Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. How systemic and tumor microenvironment hormone signaling intersects with chronic inflammation and how this shapes aging-associated tumor biology remain incompletely understood. Here, using an aged rat model of ER+ tumors, we identify age-associated differences in tumor development and immune features. In parallel, analysis of samples from patients with ER+/HER2- breast cancer and age-matched controls demonstrated estrone-predominant systemic estrogen patterns and increased tumor HSD17B7 expression in older patients, consistent with enhanced local estrone-to-estradiol conversion. In patient-derived organoids from older women, pharmacologic inhibition of HSD17B7 reduced estrogen conversion and proliferation-associated transcriptional programs. Tumors from older patients also exhibited chemokine enrichment, including CCL2, associated with immunosuppressive macrophage features. Targeting both estrogen signaling and chemokine pathways attenuated macrophage polarization ex vivo. These findings support a model linking age-associated hormonal and inflammatory changes to features of a tumor-permissive microenvironment in ER+ breast cancer.

ObjectiveThe aim of this study was to use bupropion as a cytochrome P450 (CYP) 2B6 probe to determine CYP2B6 function by using a population pharmacokinetic approach of parent bupropion and metabolite hydroxybupropion to explore the impacts of chronic kidney disease (CKD) and vitamin D status in patients and control subjects.MethodsPlasma concentration data from 19 subjects after administration of 150 mg of sustained-release bupropion were used in pharmacokinetic modeling. Blood samples were collected pre-dose and serially post-dose and analyzed by LC-MS/MS. Population pharmacokinetic analysis was conducted using nonlinear mixed-effect modeling (Phoenix NLME v8.6.1.6, Certara Inc.). A separate post hoc analysis evaluated the formation clearance of hydroxybupropion as an assessment of CYP 2B6 functional activity.ResultsThe final model was composed of 2 compartments with first-order formation and elimination for bupropion and hydroxybupropion. A multiplicative error model explained residual variability. Covariates tested in the model, including vitamin D baseline concentrations and CKD, did not have a significant impact on the pharmacokinetics of bupropion and hydroxybupropion. Model validation was performed using visual predictive check. A trend toward increased formation clearance was observed within the CKD group (2.21 L/h vs. 2.65 L/h, p = 0.39) and a slight reduction in the control group (2.96 L/h vs. 2.66 L/h, p = 0.85) with vitamin D repletion vs. insufficiency.ConclusionThe study contributes to the understanding of CYP 2B6 function in CKD and exhibited increased CYP2B6 function in CKD subjects with vitamin D repletion.

OBJECTIVE: CytoSorb (CS) hemoadsorption is increasingly used in critical care and cardiac surgery to remove inflammatory mediators and select drugs. This systematic review aimed to summarize available evidence on intentional drug removal as well as unintentional drug removal during CS therapy. DATA SOURCES: PubMed, congress abstracts, and CytoSorbents online literature database. STUDY SELECTION: Eligible studies included benchtop, animal, and human pharmacokinetic investigations of drug removal during CS therapy as well as clinical reports describing CS use for drug overdose. DATA EXTRACTION: Data from the eligible studies were extracted independently by two authors into Microsoft Excel. DATA SYNTHESIS: Data were identified for drugs across multiple therapeutic classes, including analgesics, antiarrhythmics, anticonvulsants, antidepressants, antihypertensives, anti-infectives, antithrombotics, anxiolytics, and immunosuppressants. Drugs were categorized into low (< 30%), moderate (30–60%), or high (> 60%) removal rate, or by the relative increase in clearance attributable to CS: negligible (< 25%), low (25–100%), moderate (100–400%), or high (> 400%). Based on the assembled data and considering drug-, patient-, and circuit-specific factors, general dosing recommendations for concomitant medications were developed. CONCLUSIONS: CS therapy can alter drug concentrations for select agents with variable clinical relevance. CS can reduce perioperative bleeding risk through antithrombotic removal and treat certain drug overdoses. Unintentional drug removal during CS therapy may occur and practical guidance is provided for drugs with known susceptibility to removal.

