-1.28). No heterogeneity was observed between PD and HD patients for these endpoints in ASCEND-D. Serum hepcidin was lower with daprodustat; there was no difference in other iron parameters, intravenous iron usage, transfusion requirement, blood pressure, or quality of life. There were no differences in adverse events or incidence of peritonitis between the groups.Conclusions This subgroup analysis of the ASCEND-D trial demonstrated comparable efficacy and safety of daprodustat versus darbepoetin alfa in PD patients, supporting its use in the treatment of anemia in these patients.

BACKGROUND Anemia is common in patients with chronic kidney disease and type 2 diabetes. Finerenone improved heart and kidney outcomes in patients with chronic kidney disease and type 2 diabetes in FIDELITY. OBJECTIVES This post hoc analysis investigated the efficacy and safety of finerenone vs placebo by baseline anemia status. METHODS Anemia was defined as serum hemoglobin levels <13 g/dL (male) or <12 g/dL (female) or treatment with an erythropoiesis-stimulating agent at baseline. Outcomes included cardiovascular (CV) and kidney composites, hospitalization for heart failure, and all-cause mortality. Safety was assessed through treatment-emergent adverse events. RESULTS Of 12,971 patients, 33% had anemia at baseline. Finerenone reduced the risk of the CV composite outcome to a greater extent in patients with vs without anemia (HR: 0.75 [95% CI: 0.65-0.88] vs HR: 0.93 [95% CI: 0.82-1.05]; P for interaction = 0.03). Finerenone reduced the risk of the kidney composite outcome vs placebo, with no heterogeneity between patients with vs without anemia (HR: 0.79 [95% CI: 0.65-0.95] and HR: 0.74 [95% CI: 0.60-0.91]; P for interaction = 0.77). The risk of hospitalization for heart failure and all-cause mortality was lower with finerenone vs placebo, irrespective of anemia status. Patients with anemia experienced higher incidence of treatment-emergent hyperkalemia vs those without. CONCLUSIONS Finerenone demonstrated CV and kidney benefit in patients with and without anemia. The benefit of finerenone on CV outcomes was greater in patients with vs without anemia at baseline. Anemia is likely a marker for higher-risk patients who are more susceptible to the benefits of finerenone. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease [FIGARO-DKD], NCT02545049) (JACC Adv. 2025;4:101524) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is a common clinical problem and is associated with major adverse cardiovascular events (MACE). Although several definitions have been proposed, data examining associations with MACE in clinical trials are limited. METHODS:ASCEND-D (NCT02879305), a large event-driven cardiovascular outcomes trial, randomized 2,964 patients receiving maintenance dialysis to either daprodustat or conventional ESAs. All patients received an ESA for at least 6 weeks before randomization and were managed with dosing algorithms for iron and randomized treatment. Three definitions of ESA hyporesponsiveness were prespecified: 1) HypoR1: an erythropoietin resistance index (ERI) ≥2U/kg/wk/g/L or prior ESA dose/estimated dry weight ≥450 U/kg/wk; 2) HypoR2: ERI ≥1.5U/kg/wk/g/L; 3) HypoR3: baseline ESA dose (U/week) in top 20th percentile. Adjusted Cox regression models were fit to examine the association of each definition with the adjudicated MACE composite (death, non-fatal myocardial infarction, non-fatal stroke). RESULTS:Baseline ESA hyporesponsiveness was present in 12%, 20%, and 20% of patients according to definitions HypoR1, HypoR2, and HypoR3, respectively. Compared to those without hyporesponsiveness, all definitions were associated with a higher risk of the composite MACE outcome: adjusted hazard ratio [HR] 1.32 (95%CI 1.04, 1.68) for HypoR1; HR 1.33; 95%CI 1.08, 1.63) for HypoR2; HR 1.36 (95%CI 1.12, 1.66) for HypoR3. There was no evidence for effect modification by randomized treatment (P-interaction >0.40 for all). CONCLUSIONS:Baseline ESA hyporesponsiveness is a potent predictor of MACE among patients receiving maintenance dialysis in ASCEND-D. All pre-specified definitions were similarly associated with a higher risk of MACE.

Chronic kidney disease (CKD) progression is associated with a significant incremental economic burden. Previous work has demonstrated high accuracy of the laboratory-based machine learning model, Klinrisk, in predicting the risk of CKD progression. We sought to use the Klinrisk model to evaluate the association of risk of CKD progression with healthcare resource utilization (HRU) and costs of care in adults with type 2 diabetes and CKD. This retrospective observational study included 413,177 eligible patients from Optum’s electronic health records database (1/1/2007–9/30/2022). Patients were classified into low-, medium-, and high-risk groups based on their 2-year risk of CKD progression as predicted by the Klinrisk model. All-cause HRU and medical costs during the 1 year after CKD were estimated for each group. Of the 413,177 patients included, 110,399 (26.7

The reproducibility of chemical reactions, when obtaining protocols from literature or databases, is highly challenging for academicians, industry professionals and even now for the machine learning process. To synthesize the organic molecule under the photochemical condition, several years for the reaction optimization, highly skilled manpower, long reaction time etc. are needed, resulting in non-affordability and slow down the research and development. Herein, we have introduced the DigiChemTree backed with the artificial intelligence to auto-optimize the photochemical reaction parameter and synthesizing the on demand library of the molecules in fast manner. Newly, auto-generated digital code was further tested for the late stage functionalization of the various active pharmaceutical ingredient. Light-induced reactions of diazo compounds have become crucial in organic synthesis and drug discovery, however, optimization of reaction conditions is still very time-consuming. Here, the authors develop a DigiChemTree platform using artificial intelligence to auto-optimize the photochemical reaction parameters and rapidly synthesize an on-demand library of molecules.

A novel nanotextured Ni@Cu material embedded electromicroflow reactor with minimal electrode distance has been employed to synthesize biphenyls via the construction of a new C-C bond. The reported protocol is devoid of noble metals and involves co-reductant/oxidant-free conditions in a fast manner for the synthesis of substituted/unsubstituted biphenyl systems. The electro-reactor volume was optimized for gram-scale biphenyl synthesis and further extended for an integrated total process system reducing the tedious downstream process by selective removal of unwanted chemicals/solvent. The continuous microflow synthesis of daclatasvir has now been accomplished with a good yield.

The experiment was conducted during 2017–18 and 2018–19 at instructional farm, College of Horticulture, Banda University of Agriculture and Technology, Banda, Uttar Pradesh, to study the genetic variation, correlation and path analysis in gladiolus (Gladiolus hybridus Hort.) in Bundelkhand region of Uttar Pradesh. 14 varieties of gladiolus, viz. Black Star, Peter Pears, Gold Star, Trader Horn, Pink Rose, White Prosperity, Red White, Novalux, Yellow Gold, Candyman, Willas Pink, Jester, Nathan Red and Punjab Morning were planted in randomized block design (RBD). All parameters showed significant differences indicating that genotypes have a lot of variation. Length of the spike varied from 65.07 to 110.65 cm and size of the floret from 8.27 to 9.66 cm. Mean values for time to flowering, size of floret and vase life were 109.38 days, 8.95 cm and 8.95 days, respectively. Length of rachis (19.97 and 15.90), spike (18.49 and 14.40) and florets/spike (14.88 and 12.05) showed moderate values for PCV and GCV. Maximum heritability value was oberved in days to flowering (68.22) and minimal in floret size (35.63). Positive and significant correlations were found between plant height, length of spike and rachis, florets/spike and days to flowering. Path coefficient study revealed that length of spike (1.162), days to spike initiation (0.881) and blooming time (0.392) had biggest positive direct effects on plant height.