INTRODUCTION:Patients with chronic kidney disease (CKD) are at risk of medication therapy problems (MTPs) due to high comorbidity and medication burden. Using data from the Kidney Coordinated HeAlth Management Partnership (Kidney CHAMP) trial, we used machine learning to build a predictive model to identify MTP high-risk patients with CKD in the primary care setting. METHODS:We used baseline data from patients enrolled in the intervention arm of the Kidney CHAMP trial, completed May 2019-July 2022, which tested a population health management strategy, including medication management, for improving CKD care. The dataset was divided into 80% training and 20% testing subsets. The area under the ROC curve (AUROC) was used to assess classification accuracy in distinguishing between patients with and without MTP. Eight candidate models were considered, and the top three performing models (random forest, support vector machines, and gradient boosting), based on cross-validated AUROC on training data, underwent further refinement. The model with the highest AUROC in the testing set, while considering the bias/variance trade-off, was selected as the best-performing model. SHapley Additive exPlanations was then leveraged using the best-performing model to evaluate the impact of each predictor to the final risk score. RESULTS:Among 730 patients who received medication review at baseline, 566 (77.5%) had at least 1 MTP. Key demographics were mean age 74 years, 55% female, 92% white, 64% with diabetes, and the mean number of medications 5.8 at baseline. The random forest model had the best performance on the testing set with AUROC 0.72, sensitivity 0.80, and specificity 0.64. The five most influential variables, ranked in descending order of importance for predicting individuals with MTP, were diabetes status (yes/no), hemoglobin A1C (HbA1C), urine albumin-to-creatinine ratio (UACR), systolic blood pressure, and age. CONCLUSION:In outpatient primary care, a machine learning-based MTP risk calculator that uses routinely available clinical data can identify patients with moderate-high-risk CKD who are at high risk for developing MTPs.

CHEK1 (CHK1) is a key regulator of the G2/M checkpoint and DNA damage response. Although CHK1 inhibitors (CHK1is) show promise in multiple clinical trials, their further advancement is hampered by the lack of reliable predictive biomarkers. Our previous study demonstrated a nearly 20-fold difference in the sensitivity to a clinical-stage CHK1i SRA737 in prostate cancer (PC) cells. Through bioinformatics analysis, an epigenetic regulator, lysine demethylase 5D (KDM5D), was identified as a potential mediator of differential responses to SRA737. Gain- or loss-of-function studies were performed to investigate how altered KDM5D expression affects CHK1i sensitivity and the underlying mechanisms. Our data demonstrated that higher KDM5D expressions correlated with greater sensitivity to CHK1is in PC cells. In castration-resistant PC patients, a high KDM5D score predicted a better patient response to CHK1i. Knockdown of KDM5D in SRA737-sensitive KDM5D-expressing cells causes resistance to SRA737. Correspondingly, a higher sensitivity to SRA737 was observed in a docetaxel-resistant CRPC cell line with elevated KDM5D, and silencing KDM5D caused resistance to this inhibitor. Mechanistically, depletion of KDM5D activated p38 and induced COX-2 and ABC transporter expression. Inhibition of p38 or COX-2 partially reversed the resistance to CHK1i induced by KMD5D knockdown. Additionally, silencing of p38 increased KDM5D protein expression, indicating a negative feedback loop that may serve to maintain a homeostatic balance between the two genes. These data support a key role for KDM5D in modulating CHK1i sensitivity through a novel p38/COX-2 pro-survival pathway in PC cells, with potential predictive value for CRPC patients receiving these anticancer agents.

Purpose:Topical eye drops combining multiple antiglaucoma agents are often required when monotherapy fails to reduce intraocular pressure (IOP). However, their effectiveness is compromised by low bioavailability and poor patient compliance. To address these issues, we developed a novel gel/microsphere eye drop (GME) containing brimonidine and timolol, aimed at enhancing ocular bioavailability, reducing dosing frequency, and improving patient compliance. Methods:The GME system comprises separate formulations of brimonidine-loaded and timolol-loaded polymer microspheres within a thermoresponsive hydrogel, enabling simple off-the-shelf preparation. We examined the in vitro drug release, compared the biodistribution with traditional eye drops, and assessed pharmacodynamic effects in New Zealand white rabbits and Dutch Belted rabbits. Results:Brimonidine and timolol reached high concentrations in the aqueous and vitreous humor at 1 hour following eye drop administration, declining to nearly undetectable levels by 24 hours. The GME system at a similar dose extended the drug release to 27 days with initially lower drug levels but decreasing more slowly. The GME system also resulted in significantly lower plasma drug concentrations than eye drops, suggesting a reduced risk of systemic side effects. Neither the GME nor eye drops significantly reduced IOP in normotensive rabbits. Conclusions:The GME system presents a promising alternative to traditional eye drops for controlled drug release in ocular applications, enabling sustained drug delivery while minimizing systemic exposure and thereby potentially enhancing the safety and efficacy of ocular therapies. Translational Relevance:The GME system bridges basic research and clinical application by providing a controlled-release platform that sustains drug delivery, reduces systemic side effects, and enhances patient adherence.

Rationale & Objective:Medication therapy problems (MTPs) are therapeutic issues related to medications that may cause undesirable events. People with chronic kidney disease (CKD) are at high risk of experiencing MTPs owing to comorbid conditions and medication burden. This study characterizes MTPs in individuals enrolled in the Kidney Coordinated Health Management Partnership trial and evaluates the intervention's effect on MTPs. Study Design:Post hoc analysis of a pragmatic, cluster-randomized trial. Setting & Participants:Individuals aged 18-85 years with an estimated glomerular filtration rate of <60 mL/min/1.73 m2, moderate to high risk of CKD progression, and not seeing a nephrologist enrolled from 101 primary care practices (May 2019 to November 2021). Interventions:Electronic health record-based multidisciplinary care including nephrology e-consult, pharmacist medication review, and patient education at baseline and every 6 months. Outcomes:MTP type and frequency of occurrence were characterized along with associated medication classes. Descriptive statistics of MTPs were conducted, and cumulative probabilities of resolution over time were estimated using the discrete-time survival method. Results:Baseline medication reviews were completed by telephone (52%) or chart review (48%) in 730 out of 754 (97%) intervention-arm participants (mean age, 74 ± 9 years and estimated glomerular filtration rate, 37 ± 8 mL/min/1.73 m2). Polypharmacy was evident in 63% of participants. At baseline, 78% had MTPs and 79% had medication discrepancies. The most common MTP was indication without drug therapy, associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The average number of MTPs per participant decreased from 2.01 at baseline to 1.28 at 6 months (36% reduction), and 1.15 at 12 months (43% reduction). Based on the discrete-time survival model, an estimated 92% of MTPs were resolved by 12 months. Limitations:Medication management was not completed for control-arm participants. No standardized tool was used to assess medication adherence. We relied on electronic health record chart review to identify MTPs in participants who could not be reached by telephone. Conclusions:MTPs and medication discrepancies are highly prevalent in nondialysis-dependent CKD. Medication management through multidisciplinary team care can optimize medication therapy in CKD.

As antiretroviral therapy (ART) prolongs lifespans, people with HIV (PWH) face a new syndemic: Cardiovascular‐Kidney‐Metabolic (CKM) syndrome. Yet CKM in PWH is poorly characterized. Inflammation, complex pharmacokinetic (PK) alterations, ART‐associated metabolic effects, and gut dysbiosis amplify risk. Managing CKM increases medication burden, thereby heightening the risk of drug–drug interactions and adverse drug effects. Therefore, CKM in PWH represents an emerging clinical pharmacology priority. We outline gaps and challenges and call for CKM research in PWH.

Key PointsA population health management intervention for CKD reduced inpatient hospitalizations by 27% compared with usual care over a 1-year follow-up.Despite lower hospitalizations, total healthcare costs were not significantly different between population health management and usual care.BackgroundCKD represents a substantial economic burden, particularly in the Medicare population in the latter stages of disease progression. There are potential opportunities to provide quality care through population health management (PHM) interventions in the hopes of improving downstream outcomes and costs. In Kidney Coordinated HeAlth Management Partnership, a pragmatic, cluster randomized trial, patients received a PHM, multidisciplinary team approach to improve CKD care or usual care. The primary objective of this study was to conduct a post hoc comparative analysis of the 1-year healthcare utilization between patients who received the PHM intervention compared to usual care with a secondary objective of comparing standardized costs.MethodsA subset of Kidney Coordinated HeAlth Management Partnership patients who had available health insurance claims with enrollment for the full 12 months in the year after trial enrollment were included. Inpatient, outpatient, and pharmacy standardized costs were estimated using diagnosis-related groups, current procedural terminology, and National Drug Codes, respectively. Resource utilization was analyzed using negative binomial models, and costs were analyzed using two-part models. All analyses were adjusted for demographic and clinical characteristics. Subgroups were analyzed by age, sex, CKD stage, and diabetes status.ResultsOf the 1596 trial participants, 614 patients met inclusion criteria (PHM: 300; usual care: 314). Patients in the PHM arm had 27% fewer inpatient hospitalizations than usual care (incident rate ratio=0.73; 95% confidence interval, 0.54 to 0.99), but outpatient visits did not differ significantly. Total standardized costs were similar between the PHM and usual care treatment arms across inpatient, outpatient, and pharmacy categories.ConclusionsThe PHM intervention reduced inpatient hospitalizations but did not significantly affect healthcare costs over 1 year. The reliance on standardized costs and the short follow-up may have obscured potential differences. Longer term data would help provide insight into the economic and resource utilization effect of the PHM intervention.

Introduction: Chronic kidney disease (CKD) represents a substantial economic burden, particularly in the Medicare population in the latter stages of disease progression. There are potential opportunities to provide quality care through population health management (PHM) interventions in the hopes of improving downstream outcomes and costs. In Kidney Coordinated HeAlth Management Partnership (CHAMP), a pragmatic, cluster randomized trial, patients received a PHM, multidisciplinary team approach to improve CKD care or usual care. The primary objective of this study was to conduct a post-hoc comparative analysis of the one-year healthcare utilization between patients who received the PHM intervention compared to usual care with a secondary objective of comparing standardized costs. Methods: A subset of Kidney CHAMP patients who had available health insurance claims with enrollment for the full 12 months in the year following trial enrollment were included. Inpatient, outpatient, and pharmacy standardized costs were estimated using diagnosis-related groups, current procedural terminology, and National Drug Codes, respectively. Resource utilization was analyzed using negative binomial models and costs were analyzed using two-part models. All analyses were adjusted for demographic and clinical characteristics. Subgroups were analyzed by age, sex, CKD stage, and diabetes status. Results: Of the 1,596 trial participants, 614 patients met inclusion criteria (PHM: 300; usual care: 314). Patients in the PHM arm had 27% fewer inpatient hospitalizations than usual care (incident rate ratio=0.73; 95% CI: 0.54-0.99), but outpatient visits did not differ significantly. Total standardized costs were similar between the PHM and usual care treatment arms across inpatient, outpatient, and pharmacy categories. Conclusion: The PHM intervention reduced inpatient hospitalizations but did not significantly impact healthcare costs over one year. The reliance on standardized costs and the short follow-up may have obscured potential differences. Longer term data would help provide insight into the economic and resource utilization impact of the PHM intervention.

Purpose: The goals of this paper are to (1) provide evidence and expert consensus to support a unified approach to estimating kidney filtration in adults with stable kidney function using race-free estimated glomerular filtration rate (eGFR) in place of Cockcroft-Gault estimated creatinine clearance (C-G eCrCL) for medical and medication-related decisions, and (2) demonstrate how adjusting eGFR results for an individual's body surface area (BSA) when it is higher or lower than 1.73 m(2) will improve results for medication-related decisions. Summary: C-G eCrCL is predominantly used by US pharmacists to determine eGFR for the purposes of medication-related decisions, even though more accurate eGFR equations exist. Several driving factors make it the ideal time to shift clinical practice from using C-G eCrCL to eGFR. These factors include the following: (1) 2024 Food and Drug Administration (FDA) guidance for industry recommends eGFR over C-G eCrCL to evaluate the impact on pharmacokinetics in patients with impaired kidney function; (2) a joint National Kidney Foundation (NKF) and American Society of Nephrology task force recommends 3 race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equations for medical and medication-related decision-making; (3) the almost ubiquitous use of standardized serum creatinine assay methods in US clinical laboratories; and (4) increasing availability and use of serum cystatin C for eGFR assessment. This publication guides practitioners through the rationale for using race-free eGFR equations for medication-related decisions and how to implement this practice change. Conclusion: The NKF Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions suggests that health systems, health settings, clinical laboratories, electronic health record systems, compendia and data vendors, and healthcare practitioners involved with medication-related decision-making transition away from C-G eCrCL and towards the race-free eGFR equations for more accurate assessment of kidney filtration and consistency in medication and medical decision-making across the US.

This study investigates the effects of traumatic brain injury (TBI) on the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), and their influence on neuroinflammation and systemic inflammation. We hypothesized that disruptions in the blood-brain barrier (BBB) due to TBI would enhance M3G exposure to the brain, which could potentially trigger inflammatory responses. We implemented a rat model of controlled cortical impact (CCI) injury to assess systemic pharmacokinetics of morphine and M3G over 24 hours postintravenous bolus administration. To gain an understanding of relative levels in the brain, we measured the drug and metabolite concentrations in both brain tissue and plasma at the systemic maximum concentration, which occurred at 1 hour post-CCI. While this study was designed to conduct a thorough acute pharmacokinetic analysis, the design also afforded an early examination of potential pharmacodynamic effects. Markers of neuroinflammation and systemic inflammation were measured in plasma and cerebrospinal fluid at 24 hours post-CCI. Results showed a 2-fold increase in systemic M3G exposure and doubled concentrations of both morphine and M3G in the brain. Notably, only M3G demonstrated a significant increase in the brain/plasma ratio at 1 hour. Despite these pharmacokinetic changes following a single bolus, there were limited morphine-induced or M3G-induced increases in markers of neuroinflammation or systemic inflammation at 24 hour post-CCI. This study highlights that TBI significantly alters the pharmacokinetics of morphine and M3G, increasing their brain penetration without worsening acute inflammation. Future research will need to explore the implications of extended and repeated dosing on these pharmacokinetic and inflammatory outcomes after TBI. SIGNIFICANCE STATEMENT: To our knowledge, this is the first pharmacokinetic analysis of morphine and its metabolite morphine-3-glucuronide (M3G) following traumatic brain injury (TBI). This research provides the first evidence that morphine and M3G show increased systemic and brain concentrations following experimental TBI, with an acute rise in M3G's brain/plasma ratio. Although no exacerbation of acute TBI-induced inflammation was observed with either morphine or M3G, the impact of longer, more frequent dosing needs evaluation because its longer administration could exacerbate TBI's neuroinflammatory response.

CHEK1 (CHK1) is a key regulator of the G2/M checkpoint and DNA damage response. Although CHK1 inhibitors (CHK1is) show promise in multiple clinical trials, their further advancement is hampered by the lack of reliable predictive biomarkers. Our previous study demonstrated a nearly 20-fold difference in the sensitivity to a clinical-stage CHK1i SRA737 in prostate cancer (PC) cells. Through bioinformatics analysis, an epigenetic regulator, lysine demethylase 5D (KDM5D), was identified as a potential mediator of differential responses to SRA737. Gain- or loss-of-function studies were performed to investigate how altered KDM5D expression affects CHK1i sensitivity and the underlying mechanisms. Our data demonstrated that higher KDM5D expressions correlated with greater sensitivity to CHK1is in PC cells. In patients with castration-resistant PC (CRPC), a high KDM5D score predicted a better patient response to CHK1i. Knockdown of KDM5D in SRA737-sensitive KDM5D-expressing cells caused resistance to SRA737. Correspondingly, a higher sensitivity to SRA737 was observed in a docetaxel-resistant CRPC cell line with elevated KDM5D, and silencing KDM5D caused resistance to this inhibitor. Mechanistically, depletion of KDM5D activated p38 and induced cyclooxygenase-2 (COX-2) and ATP-binding cassette transporter expression. Inhibition of p38 or COX-2 partially reversed the resistance to CHK1i induced by KDM5D knockdown. Additionally, silencing of p38 increased KDM5D protein expression, indicating a negative feedback loop that may serve to maintain a homeostatic balance between the 2 genes. These data support a key role for KDM5D in modulating CHK1i sensitivity through a novel p38/COX-2 prosurvival pathway in PC cells, with potential predictive value for patients with CRPC receiving these anticancer agents. SIGNIFICANCE STATEMENT: This study demonstrated an important role of an epigenetic regulator KDM5D in regulating CHK1 inhibitor sensitivity via a p38/COX-2-mediated prosurvival pathway in certain castration- or drug-resistant PC cells. Our results indicate that PC cells expressing KDM5D may be more sensitive to targeted inhibition of CHK1 kinase, highlighting the potential predictive value of this gene for CHK1-targeted therapies in PC.

The persistence of human immunodeficiency virus (HIV) reservoirs in the lymphatic system remains a major obstacle to a complete cure, largely due to subtherapeutic concentrations of antiretrovirals (ARVs) in lymphatic tissues under current regimens. Developing innovative strategies to enhance ARV delivery to lymphatic tissues could therefore represent a paradigm shift in the pursuit of an HIV cure. Here, we describe a delivery strategy involving an Evans Blue (EB)-based prodrug conjugated with dolutegravir (DTG), a model ARV. This construct is designed to bind albumin with high affinity, facilitating transport to lymph nodes (LNs) via albumin-mediated trans-endothelial transcytosis. EB modification substantially improved the distribution of the conjugated molecule to LNs throughout the body, and the hEB-DTG prodrug increased DTG concentrations in LNs by up to 10-fold, suggesting a promising strategy for eradicating HIV reservoirs. STATEMENT OF SIGNIFICANCE: A major barrier to curing HIV infection is the persistence of viral reservoirs in lymphatic tissues, which current ARV therapies fail to eliminate due to poor drug penetration. To overcome this limitation, we developed a prodrug strategy that harnesses the natural trafficking of albumin to the lymphatic system. In this approach, ARVs are conjugated to EB, a high-affinity albumin-binding dye, to generate EB-ARV prodrugs that hijack albumin's endogenous transport pathways. After intravenous administration, these conjugates rapidly associate with circulating albumin, which mediates their transcytosis across endothelial barriers and directs their accumulation in lymph nodes and other lymphoid tissues. This strategy substantially enhances ARV exposure at the primary sites of viral persistence, representing a promising and potentially transformative approach for eradicating HIV reservoirs and advancing toward a functional cure.

Metabolic reduction is an adaptation employed by animals encountering environmental stressors or scarce resources. Lowering metabolism in humans may be useful to reduce consumables, oxygen utilization and carbon dioxide excretion. This is relevant for payload optimization or resource-restricted scenarios such as long-duration spaceflight or austere terrestrial environments (e.g., Arctic/Antarctic, submarine, cave or mine extraction). We previously demonstrated intravenous and single oral or sublingual doses of dexmedetomidine reduce oxygen consumption, wakefulness, and core body temperature in healthy humans. However, longer-acting dosing strategies are required to achieve greater levels of metabolic reduction. We explored whether a sublingual loading dose followed by subcutaneous infusion (SQI) of dexmedetomidine with and without surface cooling can decrease metabolic rate for 6 hours. We recruited 11 healthy volunteers, 4 male, median age 23 (IQR 21-25), who completed one-day laboratory studies measuring core body temperature via telemetry and metabolic rate via indirect calorimetry. Participants consumed an oral loading bolus of dexmedetomidine (2 μg/kg) followed by a six-hour SQI of dexmedetomidine (1 μg/kg/hr). Surface cooling pads were placed on the backs of 7 participants to promote heat loss. We collected vital signs continuously and monitored participants until they could be safely discharged. Energy expenditure (EE; kcals per day) dropped from baseline regardless of surface cooling. With surface cooling, median temperature decreased from 36.9°C (IQR 36.7-37.0°C) at baseline to 35.4°C (IQR 35.3-35.5°C) at 6 hours. Sublingual loading dose followed by 6-hour SQI of dexmedetomidine safely and effectively reduces metabolic rate. Future studies should be evaluating the effectiveness of SQI dexmedetomidine without a sublingual loading bolus, evaluating novel administration methods, and determining if tolerance develops with long-term use.

Background Gaps in guideline-concordant care for CKD lead to poor outcomes. The Kidney Coordinated HeAlth Management Partnership (K-CHAMP) cluster randomized trial tested the effect of a population health management intervention versus usual care on CKD progression and evidence-based care delivery in the primary care setting. Methods K-CHAMP included adults aged 18-85 years with eGFR<60 ml/min per 1.73 m(2) and moderate-high risk of CKD progression who were not seeing a nephrologist. The multifaceted intervention included nephrology e-consult, pharmacist-led medication management, and patient education. In this post hoc analysis, we evaluate the effectiveness of K-CHAMP on guideline-concordant care processes (BP and glycemic control, annual albuminuria testing) and medication exposure days (angiotensin-converting enzyme inhibitor [ACEi]/angiotensin receptor blocker [ARB], moderate-high intensity statin, sodium-glucose cotransporter-2 inhibitor [SGLT2i], glucagon-like peptide-1 receptor agonists [GLP-1RA]). Given multiplicity of outcomes, Benjamini-Hochberg method was used to control false discovery rate. Results All 1596 (754 intervention, 842 usual care) enrolled patients (mean age 74 +/- 9 years, eGFR 37 +/- 8 ml/min per 1.73 m2, 928 [58%] female, 127 [8%] Black) were analyzed. After a median 17-month follow-up, intervention arm patients had significantly higher exposure days per year to SGLT2i (56 versus 32 days; relative benefit 1.72; 95% confidence interval [CI], 1.14 to 2.30) and GLP-1RA (78 versus 29 days; relative benefit 2.65; 95% CI, 1.59 to 3.71) compared with usual care in adjusted analysis. At study initiation in 2019, similar proportion of patients were prescribed SGLT2i and/or GLP-1RA in intervention and control arm (8% versus 6%, respectively; rate ratio 1.23; 95% CI, 0 to 2.99), but by 2022, prescription of these medications was significantly higher in intervention arm (44% versus 27%, respectively; rate ratio 1.63; 95% CI, 1.32 to 1.94). There was no significant difference in any process measures or exposure days to ACEi/ARB in patients with albuminuria or moderate-high intensity statin. Conclusions K-CHAMP was effective in accelerating implementation of SGLT2i and GLP-1RA but did not increase ACEi/ARB in patients with albuminuria or moderate-high intensity statin use or improve BP control, glycemic control, or albuminuria testing in individuals with CKD in the primary care setting.